(Dermatology) Javier Avalos - Howard I Maibach-Dermatologic Botany-CRC Press (2000)

Library of Congress Cataloging-in-Publication Data
Dermatologic botany / edited by Javier Avalos and Howard I. Maibach

p. ; cm. -- (CRC series in dermatology)
Includes bibliographical references and index.
ISBN 0-8493-7361-1 (alk. paper)
1. Contact dermatitis. 2. Poisonous plants. 3. Dermatitis. I. Avalos, Javier. II. Maibach,
Howard I. III. Series.
[DNLM: 1. Dermatitis--etiology. 2. Plants--adverse effects. 3. Plants, Toxic--adverse
effects. WR 160 D435 1999]
RL244 .D476 1999
616.5′1--dc21
99-046442
CIP
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Series Preface
Our goal in creating the Dermatology: Clinical & Basic Science series is to present the insights of
experts on emerging applied and experimental techniques and theoretical concepts that are, or will
be, at the vanguard of dermatology. Books will cover new and exciting multidisciplinary areas of
cutaneous research. We want these to be the books every physician will use in order to get acquainted
with new methodologies in skin research. These books can be given to graduate students and
postdoctoral fellows when they are looking for guidance to start a new line of research.
The series will consist of books that will be edited by an expert and will consist of chapters
written by the leaders in a particular field. Books will be richly illustrated and contain comprehensive
bibliographies. Each chapter will provide substantial background material relevant to the particular
subject. These books will contain detailed “tricks of the trade” and information as to where the
methods presented can be safely applied. In addition, information on where to buy equipment and
web sites that will be helpful in solving both practical and theoretical problems will be included.
We are working with these goals in mind and hope that as the books become available, the
effort put in by the publisher, the book editors, and individual authors will contribute to the further
development of dermatology research and clinical practice. The extent to which we achieve this
goal will be determined by the utility of these books.
Howard I. Maibach, M.D.

Series Editor

Preface
Plants and plant products are widespread in offices and homes and are part of many cosmetics,
toiletries, and medications. They are an integral part of our lives that provide us with such essential
items as oxygen, food, and vitamins. However, plants have evolved elaborate defensive mechanisms
to combat and compete with other plants and predators including man. These defensive mechanisms
range from physical barriers or processes to a diverse and abundant array of secondary chemical
compounds. The combination of the secondary chemical compounds and specialized anatomical
appendages (i.e. thorns and trichomes), with the widespread exposure to plants, is responsible for
the many dermatologic conditions reported in clinics, hospitals, and literature reports.
In order to address the many topics and issues associated with dermal reactions caused by
plants, Dermatologic Botany will be delivered in a series of volumes. The series will provide
practical and vital information for every health practitioner. The intent of the series is to describe
the etiology of adverse reactions to plants and delineate methodologies employed in diagnosis of
plant dermatitis. Dermatologists, general practitioners, physicians, nurses, and pharmacists will
also find of value the analysis on mechanical injury and phytophotodermatoses. Additionally, health
professionals will enjoy and appreciate the chapters describing clinical and botanical investigations.
These topics include phytochemical procedures, patch testing methodologies, practical aspects of
patch testing, and difficulties in investigating dermatitis from plants.
The rest of the series will focus on plant families responsible for dermatologic reactions and
occupational exposures. Health professionals as well as botanists, toxicologists, and chemists will
enjoy the comprehensive reviews for each plant family. General descriptions will include the
location, number of genera, and characteristics of each plant family. Additionally, the most current
dermatologic information will be included for all known species of the genera. Furthermore, each
chapter will attempt to identify the causative agents for the dermatologic condition.
The collaboration of a large number of distinguished authors was needed to ensure that the
series is extensive and complete. The authors were selected for their depth of knowledge and
reputation in their subject areas. The contents of the series will be updated regularly in order to
incorporate emerging methodologies and data identifying new causative agents or plants into the
series. It is hoped that the series will be a useful reference for medical, phytochemical, and botanical
audiences interested in phytodermatotoxicology.
Javier Avalos
Howard I. Maibach

The Editors
Javier Avalos, Ph.D., is a Research Leader in Toxicology in the Product Development Group at
the Andrew Jergens Company. Prior to joining the Andrew Jergens Company, he was a regulatory
toxicologist with the Division of Dermatologic and Dental Drug Products, Food and Drug Admin-
istration (FDA). Dr. Avalos received his B.S. in biochemistry and Spanish from the University of
California at Davis in 1987 and his Ph.D. in environmental toxicology from the University of
California at Irvine in 1993. He did post-doctoral research in dermatotoxicology with Dr. Howard
Maibach at the University of California at San Francisco.
Dr. Avalos’ scientific career has been focused on the unwarranted effects of chemical agents
on the human skin. He has been actively involved in the isolation and identification of naturally
occurring dermatotoxins. As a regulatory toxicologist, he was charged with interpreting and assess-
ing the safety of various classes of drug products based on toxicology, pharmacology, and phar-
macokinetic data. More recently, he has been involved in evaluating the safety of ingredients to be
used in the development of new consumer products. Dr. Avalos is a member of the Society of
Toxicology, the American Society for Photobiology, and the American College of Toxicology.
Howard I. Maibach, M.D., is Professor of Dermatology, School of Medicine, University of

California, San Francisco. Dr. Maibach graduated from Tulane University, New Orleans, LA (A.B.
and M.D.), and received his research and clinical training at the University of Pennsylvania,
Philadelphia. He received an honorary doctorate from the University of Paris Sud in 1988.
He has long had a laboratory and clinical interest in the effects of chemicals — including
moisturizers — on normal and abnormal skin.
Mr. Maibach is a member of the International Contact Dermatitis Research Group, the North
American Contact Dermatitis Group, and the European Environmental Contact Dermatitis Group.
He is the author, co-author, and/or editor of 1600 publications and 60 volumes.

Contributors
Klaus E. Andersen, M.D. Lars P. Christensen, Ph.D.
Odense University Hospital Danish Institute of Agriculture and Sciences
Odense, Denmark Department of Fruit, Vegetable, and Food
Science
Manuel Aregullin, Ph.D. Arslev, Denmark
Cornell University
Ithaca, New York Ai-Lean Chew, M.D.
Department of Dermatology
Javier Avalos, Ph.D. University of California
Andrew Jergens Company San Francisco, California
Cincinnati, Ohio
Geoffrey Cordell, Ph.D.
Harold Baer, Ph.D. Department of Medicinal Chemistry and
Food and Drug Administration (retired) Pharmacognosy
Bethesda, MD College of Pharmacy
Chicago, Illinois
John Beaman, M.D.
Felix Cordoba Alva, Ph.D.
Botanical Taxonomist
Universidad de Mexico
Michigan State University
Instituto Tecnologico de Oaxaca
East Lansing, MI
Oaxaca, Mexico
J. Del Valle Cantu, M.D.

Oluwatoyin A. Binutu, Ph.D. Centro de Investigacion Biomedica del Noreste,
Department of Pharmacognosy IMSS
College of Medicine Monterrey, Nuevo Leon, Mexico
University of Ibadan, Nigeria
George Ducombs, M.D.
Heimo Breiteneder, Ph.D. Bordeaux, France
Department of General and Experimental
Pathology Jere D. Guin, M.D.
University of Vienna Professor Emeritus of Dermatology
Vienna, Austria University of Arkansas for Medical Sciences
Little Rock, Arkansas
C. Calzado Flores, Ph.D.
Centro de Investigacion Biomedica del Noreste, Matti Hannuksela, M.D., Ph.D.
IMSS South Karelia Central Hospital
Monterrey, Nuevo Leon, Mexico Lappeenranta, Finland
Jose G. Camarasa, M.D., Ph.D. Bjoern M. Hausen, M.D.

Dermatology Department Dermatology Center
Hospital del Mar General Hospital
Barcelona, Spain Buxtehude, Germany

Michael Heinrich, Ph.D. Eduardo Perez Campos, M.D.
Institute of Pharmaceutical Biology Oaxaca, Mexico
Albert Ludwig University
Freiburg, Germany Dr. Luisa Pistelli, Ph.D.
Dipartimento di Chimico Bioorganica
Kell Kristiansen, Ph.D. Universita di Pisa
Department of Ornamentals Pisa, Italy
Danish Institute of Plant and Soil Sciences
Arslev, Denmark Marius Rademaker, D.M., M.R.C.P.
Waikato Hospital
Jean-Pierre Lepoittevin, Ph.D. Department of Dermatology
Laboratoire de Dermatochimie Hamilton, New Zealand
Universite Louis Pasteur
Strasbourg, France Mario Robles, Ph.D.
Learning and Academic Resource Center
Chris Lovell, M.D. Division of Undergraduate Education
Dermatology Department University of California
Royal United Hospital Irvine, California
Bath, England
Eloy Rodriguez, Ph.D.
Howard I. Maibach, M.D.
L.H. Baily Hortorium
Department of Dermatology
Cornell University
University of California
Ithaca, New York
San Francisco, California
Patricia Magana, Ph.D. Otto Scheiner, Ph.D.

Tlalpan, Mexico Department of General and Experimental
Pathology
John C. Mitchell, Ph.D. University of Vienna
University of British Columbia Vienna, Austria
Canada
J. Juan Segura, M.D., Ph.D.
Aila Niinimaki, M.D. Centro de Investigacion Biomedica del Noreste,
Department of Dermatology IMSS
University Hospital Monterrey, Nuevo Leon, Mexico
Oulu, Finland
Jun Wen, Ph.D.
Scott Norton, M.D. Department of Biology
Walter Reed Army Institute of Research Colorado State University
Washington, D.C. Fort Collins, Colorado
Marian Ørgaard, Ph.D. Jan West, Ph.D.

Botanical Section Minority Science Program
Royal Veterinary and Agricultural University University of California
Frederiksborg C, Denmark Irvine, CA
Evy Paulsen, M.D. Hongbo Zhai, M.D.

Department of Dermatology Department of Dermatology
Odense University Hospital University of California
Odense, Denmark San Francisco, California

Contents
Preface
Chapter 1
Introduction
Javier Avalos and Howard I. Maibach
Chapter 2
Botanical Heritage of Dermatology
Scott A. Norton
SECTION I PHYTODERMATOSES
Chapter 3
Etiology of Adverse Reactions to Plants
Georges Ducombs
Chapter 4
Diagnosis and Patch Testing of Plant Dermatitis
John C. Mitchell and Howard I. Maibach
Chapter 5
Prevention of Allergic Contact Dermatitis to Plants
Hongbo Zhai and Howard I. Maibach
Chapter 6
Phytophotodermatoses
Christopher Roland Lovell
SECTION II CLINICAL AND BOTANICAL INVESTIGATIONS
Chapter 7
Phytochemical Procedures
Jean-Pierre Lepoittevin
Chapter 8
Botanical Photoallergy
Ai-Lean Chew and Howard I. Maibach

SECTION III PLANT FAMILIES RESPONSIBLE FOR THE MAJORITY
OF DERMATOLOGIC REACTIONS
Chapter 9
Toxic Anacardiaceae
Jere D. Guin, John H. Beaman, and Harold Baer
Chapter 10
Araliaceae
Bjoern M. Hausen
Chapter 11
Asteraceae
Mario Robles, Jan West, Eloy Rodriguez, and Michael Heinrich
Chapter 12
The Pollen Allergens of the Betulaceae
Heimo Breiteneder, Jun Wen, and Otto Scheiner
Chapter 13
Hydrophyllaceae
Manuel Aregullin and Eloy Rodriguez
Chapter 14
Primulaceae
Lars P. Christensen
Chapter 15
Urticaceae
Javier Avalos
SECTION IV OTHER PLANT FAMILIES
Chapter 16
Agavaceae
J. Juan Segura, C. Calzado Flores, and J. Del Valle Cantu
Chapter 17
Algae
Jose G. Camarasa
Chapter 18
Alstroemeriaceae
Lars P. Christensen, Kell Kristiansen, and Marian Ǿrgaard
Chapter 19
Aristolochiaceae
Luisa Pistelli

Chapter 20
Bignoniaceae
Oluwatoyin A. Binutu and Geoffrey A. Cordell
Chapter 21
Bromeliaceae
Félix Cordoba Alva, Eduardo Pérez-Campos, and Patricia Magaña
Chapter 22
Lichens
Marius Rademaker
Chapter 23
Verbenaceae
Evy Paulsen and Klaus E. Andersen
SECTION V SPECIAL TOPICS
Chapter 24
Allergic Hardwoods
Bjoern M. Hausen
Chapter 25
Toxicodendron of the Southern Pacific
Marius Rademaker
Chapter 26
Spices
Matti Hannuksela and Aila Niinimaki

1 Introduction
Javier Avalos and Howard I. Maibach
CONTENTS
1.1 Plants
1.2 Beneficial Uses of Plants
1.2.1 Herbal Remedies
1.2.2 New Pharmaceuticals
1.2.3 Cosmetic Products
1.3 Adverse Occurrences
1.3.1 Contact Urticaria
1.3.2 Phytophotodermatitis
1.3.3 Irritant Contact Dermatitis
1.3.4 Allergic Contact Dermititis
1.4 Identification of Active Components
1.5 Summary
1.6 References
1.1 PLANTS
The plant kingdom is a critical component to man’s existence. Plants provide the basic energy
source to sustain life on this planet. Many researchers have devoted their lives to understand better
every aspect of the plant. Their efforts are evident in the thousands of literature reports that have
been published emphasizing the nutritional, medicinal, and detrimental properties of plants. Over
the years, man has adapted to its plant world and the plant in turn has been forced to evolve with
man. As a result, plants have developed intricate metabolic pathways that can generate unique and
biologically active natural products.
The focus of this book is to describe the biological activity of plants, some of their beneficial
uses, and most importantly, understand the types of adverse reactions associated with plant contact
in order to prevent re-exposure. The second chapter of this book accentuates the beneficial properties
of plants. The first section of the book describes the etiology of adverse reaction to plants and
discusses preventive methods of plant dermatitis. Clinical and botanical investigations are depicted
in the second section of the book. The major emphasis of this book, sections 3, 4, and 5, is on the
adverse properties reported with several plant families.
1.2 BENEFICIAL USES OF PLANTS

Many cultures around the world have relied on the beneficial properties of plants to treat many
diseases. Even today, the practice of preparing a botanical concoction by herbalists and indigenous
healers as well as novices worldwide for the prevention and treatment of many diseases still exists.

Botanical preparations are also being employed in the treatment and cure of new diseases. For
example, onion and garlic juices have been purported to prevent the rise of serum cholesterol. Other
plants such as Echinacea, garlic, ginger, ginkgo, St. John’s Wort, and valerian have been evaluated
in controlled clinical trials.
In dermatology, there are also some plants that have been utilized in this particular area of
medicine. Dr. Norton has a more elaborate discussion on this topic in Chapter 2.
1.2.1 HERBAL REMEDIES

Herbal remedies are preparations made from either the aerials (leaves, stems, and bark) or the roots
of plants. The most common form of a herbal remedy is a tea. However, the extract can also be
made into a paste and applied topically. The utilization of herbal medicines is widespread and
growing. For example, the number of people using a botanical remedy in the United States is 3 in
10 people in a given year. Robles et al. (Chapter 11) provide descriptions of ethnobotanical uses
specific to plants in the Asteraceae family found in Mexico and the southwest region of the United
States.
As described earlier, some herbal remedies have widespread application and the use has been
documented for thousands of years. Aloe vera (family Liliaceae) and ginseng (Panax ginseng,
family Araliaceae) are good examples of plants with widespread use and purported beneficial
properties. Investigators are continuously searching for new plants with medicinal properties. In
many instances, key information is obtained from indigenous practitioners. In addition, it is not
too uncommon for phytochemists to explore the jungles of the world in search of plants that some
day may hold a unique component capable of curing one of mankind’s current diseases.
1.2.2 NEW PHARMACEUTICALS

Ancient societies used extracts of plants as a means for treating many diseases. More than 20
percent of the commercially prepared human drugs are reported to come from biologically active
components within plants. For example, salicylic acid, obtained from the bark of the willow tree,
was used by the ancient Greeks and Native Americans, among others, to counter fever and pain.
Eventually, salicylic acid was acetylated by Felix Hoffman in 1893 to produce aspirin. Taxol from
the yew tree, the antitumor agent vinblastine from the herb periwrinkle (Vinca, family Apocyn-
aceae), and 8-methoxypsoralen from celery (Apium graveolens, family Apiaceae) are other exam-
ples of human drugs with a botanical beginning.
In more recent times, a labored process has evolved for identifying potential drug products
from natural sources. The process begins with either the phytochemist or botanist isolating and
identifying a naturally occurring agent with some medicinal properties. Dr. Lepoittevin elaborates
on some of the considerations involved in isolating and identifying naturally occurring compounds
in Chapter 7. For either the plants involved or the isolated compound, randomized, controlled
clinical trials are then conducted in order to ascertain the efficacy and safety of the proposed new
medication. With time and much effort from many scientists in academia, industry, and government,
the purified naturally occurring substance will become a new human drug.
1.2.3 COSMETIC PRODUCTS

In addition to the development of new pharmaceuticals, many plant components or extracts have
also found uses in cosmetic products. Again, the utilization of plants or botanical preparations as
beautification aids has a long history. Women in India, Egypt, and Rome used the indigo plant
(Indigofera, family Papilionoideae) to obtain a long-lasting, deep-blue color for a make-up prepa-
ration. The dye was then introduced into Europe during the sixteenth century.
Other plant extracts such as Tea tree oil, seaweed (algenic acid from kelp, brown algae), and
witch hazel (family Hamamelidaceae) are incorporated into current cosmetic formulations. In

addition, many of the fragrances found in cosmetics have components that are plant derived. The
incorporation of these and other extracts into cosmetic products are the result of the efforts of
scientists (phytochemists, clinicians, and toxicologists) whose goal is to provide the consumer with
safe and efficacious cosmetic products.
1.3 ADVERSE OCCURRENCES

Plants have evolved sophisticated biochemical processes in which unique, diverse, and biologically
active compounds are produced. These biologically active agents can have beneficial properties as
described previously. However, the biological activity could also have detrimental consequences
upon exposure. In addition, the opportunity for frequent contact with the source of the detrimental
substance can be elevated owing to the large variety of plant species that exist. Weeds, house plants,
and garden plants can elicit adverse reactions under the proper conditions.
Drs. Mitchell and Rook have identified a large number of plant families that are professed to
cause human adverse reactions (Table 1.1).1 In this book, specific details are contained in several
chapters that focus on the adverse exposure to the plant families Agavaceae, Algae, Alstroemeri-
aceae, Anacardiaceae, Araliaceae, Asteraceae, Betulaceae, Hydrophyllaceae, Primulaceae, Urti-
caceae, and others.
A total of four major types of dermal reactions have been described following exposure to plant
or plant-derived products. These are contact urticaria, phytophotodermatitis, irritant contact der-
matitis, and allergic contact dermatitis.
1.3.1 CONTACT URTICARIA

An urticarial reaction occurs immediately (within minutes of contact) and involves itching,
erythema, and/or edema. Contact urticaria may also be irritant (nonimmunological) or allergic
(immunological).2 Although the welts may form rapidly after a person brushes against the offending
plant, overall the urticarial reaction is short-lived. The weed, nettle (Urtica dioica, family Urti-
caceae), is the most common culprit. The reader is referred to Chapter 15 for more details on this
plant and members of this family. Other plants known to elicit urticarial reactions are the tulips
(Tulipa, family Liliaceae), Grivella (family Proteaceae), members of the Euphorbiceae, members
of the Hydrophyllaceae, and lichens.2,3
1.3.2 PHYTOPHOTODERMATITIS
Phytophotodermatitis occurs when the skin is exposed to sunlight after contact with an offending
plant; reactions are erythema, pruritus, vesiculation after 1 to 2 days of plant contact, and subsequent
hyperpigmentation. The common culprit plant families are the Apiaceae (Umbelliferae), Rutaceae,
and Moraceae. Some of the common names of the plants involved for the Apiaceae family are
Queen Anne’s lace, cow parsnip, celery, srping parsley, parsnip, and giant Russian hogweed.4 For
Rutaceae, these are the bergamot lime, burning bush, and gas plant. Figs are the culprit in the
family Moraceae. St. John’s Wort (family Hypericaceae) has also been implicated. The most
common phototoxic compounds are the furocoumarins (e.g., psoralen, 8-methoxypsoralen, and
5-methoxypsoralen).
1.3.3 IRRITANT CONTACT DERMATITIS

In irritant contact dermatitis, the skin is traumatized mechanically or chemically and produces an
inflammatory response. The mechanical or physical damage can be caused by thorns (roses, family
Rosaceae), sharp-edged leaves, and leaf hooks (Holly, Aquifoliaceae; Agave, Agavaceae; Yucca,
Agavaceae), spines and glochids (cacti such as Opuntia, Cactaceae), stem/leaf hairs (Borage family,
comfrey, forget-me-not; Bidens, Asteraceae), or irritant fibers (Rose hips, Rosaceae; tulip bulbs,

TABLE 1.1
Plant Families Purported to Elicit Adverse Effects on Humans
Acanthaceae Celastraceae Gesneriaceae Nyctaginaceae Sapindaceae
Aceraceae Ceratophyllaceae Gigartinaceae Ochnaceae Sapotaceae
Agavaceae Chenopodiaceae Ginkgoaceae Olacaceae Saururaceae
Aizoaceae Chrysobalanaceae Goodeniaceae Oleaceae Saxifragaceae
Algae Cleomaceae Grossulariaceae Onagraceae Scrophulariaceae
Alismataceae Clusiaceae Guttiferae Opiliaceae Simaroubaceae
Alliaceae Cochlospermaceae Gyrostemonaceae Orchidaceae Smilacaceae
Alstroemeriaceae Combretaceae Haemodoraceae Oxalidaceae Solanaceae
Altingiaceae Commelinaceae Hamamelidaceae Paeoniaceae Sonneratiaceae
Amaranthaceae Compositae Hernandiaceae Palmae Spigeliaceae
Amaryllidaceae Connaraeae Hippocastanaceae Pandanaceae Stackhousiaceae
Anacardiaceae Convolvulaceae Hydrangeaceae Papaveraceae Sterculiaceae
Annonaceae Coriariaceae Hydrastidaceae Pedaliaceae Stilaginaceae
Apiaceae Cornaceae Hydrocharitaceae Peperomiaceae Strelitziaceae
Apocynaceae Corylaceae Hydrocotylaceae Periplocaceae Strychnaceae
Aquifoliaceae Crassulaceae Hydrophyllaceae Phytolaccaceae Styracaceae
Araceae Cruciferae Hymenocardiaceae Pinaceae Taxaceae
Araliaceae Crypteroniaceae Icacinaceae Piperaceae Taxodiaceae
Aruacariaceae Cucurbitaceae Illiciaceae Pistaciaceae Theaceae
Arecaceae Cunoniaceae Iridaceae Pittosporaceae Thymelaeaceae
Aristolochiaceae Cupressaceae Juglandaceae Plantaginaceae Tiliaceae
Asclepiadaceae Curtisiaceae Labiatae Platanaceae Triliaceae
Asteraceae Cycadaceae Lecythidaceae Plumbaginaceae Tropaeolaceae
Avicenniaceae Cyperaceae Leguminosae Poaceae Typhaceae
Balanitaceae Davidsoniaceae Lemnaceae Podocarpaceae Ulmaceae
Balsaminaceae Denstaedtiaceae Leonticaceae Podophyliacee Umbelliferae
Barringtoniaceae Dichapetalaceae Liliaceae Polemoniaceae Urticaceae
Basellaceae Didiereaceae Limnanthaceae Polygalaceae Valeriananceae
Begoniaceae Dilleniaceae Linaceae Polygonaceae Verbenaceae
Berberidaceae Dioscoreaceae Loasaceae Polypodiaceae Violaceae
Betulaceae Dipsacaceae Loganiaceae Portulaceae Viscaceae
Bignoniaceae Dipterocarpaceae Loranthaceae Potaliaceae Vitidaceae
Bixaceae Droseraceae Lycopodiaceae Potamogetonaceae Winteraceae
Blepharocaryaceae Ebenaceae Lythraceae Primulaceae Xanthorrhoeaceae
Bombacaceae Ehretiaceae Magnoliaceae Proteaceae Zingiberaceae
Braginaceae Elaeocarpaceae Malpighiaceae Psiloxylaceae Zygophyllaceae
Brassicaceae Epacridaceae Malvaceae Ptaeroxylaceae
Bromeliaceae Ephedraceae Marantaceae Punicaceae
Bryophyta Equisetaceae Martyniaceae Pyrolaceae
Burseraceae Ericaceae Melastomataceae Ranunculaceae
Buxaceae Erythroxylaceae Meliaceae Resedaceae
Cactaceae Euphorbiaceae Menispermaceae Rhamnaceae
Campanulaceae Fabaceae Montiniaceae Rhizophoraceae
Canellaceae Fagaceae Moraceae Rosaceae
Cannabidaceae Flacourtiaceae Moringaceae Rubiaceae
Caprifoliaceae Flagellariaceae Myricaceae Rutaceae
Caricaceae Flindersiaceae Myristicaceae Salicaceae
Carpinaceae Fumariaceae Myrtaceae Salvadoraceae
Caryophyllaceae Fungi Najadaceae Sambucaceae
Casuarinaceae Geraniaceae Naucleaceae Santalaceae

Liliaceae). Plants containing an irritant substance include hot peppers (Solanaceae), burdock (Aster-
aceae), chicory (Asteraceae), Agrimony (Rosaceae), Cowhage (Leguminosae), pineapple (Brome-
liaceae), Hyacinth (Hyacinthaceae), daffodil (Amaryllidaceae), and several genera from Euphorbi-
aceae.5 The active material in some of these plants has been determined.5 The chemicals include
capsaicin, nicotine, protoanemonin, thiocyanates, salicylic acid, bromelin, tigliane, daphnane, and
cryptoleurine.
1.3.4 ALLERGIC CONTACT DERMATITIS

Allergic contact dermatitis is a cell-mediated immune response that occurs in previously sensitized
persons. Erythema, vesiculation, and pruritus, which usually heal without causing pigmentary
changes, may last for several weeks. The most common occurrence of allergic contact dermatitis
is owing to exposure to poison ivy (Toxicodendron spp., Anacardiaceae).
The mechanisms of allergic contact dermatitis have been described.6,7 The reactive material
(hapten) penetrates the epidermis and forms a conjugate with carrier protein to generate the allergen.
A specific clone of lymphocytes then recognizes the antigen. This is the antigen recognition phase
of the mechanism of allergic contact dermatitis. In the propagation phase, the lymphocytes migrate
from the skin via lymphatics to regional lymph nodes where they proliferate, differentiate, and
disseminate throughout the body. Upon the next encounter with the hapten, these effector and
memory T cells elicit an eczematous response at the site of contact (the elicitation phase).
Several plant families contain known allergens. Again, the urushiols found in Toxicodendron
are a good example of allergenic compounds and have been well studied. The reader is referred to
Chapter 9 by Drs. Guin et al. for more details. Other allergenic materials include the sesquiterpene
lactones (Asteraceae, Lauraceae, Magnoliaceae, and Jubulaceae), primin (primula), and tuliposide
(Alstroemeriaceae). A more detailed discussion of these compounds can be found in Chapters 11,
14, and 18, respectively. Many more plant families are also reported to contain allergenic com-
pounds. However, the actual active ingredient has not been characterized in most cases.
1.4 IDENTIFICATION OF ACTIVE COMPONENTS

With such a large number of plants with biologically active material, a basic understanding of the
types of reactions and the common plants that cause each reaction is necessary in order to inform
the affected individual of the source of the reaction. Such information would give the affected
individual a weapon of defense and, thus, prevent re-exposure to the culprit material. To achieve
this goal, the efforts and expertise of the botanist, phytochemist, toxicologist, and physician are
imperative.
Clinical research has been critical in the identification of the causative plant and/or plant
material. The investigator, with the use of a patch test, can confirm the adverse reaction observed
by the affected individual. Upon further evaluation, a plant may be identified as the source of the
reaction. Botanical classification of the plant is then utilized to name the plant in order to ensure
the proper identification of the plant. Drs. Mitchell and Maibach describe several considerations
for accomplishing this task in Chapter 4. Once the plant is identified, the actual component
responsible for the reaction can then be isolated and identified by the toxicologist or phytochemist.
Dr. Lepoittevin in Chapter 7 describes such methodologies.
1.5 SUMMARY
The identification of plants and their detrimental constituents is a challenging task. Our hope is to
introduce the reader to the intricacy of plant defenses: the generation of unique, biologically active
secondary metabolites or specialized appendages. In addition, the reader will become acquainted

with the large variety of plants capable of eliciting an adverse reaction, some of the phytochemical
procedures used to isolate and identify the active agent, patch testing methodologies, and factors
to consider in conducting these studies.
1.6 REFERENCES
1. Mitchell, J. and Rook, A., Botanical Dermatology: Plants and Plant Products Injurious to the Skin,
Greengrass, Vancouver, BC, 1979.
2. Von Krogh, G. and Maibach, H. I., The contact uriticaria syndrome—an updated review, J. Am. Acad.
Dermatol., 5, 328, 1981.
3. McGovern, T. W. and Barkley, T. M., Botanical dermatology, Int. J. Dermatol., 37, 321, 1998.
4. Johnson, B. E., Phototoxic reactions, in Plants and the Skin, Lovell, C. R., Ed., Blackwell Scientific,
Oxford, 1993, 66.
5. Lovell, C. R., Irritant plants, in Plants and the Skin, Lovell, C. R., Ed., Blackwell Scientific, Oxford,
1993, 42.
6. Dupuis, G. and Benezra, C., Allergic Contact Dermatitis to Simple Chemicals: A Molecular Approach,
Marcel Dekker, NY, 1982.
7. Polak, L., Immunological aspects of contact sensitivity. An experimental study, in Monographs in
Allergy, Vol. 15, S. Karger, Basel, 1980.

2 Botanical Heritage of
Dermatology*
Scott A. Norton
CONTENTS
2.1 Introduction
2.2 Natural Products and Ethnobotany
2.3 Literature on Botanical Dermatology
2.4 Plants and the Skin
2.5 Examples of Plants in Dermatologic Therapy
2.6 Examples of Plants in Dermatologic Diagnosis
2.7 Other Natural Products in Dermatology
2.8 The Future of Natural Products in Dermatology
2.9 Herbal Medicines, Botaniceuticals, and Entrepreneurs
2.10 Conservation, Biodiversity, and Preservation of Indigenous Cultures
2.11 References
Along the bank of the river … will grow all kinds of trees [whose] fruit will be used for food and their
leaves for medicine. Ezekiel 47:12
2.1 INTRODUCTION
Dermatologic Botany addresses mainly the harmful or injurious effects of plants upon the skin.
This chapter serves to remind readers of the beneficent role of plants in dermatology (and medicine
in general) throughout history. Many of my patients and colleagues know of my interest in botany
and often ask if I use (or believe in) herbal medicines or medicinal plants. The short answer is,
“Of course, but maybe not as you think.” The full answer, a discourse on the historical and
continuing harmonious relationship between plants and dermatology, constitutes this chapter.
The disciplines of medicine and botany have been closely allied through most of man’s history.
For millennia, healers depended on the helpful properties of plants and were, by necessity, accom-
plished botanists.1,2 For centuries, herbals (manuals of pharmacognosy in which the therapeutic
properties of plants are cataloged) served as the standard treatises of Western medicine. Healers in
both Western and non-Western models of medicine relied—and still rely—on medicinal plants. In
developing nations, approximately 80 percent of the populations are still treated with traditional
medicines made from natural products with little or no processing.3 From 1959 to 1980, medications
derived from vascular plants account for one fourth of all out-patient prescriptions in the United
States.3 Since 1980, roughly one-half of the medications submitted to the FDA were derived from
natural products.4
* The opinions and assertions contained herein are those of the author and not necessarily those of the Department of Defense.

Medical botany was once a core course in a physician’s education, but doctors trained today
in the modern biomedical fashion are often unaware of medicine’s botanical heritage. With the rise
of the chemical industry in the mid-nineteenth century, the fields of medicine and botany began to
evolve separately. The pharmacologically active components of plants were often extracted and
analyzed in the laboratory. Once the chemical structures were identified, chemists were often able
to fully synthesize the desired product. This obviated the need to collect useful plants from the
wild or from cultivation and led to the further divergence between botany and medicine. Biochemists
were also able to develop novel substances whose molecular structures were unknown in nature.
These were developed for industrial uses, such as textile dyes, but the pharmacoactivity of these
new compounds was recognized and many entered the conventional pharmacopoeia. Today synthetic
medications have largely replaced natural products and many physicians now regard plant-derived
medications such as digoxin, morphine, ipecac, and atropine as curious remnants from the anti-
quated days of medicine.
2.2 NATURAL PRODUCTS AND ETHNOBOTANY

In the past two decades, however, there has been a re-awakened appreciation of the pharmacoactive
properties of natural products. Perhaps the most widely known examples of plant products entering
the modern pharmacopoeia involve the development of chemotherapeutic agents. Vinblastine and
vincristine from Madagascar’s rosy periwinkle (Catharanthus rosea) and paclitaxel from the
Western yew tree (Taxus brevifolia) are now standard elements in our battles with cancer. The
interest in medicinal plants usually follows one of three avenues: a popular interest in herbal
medicines, ethnobotanical investigations among traditional peoples, and pharmacological inves-
tigations involving combinatorial chemistry. In Europe, particularly France and Germany, herbal
medications have long been part of the standard formularies. More recently, it has been recognized
that millions of Americans (and billions of their health care dollars) are engaged in alternative or
complementary medical practices, much of which use natural products.5 The medical and scien-
tific, social and economic, and legal and regulatory consequences of these practices are still
evolving.6
Ethnobotany has re-emerged as a medically sound and potentially profitable source of new
medications. Hundreds of reports appear in the medical literature each year on the physiologic
activity of phytochemicals in laboratory animals or in vitro. Most endeavors seek new agents for
antiviral, antibacterial, and chemotherapeutic purposes. The ethnobotanist’s principle is that there
are innumerable plants and plant products whose therapeutic activity is recognized by traditional
healers but whose pharmacological activity has not yet been recognized by Western medical
science.7 Ethnobotanical investigations require interdisciplinary skills in plant taxonomy, cultural
anthropology, biochemistry, pharmacology, linguistics, and medicine.2,8
The search for and the development of potentially valuable natural products is called bio-
prospecting. This was one of the major themes of the 1992 United Nations “Earth Summit” in
Rio de Janeiro. The United Nations Convention on Biological Diversity that arose from the
Summit endorses the proposal that nations (and their indigenous peoples) retain intellectual
property rights to biologic products derived from endemic plants and animals. Indigenous peoples
whose knowledge and skills are used in the development of a new product figure prominently in
this convention.2
Dermatological remedies are a particularly appropriate avenue for ethnopharmacologic pursuit
because the ethnopharmacopoeia of many populations are directed toward skin diseases. In tradi-
tional societies in tropical areas, skin disorders are ubiquitous, conspicuous, and cause considerable
morbidity. Skin diseases are classifiable (although not necessarily in accordance with a biomedical
system) and are amenable to observation for response to treatment. Accordingly, the dermatologist
should take great interest in ethnopharmacologic endeavors. On the other hand, the interest of

Western pharmaceutical corporations is usually more toward the major causes of morbidity and
mortality in developed countries, such as cancer, diabetes, heart disease, and infectious diseases.
In many cases, the molecular structure of the medication is unchanged, but the product is fully
synthesized to achieve large quantities more efficiently than through crude extractions. In other
cases, the molecular structure of the crude product has been modified, improving the drug’s efficacy
and safety (such as the development of atracurium from curare, the Amazonian arrow poison
obtained from Chondrodendron tomentosum (Menispermaceae).9
2.3 LITERATURE ON BOTANICAL DERMATOLOGY

A survey of books held at the National Library of Medicine (NLM) on the topics of plants and
medicine suggests an overwhelming appreciation (at least among medical writers) of the beneficial
contributions of plants to human health. As of mid-1998, the NLM held roughly 4000 books on
plants and medicine. Of these, 3596 books (91 percent) were on beneficial plants and 359 books
(9 percent) were on harmful plants. In contrast, the dermatological literature has a strong bias
against plants. Of the NLM’s 22 volumes on plants and the skin, one-half are about harmful plants.
Furthermore, all six books written in English and published in Western nations were on the toxic
effects of plants on the skin.
Dermatologic Botany and its major predecessors10-12 are among the volumes that focus on the
harmful effects of plants on the skin. Similar earlier works give the impression that plants can have
either of two consequences: bad or neutral. The subtitle of Mitchell and Rook’s opus, Botanical
Dermatology is Plants and Plant Products Injurious to the Skin.10 Their preface explains that “man’s
primitive ancestors … must have noticed that whilst some plants were harmful to everyone who
handled them, others produced ill effects in only a few.” Plant Contact Dermatitis, by Benezra et
al. tells us, “In our everyday life, we are surrounded by plants. … Many of these plants have an
adverse skin effect. Although most of the isolated and classified 3,000,000 plant species are harmless
to the skin, some can be blamed for provoking contact dermatitis.”11
This theme distorts the historically harmonious association of plants and the skin. So it is with
great pleasure that I add this brief chapter to review some of the beneficial interactions between
plants and the skin: the ways that dermatologists use plants and the ways that plants protect and
heal the skin.
2.4 PLANTS AND THE SKIN

The most obvious ways in which plants maintain the health of our skin are also the most overlooked
ways: food, clothing, and shelter. In the West, we generally do not consider food as medicine but
it is—both prophylactically and therapeutically. Most western dermatologists have not seen patients
with deficiency diseases of scurvy, pellagra, hypovitaminosis A, and kwashiorkor, yet these con-
ditions still appear in epidemic proportions among refugees and displaced people. Nutritional
diseases continue to ravage the skin (and every other organ) of millions of people. The inclusion
of proper plant-derived foods in the basic or supplemental diet will prevent or eradicate these
disorders. Furthermore, there is evidence that specific plants in the diet may protect against cancers,
usually visceral cancers, but possibly melanoma and nonmelanoma skin cancer as well. Examples
of putatively protective plants include those with abundant nonsoluble fiber or with anti-oxidative
properties (such as cruciferous vegetables).13
Worldwide, most clothing is made from plant fibers, especially cotton. Clothing, of course,
serves as barrier protection for the skin, protecting it from the physical elements of cold, water,
sunlight, rough objects, noxious plants and animals, and infectious organisms. Shelter protects
people from the same elements as do clothing but collectively and at a distance. Homes for the
vast majority of people worldwide are still made mainly from wood and other plant materials.

Continuing the theme of the obvious but overlooked interactions between plants and derma-
tologists, let us add that the paper and ink of this text (and that in every document you read or
prepare) comes from plants. The photographic film that one uses to capture images of one’s patients
has a base of cellulose acetate that comes from eucalyptus trees (Eucalyptus, Myrtaceae).14
2.5 EXAMPLES OF PLANTS IN DERMATOLOGIC THERAPY

The remainder of this chapter will review the role of vascular plants in dermatology today. Fungi,
once considered plants, are now classified as their own kingdom and so their invaluable contributions
to medicine as sources of antibiotic agents (most famously penicillin but virtually every antibacterial
antibiotic as well), antineoplastic agents (e.g., bleomycin and adriamycin), and immunomodulating
agents (e.g., cyclosporine) will not be covered here.
Pyrethrum and pyrethroids (such as permethrin) are natural or semisynthetic derivatives, respec-
tively, of the wild chrysanthemum, Tanacetum cinerariifolium (Asteraceae), native to mountains
of the Balkan peninsula. Legend has it that bouquets of dried plants were placed around homes to
deter insect infestations. Pyrethrum was used during World War I as an insect repellent both on
the skin and to impregnate clothing, tent canvas, and mosquito nets. The demand for the product
by the world’s armies led to the establishment of plantations throughout tropical mountainous areas
such as Kenya, Ecuador, and Papua New Guinea. The products continue to be used as repellants
but more recently semisynthetic derivatives have been developed for direct application to the skin
as scabicides and pediculicides.
Capsaicin is the natural substance that carries the essential fieriness of hot peppers.15 It is found
only in several members of the genus Capsicum (Solanaceae). The action of capsaicin when applied
to the skin is to deplete sensory nerve fibers of Substance P which renders the nerves incapable of
transmitting pain sensations. Consequently, capsaicin compounds are used to treat cutaneous dys-
esthesias associated with postherapetic neuralgia, diabetic neuropathy, reflex sympathetic dystrophy,
Raynaud’s phenomenon, notalgia paresthetica, and hemodialysis-related pruritus.16
Nearly all antibacterial agents in use today are derived from fungi. The story of penicillin is
well-known; many other antibiotics such as cephalosporins were developed in similar yet more
deliberate ways. Several fully synthetic antibiotics, such as the sulfa compounds, emerged from
the biochemical industry, but the only regularly used antibacterial derived from a higher plant in
modern times has been chaulmoogra which was prescribed in the treatment of leprosy.17 Chaul-
moogra oil is extracted from the seeds of several closely related plants in the genus Hydnocarpus
(Hydnocarpaceae) found in scattered areas in southeast Asia. This plant entered Western medicine
through a true combination of ethnobotany and bioprospecting (although long before either term
was in use). British physicians working in India in the mid-nineteenth century reported on the local
use of an oil made from the crushed seeds of certain trees found in the Kerala hills. The substance
was used in several forms by local healers to treat leprosy. For the next one-half century, Western
supplies of chaulmoogra were obtained from bazaars in India and Indochina, but the oils were
often in low supply and of poor quality. The United States Department of Agriculture (USDA)
dispatched Joseph Rock, a botanist at the University of Hawaii, to southeast Asia to collect viable
chaulmoogra seeds for the establishment of plantations on the Hawaiian islands. Rock succeeded
and the oil subsequently obtained from his trees supplied American leprosaria for decades. Ulti-
mately, chaulmoogra was replaced by a fungus-derived product, rifampicin, and a fully synthetic
product, dapsone.
Podophyllin18 is a crude extract from the mayapple, Podophyllum peltatum (Berberidaceae),
that grows wild in forested hills over much of the eastern one-half of the United States. A closely-
related species, Podophyllum hexandrum (syn P. emodi), is found in mountainous areas of south-
western China, a disjunct distribution that is found with a number of primitive flowering plants
such as magnolia and star anise. The mayapple has a plum-sized yellowish-green fruit that ripens

in late spring, hence its name. North America Indians used the fruit as part of their pharmacopoeia,
ingesting it as an emetic and purgative. The use of a crude extract of podophyllin to treat warts
was first practiced in New Orleans in the 1930s. Recently, a purified preparation of one of the
active ingredients, podophyllotoxin, was approved for dispensing. The compound appears to cause
mitotic arrest in actively dividing cells, the sort found in warts and some neoplasms. Indeed, a
semisynthetic derivative of mayapple, etoposide (also called VP16), is administered parenterally
to treat cancers such as small cell carcinoma of the lung and refractory testicular tumors. A recent
report suggests that etoposide may be useful in the treatment of cutaneous Langerhans cell histi-
ocytosis.19
Corticosteroids are the most frequently prescribed class of medications in dermatology, yet
they have been widely available for perhaps only the past 40 years. The history of commercial
steroids is a fascinating tale of botanical exploration to find an exploitable source of sapogenins
from which steroids could be derived.20 Until recently, almost all steroid products (sex steroids and
glucocorticoids) were derived from one of several species of wild Mexican yams (e.g., Dioscorea
mexicana, D. composita, and D. floribunda, Dioscoraceae) that contained sufficient diosgenin for
practical conversion into an active substance. Subsequently, pathways from soybean precursors
were developed and many of the products are marketed with the cachet of being a “natural” product
in both the prescription (such as Ogen, estropipate) and nonprescription markets (dehydroepiandros-
terone sulfate or DHEAS sold under many trade names at health food stores).
Antimalarial substances derived from quinine have changed the history of man and, conse-
quently, the face of the earth. The often repeated early history of quinine or Peruvian bark is a
mixture of truth and legend,21 but the extract from the bark of the Cinchona (especially, C. calisaya,
Rubiaceae) tree has contributed greatly toward the conquest of malaria and has consequently enabled
dense inhabitation of the humid tropics and subtropics. Unfortunately, the plasmodia are acquiring
resistance to quinine and its descendants, but these products are still part of the dermatologist’s
core formulary. In 1894, a physician tried quinine to treat the cutaneous lesions of discoid lupus
erythematosus on the assumption that quinine would cause vasoconstriction and clear the plaques.21
Successes here led to trials over the next century of various natural and synthetic antimalarials in
other connective tissue diseases, photosensitivity disorders, and sarcoidosis.
Colchicine is an alkaloid derived from the autumn crocus, Colchicum autumnale. The plant is
endemic to regions in the eastern Mediterranean, but it is now cultivated worldwide for both its
ornamental and its therapeutic properties. Colchicine is the classic treatment for gout, but it is also
used in neutrophilic disorders. It appears that colchicine interferes with mitoses and has other
immunomodulating effects. A variety of seemingly disparate disorders such as gout, oral aphthae,
Behçet’s disease, familial Mediterranean fever (and associated amyloidosis), and primary biliary
cirrhosis can be controlled although not cured with colchicine.
The story of psoralen-containing plants in dermatology is well known. In both Egypt and India,
people with vitiligo ate seeds from particular plants in the parsley family (Umbelliferae or Apiaceae)
and exposed themselves to sunlight. Depigmented areas became sunburned and often blistered,
after which the pigment occasionally returned. One of these plants, Psoralea corylifolia, gave its
name to the class of agents, psoralens, that are now used in the treatment of several photoresponsive
dermatoses, such as psoriasis. Most psoralen used for medical purposes comes from bishop’s weed
(Ammi majus), native to parts of southern Europe, north Africa, and southwest Asia.22-24
The precursor of anthralin used in the treatment of psoriasis was a natural preparation called
Goa powder or chrysorobin. It was obtained from the bark and wood of several closely related
trees, particularly the araroba (Vataireopsis araroba, Leguminosae), found along Brazil’s Bahia
coast.25 Portuguese traders took the tree from their New World colony and established it in their
Indian colony of Goa, hence the medication was also known as Goa powder. In the mid-to-late
1800s, chrysorobin entered the dermatologist’s formulary as a treatment for several papulosquamous
diseases, but it soon was recognized for its antipsoriatic properties. A seatrade blockade of Germany

during World War I led to the synthesis of anthralin, the most effective component of chrysorobin,
by that nation’s biochemists.26
Azelaic acid, a by-product of processed cereal grains (Graminae), has several properties that
make it useful in dermatology. It interferes with tyrosinase and, hence, can be used as a topical
agent to treat benign pigmented lesions such as melasma. It is also mildly bacteriostatic and anti-
inflammatory and is used in the treatment of mild acne vulgaris although its precise mechanism of
action is not known.27
Traditional Chinese medicine is a rich source of herbal medicines. Most Chinese medicines
are combinations of several herbs and often animal parts. These are administered under the phi-
losophy that the collective or synergistic properties of the herbs are what is beneficial. This differs
from the Western biomedical paradigm in which there are extractable and identifiable pharmaco-
logically active ingredients. Western dermatologists seem most interested in the Chinese approach
to treating psoriasis and atopic dermatitis.28,29 Issues of plant identification, potency of the materials,
and purity of the concoctions makes these products difficult for Western pharmacologists to analyze
and assess. There are dangers of uncritical enthusiasm for these products and many reports of toxic
adulterants in traditional Chinese medicines.30-32
It has been noted recently that ulcerative colitis is uncommon in cigarette smokers. It appears
that in some way, tobacco is protective or therapeutic. The likeliest explanation is that nicotine, an
alkaloid found in tobacco (Nicotiana tabacum, Solanaceae), has some hitherto undetected salutary
properties. Open trials of topical nicotine in the treatment of a cutaneous manifestation of ulcerative
colitis, namely pyoderma gangrenosum, also show some benefit.33
Oats can be made into an antipruritic remedy; the oatmeal bath is used as a palliative for
intensely itchy conditions such as severe atopic dermatitis. The Latin name for oats, Avena (Gram-
inae) gives a clue for the trade name of the most commonly used form of oats. Other antipruritic
agents include menthol from mint (Mentha spp., Labiatae) and camphor from several trees (espe-
cially in Lauraceae and Myrtaceae), although these agents are now synthesized. These are both
mild topical anesthetics that can help reduce severe itching.
Papain, an enzyme from papaya (Carica papaya, Caricaceae) is often touted as and used for
the treatment of minor envenomations (such as from jellyfish or fire ants) to denature the toxic
proteins, despite uncertain evidence.34 Papain has also been used for enzymatic debridement of leg
ulcers.35
Aloe vera (Aloe vera, Agavaceae) is one of the most popular of the botaniceuticals. Aloe is
used as direct application of freshly cut aloe leaves. Extracts of tissue juices are also prepared for
commercial products. There are pharmacologically active substances in aloe vera that may promote
wound healing and retard bacterial growth.36
Most flavorings, fragrances, colorings, and many of the vehicles in which topical and oral
medications are prepared are derived from plants.37 Tincture of benzoin is made from the storax
tree, Styrax (Styracaceae). Alcohol, used in so many fashions, is a by-product from the grain
industry. Balsam of Peru is derived from the black balsam tree, Myroxylon balsamum var. pereirae,
which naturally occurs in lowland forests of central America although it is now grown in plantations
throughout the tropics. The useful product, balsam, is a viscous liquid with a vanilla-like odor that
is used in perfumes.
Other topical preparations prepared from plants include liniments, rubifacients, astringents,
emollients, and counterirritants such as turpentine, capsaicin, salicylates, menthol, and thymol.37
Rubifacients are preparations that increase the cutaneous blood flow. Salicylic acid is used as both
a rubifacient and as a keratolytic compound in many formulations. By legend, the original source
of salicylic acid was the bark of willow trees (in Latin, willow is Salix). Later, salicylates were
obtained from Spiraea (Rosaceae), but a century ago, a synthetic version was made “without Spiraea
(a-spiraea),” hence the name “aspirin.” Witch hazel from Hamamelis virginiana (Hamamelidaceae)
is an astringent used to calm external hemorrhoids. Thymol, an extract from thyme, Thymus vulgaris

(Labiatae), has been used as a fungistatic agent for fungal infections of nails. The oils that one
applies to the skin as lubricants, moisturizers, and emollients are often plant-based as is the glycolic
acid now used in skin resurfacing. Evening primrose oil and green tea extracts enjoy waves of
popularity among both the public and the medical community for their actions on several inflam-
matory conditions.
2.6 EXAMPLES OF PLANTS IN DERMATOLOGIC DIAGNOSIS

Some of the simplest diagnostic tests that use plant products are sensory testing with wisps of
cotton when one suspects leprosy and the acetowhitening technique to check for genital epithelial
growths, such as warts. Acetic acid, of course, is a by-product of common fermentation of any of
a number of plant sources.
Several histochemical stains are derived from plants. The most widely used stain is haemotox-
ylin, a natural dye, in combination with eosin, a synthetic dye. Haematoxylin is derived from the
red-colored heartwood of the logwood tree, Haematoxylum campechianum (Leguminosae), a scrub
tree indigenous to southern Mexico but now planted commercially on several Caribbean islands.38
An extract of the wood was used as a traditional textile dye by Indians of the region. In the sixteenth
and seventeenth centuries, Spanish and English mercantile ships vied for supplies of logwood to
produce textile dyes for much of Europe. The chemical structure of hematoxylin is known, but
attempts at commercial synthesis have been unsuccessful. The product remains in use today much
as it was by Virchow 130 years ago.
Alizarin red is one of several histochemical stains that are used to detect dermal calcium in
disorders such as pseudoxanthoma elasticum and calcinosis cutis.39 The original alizarin was
prepared from the madder plant, Rubia tinctorum (Rubiaceae), and was originally used as a textile
dye. Nowadays a synthetic product, chemically identical, is used instead in histochemistry.
Many agents used in immunohistochemistry are derived from plants. Phytohemagglutinins and
lectins are naturally occurring proteins that adhere to glycoproteins on the surface of red blood
cells. This confers upon these substances the curious ability to agglutinate red blood cells in vitro.40
Examples of phytohemagglutinins that are used in dermatologic immunopathology are concanavalin
A (jackbean, Canavalia ensiformis), peanut antigen (Arachis hypogaea), Ulex europaeus (European
common gorse) antigen, and soybean (Glycine max) lectin. The U. europaeus antigen helps identify
the vascular origins of tissues. Not all plants with lectins are botanically related but most (including
all those listed previously) are from the pea family, Leguminosae. Pokeweed (Phytolacca ameri-
cana, Phytolaccaceae) mitogen is used in an assay to test the B-cell origin of lymphocytes.
Gallotannin or tannic acid, derived from oak galls (a sort of tumorous response to insect invasions),
enhances fixation of specimens for electron microscopy and immunoelectron microscopy.41 Perox-
idases derived from several plants, horseradish (Amoracia rusticana, Cruciferae) in particular, are
used in immunohistochemistry and a number of other diagnostic tests.
2.7 OTHER NATURAL PRODUCTS IN DERMATOLOGY

Biochemists have had tremendous accomplishments in the duplication of natural chemicals and
the creation of new ones. Nature, however, remains the consummately innovative and prolific
producer of useful substances. The biochemical machinery of plants and animals far exceeds that
which man or machines can generate. Nature also provides the finest combinatorial chemists in
the form of her most diverse class of organisms: the insects. The myriad phytochemicals (such as
alkaloids and flavonoids) often serve as chemoattractants or chemorepellants. There is an evolu-
tionary chess game that exists between plants and insects (or between any two organisms that have
an ecological relationship). When a herbivore, such as an insect, feeds on a plant, natural selection
favors the plants with defenses: chemical (e.g., alkaloids) or physical (e.g., thorns). The herbivorous

insects digest, metabolize, and transform the phytochemicals to their own advantage. Occasionally
these insect-modified substances also serve useful functions for humans. Insect-modified products
used in dermatology include silk sutures made from threads that the silkworm (Bombyx mori)
makes from mulberry leaves (Morus spp., Moraceae); cantharone for the treatment of warts from
blister beetles (Cantharus vesicatoria); mucicarmine for histology made from excreta that the
cochineal bug (Dactylopius spp.) deposits on its host plant, the nopal cactus (Nopalea, Cactaceae);
beeswax used in some topical preparations, and honey once used to clean deep ulcers. The full
opportunities afforded by other insect-modified substances have not been well explored. Until
recently, we have rarely capitalized on the biochemical abilities of insects. Other than the medical
uses listed previously, we know that some honeys have psychoactive properties. Bees transfer traces
of phytochemicals from the nectar of psychoactive plants.42 Medicine Man, a 1992 movie starring
Sean Connery, elaborated on this theme with the story of a serendipitous anticancer treatment that
was extracted from an nectar-feeding insect inadvertently blended into an Amazonian herbal remedy.
Vertebrate sources also provide a number of natural products regularly used in conventional
dermatology. Examples include injectable bovine collagen, glycerin from animal fat, lanolin from
sheep’s wool, suture made from sheep intestines (catgut), and sodium morrhulate for sclerotherapy
from cod liver oil.
The cosmetic industry has incorporated dozens of animal-derived products into creams, lotions,
emollients, polishes, shampoos, and especially into anti-aging products including collagen from
shredded calfskin, elastin from bovine neck ligaments, hyaluronic acid from a variety of bovine
and avian organs, oils from bird fat, and keratin from bovine, ovine, and porcine sources. More
mysterious ingredients include extracts from mammalian brains, placentae, amniotic fluid, and
pancreases that are used in some cosmeceutical preparations.43,44
2.8 THE FUTURE OF NATURAL PRODUCTS IN DERMATOLOGY

Every month’s scientific publications report various natural products that have pharmacologic
activity in vivo or in vitro. Some of these report early investigations; others describe clinical trials.
Nevertheless, most of these will not reach the commercial market as the overall success ratio of
tested products to marketed products is very low. Recent reports include a fern extract with possible
application in the treatment of vitiligo; a birch extract in the treatment of melanoma; castor bean
extract in the treatment of cutaneous T-cell lymphoma; and a coffee bean extract in the treatment
of HIV infection.45-48
Another promising endeavor is to use plant cell cultures to produce recognized or novel
phytochemicals. A novel way to administer vaccines to people is via genetically engineered food
plants such as the potato or banana. Oral administration is a practical way to immunize patients.49
Measles, chickenpox, diphtheria, and tetanus are examples of vaccine-preventable diseases in which
the skin figures prominently in either the disorder or its acquisition.
The role of vitamins is changing from protection from deficiency diseases to now consider a
more active role as antioxidants 50 in which vitamins protect not only from their respective deficiency
diseases but serve as antioxidants to protect from aging and degenerative conditions. A number of
cosmeceutical preparations include Vitamins A, B complex, C, and E.51
2.9 HERBAL MEDICINES, BOTANICEUTICALS, AND

ENTREPRENEURS
There is a burgeoning commercial market for herbal remedies known as botaniceuticals. The
manufacturers of these products vaunt them for one’s health and appearance. No regulatory agency
has established a definition for botaniceuticals and the Dietary Supplement Health and Education
Act (DSHEA) prevents the United States Food and Drug Administration from regulating most of

these products as long as the manufacturer does not claim prevention, diagnosis, treatment, or cure
of a disease. The manufacturers’ claims of safety and efficacy, often stated evasively, need more
critical examination by both the target market and by health agencies.52 The claims of efficacy that
accompany many herbal medicines are impressive but the research substantiating them, regrettably,
is not.52 An example of this is topical creams that contain plant-derived methylxanthines (caffeine
and theophylline) that purportedly reduce “cellulite.”53 Furthermore, the notion that natural products
are inherently purer or safer than manufactured products is false54 and is aimed at a wishful but
naïve and credulous market. There are few assurances for the purity and consistent potency of the
herbal medications, hence innumerable episodes of toxicities from their use. Harm may arise from
impurities (contamination, intentional adulteration, and misidentification),30,31,54-56 but most prob-
lems are caused by the intrinsic pharmacological activity of the herbs.57 Then again, phytomedicines
in the conventional pharmacopoeia have their hazards as well when consumed in the wrong dose
or manner. Digitalis can be toxic as can cocaine, opium, and virtually every plant product. Phar-
macologically active plants (such as tobacco) and plant derivatives (such as alcohol) are among
the main threats to human health today. The Ames test shows us that seemingly innocuous plants,
even lettuce, have mutagenic properties.58 Herbal preparations, sold under the guise of a natural
beneficence may not be as innocent as some would have us believe.57
Many physicians (the author included) believe that there should not be two forms of medicine,
one conventional and one alternative.52 Most of what is considered alternative medicine has never
been tested in a rigorous scientific and intellectually honest manner. If an alternative technique or
method or remedy can be shown to be safe and effective, it would then be embraced as mainstream
medicine. In the case of natural products, most practitioners with biomedical training believe an
important step is to extract and identify the pharmacologically active ingredient (or ingredients) to
better understand its actions and the insights it might offer for disease pathophysiology, prevention,
and treatment.
2.10 CONSERVATION, BIODIVERSITY, AND PRESERVATION OF

INDIGENOUS CULTURES
Many in the medical community believe it is incumbent on us for many reasons to take an active
role in conservation concerns.2,59-61 There are estimated 10–20 million species of plants, animals,
and other organisms on earth.62 Perhaps only one tenth of these species, however, have been
identified and named. A much smaller fraction of these has been assessed for economic utility,
such as possible medical contributions. An alarming concern is that one-half of all species may
become extinct in the next one-half century—possibly destroying any opportunity that these will
become economically useful. How then can we improve the chances of survival for the remaining
millions of species? Population biology and ecological principles show that our pursuit should not
be merely to save individual species but to save entire environments. An appropriate metaphor is
that organisms are threads in a delicate fabric of life; disruption of one thread may cause the entire
fabric to unravel and sunder. One cannot simply preserve fragments of an ecosystem; scattered bits
of remnant habitats, such as small parks, are less able to sustain species diversity and environmental
complexity than are a smaller number of larger preserves.63 At first glance, this may appear to be
commercially untenable, but economic analyses have shown that sustainable enterprises in preserved
lands (vs. timber, mining, and the ruinous effects of single-cycle tropical agriculture) can generate
more revenue than intensive use—and its consequent destruction—of habitats.61 Consequently one
should pursue the preservation of entire environments, not to simply focus on selected economic
or charismatic species alone.
In those days Hezekiah was sick and near death … . Then Isaiah said, “Let them take a lump of figs
and apply it as a poultice on the boil, and he shall recover.” Isaiah 38:21

2.11 REFERENCES
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Development of Modern Medicine, Swain T., Ed., Harvard University Press, Cambridge, 1972, 103.
2. King, S. R., Carlson, T. J., and Moran, K., Biological diversity, indigenous knowledge, drug discovery
and intellectual property rights: creating reciprocity and maintaining relationships, J. Ethnopharma-
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3. Balandrin, M. F., Klocke, J. A., Wurtele, E. S., and Bollinger, W. H., Natural plant chemicals: sources
of industrial and medicinal materials, Science, 228, 1154, 1985.
4. Marwick, C., Nature’s agents help heal humans—some now take steps to reciprocate, JAMA, 279,
1679, 1998.
5. Eisenberg, D. M., Kessler, R. C., Foster, C., Norlock, F. E., Calkins, D. R., and Delblanco, T. L.,
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328, 246, 1993.
6. Lipp, F. J., The efficacy, history, and politics of medicinal plants, Altern. Ther., 2, 3641, 1996.
7. Cox, P. A. and Balick, M. J., The ethnobotanical approach to drug discovery, Sci. Am., 82, 1994.
8. Davis, W., One River: Explorations and Discoveries in the Amazon Rain Forest, Simon & Schuster,
New York, 1996.
9. Anon., Pharmaceuticals from plants: great potential, few funds, Lancet, 343, 1513, 1994.
10. Mitchell, J. and Rook, A., Botanical Dermatology: Plants and Plant Products Injurious to the Skin,
Greengrass, Vancouver, BC, 1979.
11. Benezra, C., Ducombs, G., Sell, Y., and Foussereau J., Plant Contact Dermatitis, B. C. Decker, Toronto,
1985.
12. Lovell, C., Plants and the skin, Blackwell, London, 1993.
13. Mukhtar, H. and Agarwal R., Skin cancer chemoprevention, J. Invest. Dermatol. Symp. Proc. 1, 209, 1996.
14. Morris, K., Celebrating the vegetable kingdom, Lancet, 352, 660, 1998.
15. Norton, S. A., The useful plants of dermatology. V. Capsicum and capsaicin, J. Am. Acad. Dermatol.,
39, 626, 1998.
16. Markovits, E. and Gilhar, A., Capsaicin—an effective topical treatment in pain, Int. J. Dermatol., 36,
401, 1997.
17. Norton, S. A., The useful plants of dermatology. I. Hydnocarpus and chaulmoogra, J. Am. Acad.
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18. Miller, R. A., Podophyllin, Int. J. Dermatol., 24, 491, 1985.
19. Helmbold, P., Hegemann, B., Holzhausen, H.-J., Klapperstück, T., and Marsch, W. C., Low-dose oral
etoposide monotherapy in adult Langerhans cell histiocytosis, Arch. Dermatol., 134, 1275, 1998.
20. Norton, S. A., The useful plants of dermatology. III. Dioscorea, Strophanthus, and corticosteroids, J.
Am. Acad. Dermatol., 38, 256, 1998.
21. Wallace, D. J., The history of antimalarials, Lupus, 5 (Suppl 1), S2, 1996.
22. Fitzpatrick, T. B. and Pathak, M. A., Historical aspects of methoxsalen and other furocoumarins, J.
Invest. Dermatol., 32, 229, 1959.
23. Benedetto, A. V., The psoralens: an historical perspective, Cutis, 20, 469, 1977.
24. Duke, J. A., Bishop’s weed (Ammi majus L., Apiaceae), Econ. Bot., 42, 442, 1988.
25. Lewis, G. P., Legumes of Bahia, Royal Botanic Gardens, Kew, 1987, 215.
26. Ashton, R. E., Andre, P., Lowe, N. J., and Whitefield, M., Anthralin: historical and current perspectives,
J. Am. Acad. Dermatol., 9, 173, 1983.
27. Mackrides, P. S. and Shaugnessy, A. F., Azelaic acid therapy for acne, Am. Fam. Phys., 54, 2457, 1996.
28. Atherton, D. J., Sheehan, M. P., Rustin, M. H. A., Whittle, B., and Guy, G., Treatment of atopic
eczema with traditional Chinese medicinal plants, Pediatr. Dermatol., 9, 373, 1992.
29. Koo, J., Traditional Chinese medicine for psoriasis in the US?, Natl. Psoriasis Found. Bull., 26(6),
4, 1995.
30. Horowitz, R. S., Feldhaus, K., Dart, R. C., Stermitz, F. R., and Beck, J. J., The clinical spectrum of
jin bu huan toxicity, Arch. Intern. Med., 156, 899, 903.
31. Ernst, E., Harmless herbs? A review of the recent literature, Am. J. Med., 104, 170, 1998.
32. Skolnick, A. A., China is eager to export its traditional medicine, but some Chinese scientists urge
more skepticism, JAMA, 276, 1707, 1996.

33. Wolf, R. and Ruocco, V., Nicotine for pyoderma gangrenosum, Arch. Dermatol., 134, 1071, 1998.
34. Ross, E. V., Jr., Badame, A. J., and Dale, S. E., Meat tenderizer in the acute treatment of imported
fire ant stings, J. Am. Acad. Dermatol., 16, 1189, 1987.
35. Laidet, B. and Letourner, M., Enzymatic debridement of leg ulcers using papain, Ann. Dermatol.
Venereol., 120, 48, 1993.
36. Klein, A. D. and Penneys, N. S., Aloe vera, J. Am. Acad. Dermatol., 18, 714, 1988.
37. Fisher, A. A., Contact Dermatitis, 3rd ed., Lea and Febiger, Philadelphia, 1986, 167.
38. Norton, S. A., The useful plants of dermatology. II. Haematoxylum and haematoxylin, J. Am. Acad.
Dermatol., 34, 149, 1996.
39. Norton, S. A., The useful plants of dermatology. IV. Alizarin red and madder, J. Am. Acad. Dermatol.,
39, 484, 1998.
40. Leiner, I. E., Seed hemagglutinins, Econ. Bot., 18, 27, 1964.
41. Chaplin, A. J., Tannic acid in histology: an historical perspective, Stain Technol., 60, 219, 1985.
42. Ott, J., The Delphic bee: bees and toxic honeys as pointers to psychoactive and other medicinal plants,
Econ. Bot., 52, 260, 1998.
43. Draelos, Z. D., The use of biological additives in cosmetic products. I., Cosmet. Dermatol., 7(2), 16, 1994.
44. Zemstov, A., Gaddis, M., and Montalvo-Lugo, V. M., Moisturizing and cosmetic properties of emu
oil: a pilot double blind study, Austral. J. Dermatol., 7, 159, 1996.
45. Pisha, E., Chai, H., Lee, I. S., Chagwedera, T. E., Farnsworth, N. R., Cordell, G. A., Beecher, C. W.,
Fong, H. H., Kinghorn, A. D., and Brown, D. M., Discovery of betulinic acid as a selective inhibitor
of human melanoma that functions by induction of apoptosis, Nat. Med., 1, 1046, 1995.
46. Gonzalez, S., Pathak, M. A., Cuevas, J., Villarrubia, V. G., and Fitzpatrick, T. B., Topical or oral
administration with an extract of Polypoidum leucotomos prevents acute sunburn and psoralen-induced
phototoxic reactions as well as depletion of Langerhans cells in human skin, Photodermatol. Photo-
immunol. Photomed., 13, 50, 1997.
47. O’Toole, J. E., Esseltine, D., Lynch, T. J., Lambert, J. M., and Grossbard, M. L., Clinical trials with
blocked ricin immunotosins, Curr. Top. Microbiol. Immunol., 234, 35, 1998.
48. Vlietinck, A. J., De Bruyne, T., Apers, S., and Pieters, L. A., Plant-derived compounds for chemo-
therapy of human immunodeficiency virus (HIV) infection, Planta. Med., 64, 97, 1998.
49. Wise, J., Plant based vaccines move a step closer, BMJ, 316, 1333, 1998.
50. Keller, K. L. and Fenske, N. A., Uses of vitamins A, C, and E and related compounds in dermatology:
a review, J. Am. Acad. Dermatol., 39, 611, 1998.
51. Mestel, R., Beautiful skin from A to E, Health, 12(7), 72, 1998.
52. Angell, M. and Kassirer, J. P., Alternative medicine: the risks of untested and unregulated remedies,
N. Engl. J. Med., 339, 839, 1998.
53. Dickinson, B. I. and Gora-Harper, M. L., Aminophylline for cellulite removal, Ann. Pharmacother.,
30, 292, 1996.
54. Slifman, N. R., Obermeyer, W. R., Aloi, B. K., Musser, S. M., Correll, W. A., Jr., Cichowicz, S. M.,
Betz, J. M., and Love, L. A., Contamination of botanical dietary supplements by Digitalis lanata, N.
Engl. J. Med., 339, 806, 1998.
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56. Drew, A. K. and Myers, S. P., Safety issues in herbal medicine: implications for the health professions,
Med. J. Austral., 166, 538, 1997.
57. Huxtable, R. J., The myth of beneficent nature: the risks of herbal preparations, Ann. Intern. Med.,
117, 165, 1992.
58. Ames, B. N., Dietary carcinogens and anticarcinogens: oxygen radicals and degenerative diseases,
Science, 221, 1256, 1983.
59. Plotkin, M. J., Conservation, ethnobotany, and the search for new jungle medicines: pharmacognosy
comes of age … again, Pharmacotherapy, 8, 257, 1988.
60. Bentz, G. D., Medicine’s stake in preserving the tropical rain forest, South. Med. J., 83, 491, 1990.
61. Fellows, L., What are the forests worth?, Lancet, 339, 1330, 1992.
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York, 1996.

Section I
Phytodermatoses
3 Etiology of Adverse Reactions
to Plants
Georges Ducombs
CONTENTS
3.1 Introduction
3.2 Clinical Aspects
3.2.1.1 Mechanical Causes
3.2.1.2 Chemical Causes
3.2.2 Allergic Contact Eczema
3.2.3 Phototoxic Dermatitis
3.2.4 Photoallergic Dermatitis
3.2.5 Contact Urticaria
3.2.6 Erythema-Multiform-Like Eruptions
3.3 Important Plant Species
3.3.1 Alliaceae
3.3.2 Alstromeriaceae
3.3.3 Amaryllidaceae
3.3.3.1 Tulipa gesneriana L
3.3.4 Anacardiaceae
3.3.5 Asteraceae (Compositae)
3.3.5.1 A Panorama of Contact Dermatitis Owing to Compositae
(Asteraceae)
3.3.5.1.1 Ambrosia p.p. or Ragweed
3.3.5.1.2 Anthemis Species
3.3.5.1.3 Arnica p.p. Species
3.3.5.1.4 Artemisia p.p. Species
3.3.5.1.5 Chrysanthemum p.p. Species
3.3.5.1.6 Cichorium p.p. Species
3.3.5.1.7 Cynara p.p. Species
3.3.5.1.8 Dahlia Variabilis (Willd) Desf., Dahlia
3.3.5.1.9 Inula helenium L.
3.3.5.1.10 Lactuca sativa L., Lettuce
3.3.5.1.11 Parthenum hysterophorus
3.3.5.1.12 Saussurea costus
3.3.5.1.13 Miscellanenous Contact Dermatitis Causing Asteraceae
3.3.6 Primulaceae
3.3.7 Ginkgoaceae
3.3.8 Lichens
3.3.9 Liverworts

3.3.10 Woods
3.3.10.1 Native Woods
3.3.10.1.1 Turpentine
3.3.10.1.2 Colophony
3.3.10.2 Tropical Woods
3.3.10.2.1 Bignoniaceae
3.3.10.2.2 Cupressaceae
3.3.10.2.3 Fabaceae (Papilionaceae)
3.3.10.2.4 Moraceae
3.3.10.2.5 Sapotaceae
3.3.10.2.6 Sterculiaceae
3.3.10.2.7 Verbenaceae
3.3.10.2.8 Meliaceae
3.4 References
3.1 INTRODUCTION
It is difficult to evaluate the frequency of phytodermatosis. In Sweden, 1752 patients suffering from
professional dermatosis were systematically tested with vegetal allergens: 8 percent of women and
6 percent of men reacted positive to one or more of them.1 Nevertheless, the investigation did not
enable us to understand the relevance of these positive tests compared with the clinical history of
each patient tested. We can state, nonetheless, that these positive results were irrelevant with regard
to the clinical history of the patients.
Dermatosis of plant origin are attributable to different mechanisms. They may be owing to a
contact irritation or allergic reaction. The simultaneous exposure to sun and plants can lead to a
phototoxic or a photoallergic reaction. These dermatoses occur when there is a direct contact with
the plant, a part of it, or even with an extract (industrial product, pharmaceutical, or cosmetic). The
patients more at risk are florists, farmers, gardeners, foresters, and wood-workers. A simple walk
or leisure activities in the forest (shooting, fishing, many sports) may be risky.
3.2 CLINICAL ASPECTS

3.2.1.1 Mechanical Causes
The shape of the plants could in itself explain some of the problems caused by contact. Prickly
and cutting-leafed plants can lacerate the skin and leave wounds and many scratches. Cactus
wounds, for example, may cause secondary infections. The bristles and barbs (trichomes and
glochides) of some plants and their leaves, stems, and seeds often have a pointed and stinging
composition that can provoke papules, prurigo, and urticaria by penetrating the skin. These tri-
chomes may even break down and remain in the skin which creates foreign body granulomes.
3.2.1.2 Chemical Causes
Cutaneous plant reactions are mostly of a chemical nature. Acids (acetic, citric, formic, malic, and
oxalic), glucosides, and proteolic enzymes are frequently responsible for the irritation (lemon juice,
onions, hyacinth, and tulip). Urticant reactions and even edematous stomatitis can occur with people
who have handled or chewed by mistake the leaves of Diffenbachia: the crystals of oxalate contained
by the plant can provoke a massive, rapid, and acute irritation, within a few hours, sometimes less.
Chronic irritation occurs with repeated contact with the irritant factor or on skin already affected.

The place where the dermatosis appears is linked to the contact point with the plant: hands, forearms,
mucous membranes, perioral regions, and buttocks. The clinical aspect of the irritation can have
several appearances (polymorphic): dryness of the skin, cracks, hyperkeratotic, inflammatory reac-
tions with edema, erythema, papules, and vesicles. When the irritant substance is strong (e.g., the
latex of Euphorbia), we can see bullae, superficial necrosis, or ulcers. The finger pulp can be dry,
keratotic, and cracked, which may induce a problem of a differential diagnostic connected with
allergic pulpites.
3.2.2 ALLERGIC CONTACT ECZEMA

Allergic contact eczemas caused by plants have different clinical aspects depending on the particular
exposure circumstances and the allergens responsible. In certain cases, it may be a classic allergic
contact dermatitis affecting exposed areas such as the forearms, eyelids, and sometimes even the
genital area, which may become infected by the hands or clothes. The initial erythemato-vesicular
rash may change into an erythroderma as is the case with Frullania dermatitis.
Chronic eczema such as tulip finger is another possibility. This a dry eczema-fissured hyperk-
eratotic and painful restricted to the pulp of the fingers and the subungueal area with patients who
are tulip pickers. Other plants may generate a similar pathology: garlic, alstroemeria, narcissus,
daffodils, and so on.
An airborne mechanism is another factor of many eczemas caused by plants. Hjorth was the
first to describe this airborne contact dermatitis as a kind of dry lichenified dermatosis caused by
pollen conveyed by the wind. This type of airborne dermatitis must be distinguished from photo-
dermatoses which usually spares the skin behind the earlobes. In the same way, people sensitive
to Frullania can become dermatitic simply by taking a walk through the forest. Other plants can
also be responsible for airborne eczema. In California, firemen become sensitized to poison ivy
through the smoke of forest fires.
3.2.3 PHOTOTOXIC DERMATITIS

In 1926, Oppenheim described dermatitis bullosa striata (known as meadow dermatitis).2 It occurs
in particular circumstances. A bath followed by exposure to the sun and then contact with wet grass
provokes an erythemato-bullous pruriginous dermatitis. The reaction on the skin may reproduce
the imprint of the plant with the veins of the leaves on the exposed skin.
Taking a bath is not a prerequisite. It also happens with sweat and prevailing humidity. The
normally linear and vesiculo-bullous aspect of the lesion is a sure sign of the phototoxic nature of
the dermatosis. Heating follows a period of pigmentation of the skin.
Another form of phototoxic dermatitis has been described as berlocque dermatitis. Perfumes
and cosmetics containing photodynamic plant extracts can be the cause of it. A typical trinket
dermatitis begins with an erythema on the place where the perfume has been applied to the skin,
irradiated a second time by the sun. The erythema is replaced by a pigmentation which can remain
for months.
Phototoxic dermatitis is the result of the interaction of certain chemical substances: furocou-
marins or psoralens.3-4
3.2.4 PHOTOALLERGIC DERMATITIS

Photoallergic dermatitis is rather unusual compared to phototoxic dermatitis. These dermatoses are
owing to the plants themselves or their commercial derivatives. Concerning this last point, it is
often difficult to make a certain diagnosis. One has to weigh the difference in diagnosis between
an airborne contact allergic eczema, one not situated on uncovered parts of the body, a photo-
aggravated allergic dermatitis, and a phototoxic phytodermatosis.

Dermatitis caused by Compositae or Asteraceae, Hepaticae (frullanoids), Lauraceae or lichens
simulate down to the last detail the characteristics of a dermatitis caused by photosensitivity:
uncovered parts of the body affected, possible irradiation by the sun, and even airborne dispersal
of the allergens and photo-allergens. In the case of Frullania, it is mainly a case of photo-aggravation
rather than a real photo-allergy. A plant such as Ami majus L. has both phototoxic and photo-
allergenic properties. In India, Parthenium hysterophorus L. has caused cases of photosensitivity.
In Scandinavia, people who harvest lichen are exposed to the same risk. Finally, the relationship
between allergic phytodermatitis and persistent light reaction syndrome has been described in
people exposed to plants of the Asteraceae family and lichens.
3.2.5 CONTACT URTICARIA

The formic acid contained in the hairs of nettles causes a rash through the simple release of
histamine. Balsam of Peru and cinnamic derivatives are responsible for both allergic eczemas and
contact urticaria. The rash that was initially confined to the area of contact can spread over the
whole skin. An airborne urticaria caused by hyacinth bulb peelings, accompanied by breathing
difficulties, has been observed in a patient whose job is to sort bulbs and hyacinths.
3.2.6 ERYTHEMA-MULTIFORM-LIKE ERUPTIONS

Erythema-multiform-like eruptions have been described when in contact with primroses, tropical
woods such as rosewood, or Pao fero (iron wood or Machaerium scleroxylon Tul.) imported from
Bolivia. We have seen a similar eruption owing to contact with Olon wood that is a type of satinwood
(or Fagara heitzii Aubrév and Pellegrin, family of the Rutaceae). The first case concerns a woman
who, after having helped her cabinetmaker husband handle some wood, showed a bullous pseudo-
pemphigoid type reaction over the exposed skin area. The second patient, a cabinetmaker, showed
a rash of a nonbullous polymorphous erythema type after having regularly handled Olon wood.
Patch tests were of the eczema type and the contact mode was both direct and airborne.
3.3 IMPORTANT PLANT SPECIES

It is not possible to describe the total panorama of plants liable to provoke contact dermatitis. We
have, therefore, selected those that are most often found in occupational and nonoccupational
activities.
3.3.1 ALLIACEAE
Allium sativum L., garlic, is used in cooking, folk medicine, and pharmaceutical products. The first
dermatitis dates from 1950 by Edelstein concerning dermatitis on the wrist of a meatmincer
operator.5 Garlic is a contact sensitizer, but Bursk does not exclude an irritant potential.6 In Portugal,
garlic is a common cause of pulpitis.7 Bursk6 quoted cross sensitization between garlic and onion,
but Bleumink and Nater8 have since questioned the authenticity of cross-reaction between garlic,
onion, and tulip bulbs, or any other Liliaceae. Papageorgiou et al. have identified the allergen and
tested diallyldisulphide in man and the guinea pig.9
3.3.2 ALSTROEMERIACEAE
This family was formerly classified with the Amaryllidiaceae. Species most frequently involved
include: Alstroemeria aurantica Don (syn. A. aurea) and A. ligtu L.
Alstroemeria hybrids are increasingly popular in the cut-flower trade. Horticulturists and florists
are at risk of both irritant and allergic contact dermatitis. Handling of cut flowers provokes a
dermatitis affecting mainly the fingertips that is similar to tulip fingers. Björker described the case

of a woman with occupational dermatitis from alstroemeria.10 He also noted depigmentation of the
area of a previous dermatitis. Patch tests with alstroemeria can lead to depigmentation. Hausen et
al. determined the presence of tuliposide A in the cultivated species of Alstroemeria ligtu L.11 Only
a patch test concentration of 0.01 percent can be considered safe, because the sensitizing potential
of this allergen is high and it can provoke active sensitization. Santucci et al. have isolated 6-
tuliposide A from flowers.12 A study of 50 workers in a floriculture center allowed the incidence
of contact dermatitis from alstroemeria to be evaluated. In this study, three subjects gave positive
reactions to aqueous and ethanolic extracts of cut flowers, stems, and leaves. 6-Tuliposide A at
0.01 percent and D-methylen-J-butyrolactone at 0.001 percent were positive in the same way as
the allergens of tulips.12 Certain patients can be affected by dermatitis caused by both families; but
cross-reaction is not always present.
3.3.3 AMARYLLIDACEAE
Narcissus sp., narcissus, jonquil, daffodil, and so on, native to central Europe, the Mediterranean,
and Asia, are extensively cultivated, especially Narcissus pseudonarcissus L., N. jonquilla L.,
and N. poeticus L. Lily rash owing to the narcissus species is regularly observed in gardeners,
bulb sorters, plant growers, and florists.13 Gude et al. identified in N. pseudonarcissus L. two
fractions capable of inducing hypersensitivity in animals (masonin and homolycorin acted as
elicitors).14
3.3.3.1 Tulipa gesneriana L.
Garden tulips are derived from an unknown hybrid complex. The numerous different forms and
varieties have been obtained by selection and crossing of existing hybrids. Dermatitis among bulb
handlers and florists is an important and common hazard for tulip growers. Irritant and allergic
contact dermatitis occurs. Bulb sorters, packers, and collectors develop a characteristic dermatitis
called tulip fingers: a painful, dry, fissured hyperkeratotic eczema, at first underneath the true margin
of the nails and periungual region.13 Sometimes an irritable dermatitis spreads to the face, hands,
forearms, and genital region. Tulip fingers is common in Holland and in other parts of Europe. The
majority of the allergen is found in the epidermis of the bulb, but contact dermatitis is also possible
from handling cut flowers.
The allergen responsible for tulip dermatitis has been shown to be a glucose derivative tuliposide
A that gives (by enzymatic or acid-catalyzed hydrolysis) tulipalin A, D-methylen-J-butyrolactone).
Tulips contain a second glucoside, tuliposide B. Slob reported that patients sensitive to tulip react
to tuliposide A and tulipalin A but not to tulipalin B.15 However, Barbier and Benezra have shown
that E-hydroxy-D-methylen-J-butyrolactone is sensitizing in guinea pigs and cross-reacts with
unsubstituted tulipalins.16
Patch testing can be performed with the epidermis of the bulb. Hjorth recommended extracts
of the variety Apernoon. Bleumink and Nater reported cross-reaction between onion, garlic, and
tulip bulbs. True cross sensitization does not seem to be proven.17
3.3.4 ANACARDIACEAE
This family includes 600 species in its 60 genera and is probably more the cause of dermatitis than
all of the other plant families combined. Among members of this family, certain ones have an
economic importance as foods, drugs, oils, resins, varnishes, dyes, tans, and so on. Most occur
naturally in the tropical regions; some species occur in the Mediterranean regions, in eastern Asia,
and in America. They are cultivated in botanical gardens, and some even in private gardens.
The taxonomy of Anacardiaceae is difficult and confused. A new classification considers the
species Rhus toxicodendron within a genus Toxicodendron. There are numerous synonyms for each
species.

Rhus toxicodendron L., Toxicodendron radicans L., poison ivy, poison vine, markweed, and
creepers, are native to eastern North America. About 50 to 60 percent of the American population
is affected by allergic contact dermatitis to poison sumac.18 Dermatitis usually occurs on the fingers,
forearms, and legs, and sometimes affects the genitals. The dermatitis is characterized by papules,
vesicles, exudation, and bullae.
Rhus diversiloba Torr. and Gray is western poison oak, synonym: Toxicodendron diversiloba
Greene. This shrub is native to the west coast of North America.
Rhus quercifolia Steud. is poison oak, synonyms: Toxicodendron quercifolium (Michx) Greene,
Toxicodendron toxicodendron L. Britt., Rhus toxicodendron L. var. quercifolium Michx. This shrub
is native to North America. Clinical aspects of poison oak dermatitis is similar to poison ivy
dermatitis.
Rhus vernix L., poison sumac: synonyms Toxicodendron vernix (L) kuntze, Toxicodendron
pinnatum Mill, Rhus venenata DC, is a shrub or small tree, native to eastern North America. It
gives the same dermatitis as poison ivy.
Rhus verniciflua Stokes, Japanese lacquer tree or varnish tree: synonym Rhus vernicifera DC.
Native to Japan and western China, it is a tree about 15 to 20 m high. It produces the famous
lacquer of Japan. This dermatitis affects areas in contact with the lacquered object.
Anacardium occidentale L., cashew nut tree, is a small tree cultivated in tropical regions. The
cashew nut contains an oil that is an irritant and sensitizing to the skin. It is used in industry in
resin, mucilage, printing ink, and so on. Children playing with raw cashew nuts can be affected by
eczema. The dermatitis also affects the pickers handling cashew nuts and the ingestion of cashew
nuts can provoke dermatitis that is sometimes generalized.
Mangifera indica L., the mango tree, is a large tropical tree. People eating the fruit can develop
an acute eczema of the face and neck from contact with the peel. Rubin et al. have described an
anaphylactic reaction after the ingestion of mango.19
Sirinivas et al. have reported 10 patients with allergic contact dermatitis from Holigarnia
feruginea.20 The genus Holigarnia is commonly found along the western coast of India. Out of ten
patients who developed dermatitis, nine showed a positive patch test reaction to a 2 percent w/v
acetone extract of the plant’s exudate.
All members of the Anacardiaceae contain pentadecyl catechols (also called urushiols). There
is the possibility of cross sensitization between different species throughout the world.21
3.3.5 ASTERACEAE (COMPOSITAE)

The largest plant family is cosmopolitan, with 20,000 known species grouped into 1,000 genera,
characterized by 4 cyclic flowers, forming extremely dense influorescences, and their anthers
adhering to each other. Taxonomy and botanical aspects were summarized by Sell et al.22
Bremer reviewed the taxonomy and tribal interrelationship of the Asteraceae.23 Asteraceae can
be divided into 12 or 13 tribes, including vegetables: lettuce, artichoke, chicory, endive, salsify,
and Jerusalem artichoke. The sunflower is cultivated for its seeds, used for cooking oil, cattle
feeding, and industrial oils.
Some Asteraceae (Compositae) provide miscellaneous products. A natural rubber constituent
(Taraxacum), dyes, medicines (Artemisia, Anthemis nobilis L., and Arnica montana L.), insecticides
[Chrysanthemum cinerariaefolium (Trev)], and spices (Artemisia dracunculus L., tarragon). Mostly,
Asteraceae are cultivated as ornamental flowers, but also include many weeds, such as thistle, a
pollutant of intensive farming, and dandelions.
Brunsting and Williams noticed that “the clinical aspects of dermatitis due to sensitivity to
ragweed are almost sufficiently clear cut to be pathognomonic.”24 The first feature is the tendency
to seasonal recurrence each year. Contact dermatitis affects farmers, horticulturists, and florists,
but also people exposed because of their occupation or hobby: cemetery workers, golfing green
keepers, telephone linesmen, game-shooters, and anglers, and even sportsmen or simply walkers.

The dermatitis is generally eczematous, rarely urticarial. Accidentally exposed subjects develop
acute eczema. Continuous occupational exposure to Asteraceae provokes acute dermatitis, with
frequent relapses, and becomes chronic and lichenified. When the dermatosis is localized to elbow
flexures or popliteal fossae, it can simulate atopic dermatitis. The eczema initially localized to the
face, hands, and genitals can become generalized as an erythrodema. Wind-borne pollen seems to
be the cause of ragweed dermatitis.25 Hjorth et al. presented a series of Danish patients with a
seasonal dermatitis of areas exposed to the light. Wind disseminated fragments of dry leaves may
be the cause of airborne contact dermatitis from Asteraceae that are not wind pollinated.26 Airborne
contact dermatitis owing to Asteraceae simulates a lichenified photodermatitis. Sharma and Kaur
reported cases of airborne contact dermatitis from Asteraceae in India: 55 out of 60 patients were
positive when patch tested with extracts of Asteraceae.27
The allergens are sesquiterpene lactones and were tabulated by Mitchell and Dupuis.28 Allergic
activity of sesquiterpene lactones is linked to the presence of an D-methylene-E-butyrolactone
group. The Asteraceae (Compositae) family is renowned for the frequency of cross-reactions, not
only between its members but also with plants of other families. For example, patients can react
to Inula helenium L. and Laurus nobilis L.
3.3.5.1 A Panorama of Contact Dermatitis Owing to Compositae

(Asteraceae)
3.3.5.1.1 Ambrosia p.p. or Ragweed

Ragweed is a herbaceous plant 30 to 180 cm high. Giant ragweed (Ambrosia trifida L.) can reach
5 m in height: A. bidentada Michx., A. elatior (or A. artemisiae folia DC short), high ragweed (or
wild tansy), and A. psilostachya DC (or western ragweed). These four species are found in North
America and in Europe. They grow on the prairies, in cultivated land, on wet soils, and along the
roadside.
Ragweed has long been known to cause allergic dermatitis by direct contact of the plant with
the skin and by airborne dissemination of pollen. It is usually a chronic dermatitis with frequent
acute exacerbations and vesicular and bullous lesions. The clinical picture can resemble atopic
dermatitis. Mitchell et al. reported the role of sesquiterpene lactones in contact dermatitis owing
to ragweed.29 Artemisiifolin and isabelin are the possible allergens.
3.3.5.1.2 Anthemis p.p. Species

Contact dermatitis is not frequently described for this species.
Anthemis arvensis L., field camomile, is a biennial or annual weed growing in fields and
wasteland—vesicular dermatitis occurs from picking the plant.
Anthemis cotula L., dog camomile, dog fennel, is found as a weed in gardens and farms. A.
cotula is responsible for blistering the skin by contact with the leaves and the flowers.
Anthemis nobilis L., camomile, is often cultivated for ornamental and medical use. A. nobilis
can cause dermatitis on the hands and feet. A wet compress with camomile applied on the eyelids
may cause dermatitis. Cross-reactions seem possible between different Anthemis and Matricaria
chamomilla L. and also other Compositae plants.
The allergens of the Anthemis species are probably sesquiterpene lactones (such as nobilin
extracted from A. nobilis L.). Fernandez de Corres et al. used extracts from A. arvensis L. and A.
cotula L. to test three patients with contact dermatitis owing to Anthemis plants.30 Extracts produced
from plants gathered in the spring show more intense reaction than extracts from plants gathered
in other seasons.
3.3.5.1.3 Arnica p.p. Species

Arnica montana L., mountain tobacco, is a herbaceous plant growing in prairies and mountainous
lands in Europe, Asia, and America. For hundreds of years, it has been extensively employed

therapeutically for sprains, bruises, painful swellings, injuries, and wounds. Tincture of arnica
extracted from the flowers or other parts of the plant is used for this purpose. Contact dermatitis
is due both to contact with the plant and to the use of the tincture. Other Arnica species are used
in popular medicines: A. longifolia Eaton, A. chamissonis Less., A. sacchalinensis Reg.31 Carabron
and helenalin have been isolated by Willuhn and Herman from A. longifolia L.32 These two
sesquiterpene lactones have been shown to be the sensitizers responsible for the occupational contact
dermatitis owing to certain Arnica species.33 Hausen used carabron successfully to sensitize three
out of five guinea pigs.
3.3.5.1.4 Artemisia p.p. Species
Artemisia include 200 species. These plants can grow in Europe, Asia, and North and South America.
Artemisia vulgaris L. contains common mugwort, motherwort, fellowherb, sailors tobacco,
greenginger, and so on. A. vulgaris, a herbaceous plant, is used in folk medicine and can provoke
contact dermatitis. A. ludoviciana Nutt34 and A. absinthium L.35 were quoted as causes of erythema-
multiform-like eruptions in a patient who applied A. vulgaris to his arm, trunk, and knee as well
as consuming some of it as a tea to cure poison oak dermatitis.
Sesquiterpene lactones have been isolated from the Artemisia species. Mitchell et al. noted that
they were all good potential sensitizers.36 Among them, ludivicin (from A. ludiviciona Nutt) was
positive in patients sensitized to Compositae.
3.3.5.1.5 Chrysanthemum p.p. Species
Chrysanthemums are widely cultivated in horticulture. The terminology is confused. Variations and
hybridizations have produced the florist’s chrysanthemum, Chrysanthemum X hortorum. Hausen
and Schulz surveyed the history of the cultivation and the composition of the chrysanthemum, and
also the clinical aspects of chrysanthemum dermatitis.37 Chrysanthemum indicum L. and C. mori-
folium Ram. are most often incriminated. Leaves and flowers are the most sensitizing parts.38 In
northwest Germany, C. indicum is the principal cause of occupational dermatitis. Hausen and Schulz
reported 40 cases owing to chrysanthemums.39
Contact dermatitis affects the face, hands, and forearms. Frain-Bell et al. evoked a possible
photosensitization.40 The allergens are clearly sesquiterpene lactones.41 C. indicum contains arteg-
lasin-A (present also in Artemisia ludoviciana Nutt). The presence of an alantolactone is not clear.
The flower can be tested as is. Cross-reaction is possible with other plants of the Compositae family.
3.3.5.1.6 Cichorium p.p. Species
Cichorium endiva L. (common endive) is cultivated outdoors with roots and leaves and in green-
houses after eliminating the leaves.
Cichorium intybus L. (chicory), a herbaceous plant, grows along pathways and roadsides and
in uncultivated soils. Selected species are cultivated in salads (C. foliosum).
The roasted roots are used as a coffee substitute (chicory) and as medicine (laxative and
purgative properties). Greengrocers and supermarket workers can be affected by allergic contact
dermatitis of the face, forearms, and hands. Immediate42 and delayed dermatitis43 have been
reported. Chicory sap can also cause irritation. Leaf, as is, and extracts of leaves can be used for
testing. Krook quoted cross-reactions between Cichorium species and Lactuca. Lactucin and lac-
tucopicrin, sesquiterpene lactones were isolated from Cichorium.
3.3.5.1.7 Cynara p.p. Species
Cynara species are herbaceous plants native to Mediterranean regions and include the artichoke
(Cynara scolymus L.) and the cardoon (C. cardunculus L.). The artichoke is cultivated for the
consumption of its leaves and heart. It is also used for its diuretic and reputed aphrodisiac properties,
and is a treatment used for liver and spleen diseases. Gougerot,44 Vallet,45 and Burry et al.46 described
allergic reactions owing to contact with the artichoke. Artichoke pickers, market gardeners, and
workers in canning factories can be affected by contact dermatitis on the hands and face. Patch

testing is possible with certain other Asteraceae. The allergen is probably a sesquiterpene lactone
(cynaropicrin?).
3.3.5.1.8 Dahlia variabilis (Willd) Desf., Dahlia
Dahlia hortensis is a herbaceous plant native to Mexico is cultivated for its decorative properties.
Contact dermatitis from a dahlia seems to be rare. Calnan reported two cases.47 In the first case, a
female gardener presented an eczema of the face, hands, and arms, including the perioral areas.47
The second case affected a gardener’s assistant. Vryman previously described a case in which a
young gardener showed dyshidrosis of the palms and eczema of the face.48 Patch tests were
performed with the leaf or tuber as is. Cross-reactions seem possible with the chrysanthemum.
3.3.5.1.9 Inula helenium L.
Inula helenium L., elecampane, horse-heal, elfdock, and so on is native to Central Asia and is
naturalized in Europe, Asia Minor, Japan, and North America. I. helenium grows along rivers,
roadsides, edges of forests, and mountainous regions. It is cultivated as a medicinal plant. Roots
contains inulin, used as a vermifugal, febrifugal medicine that is also stimulating to the stomach.
Allergic contact dermatitis owing to the plant itself seems rare. Accidental sensitization is reported.49
I. helenium contains sesquiterpene lactones, among which alantolactone and isoalantolactone are
known sensitizers.50,51 Patients allergic to Frullania or laurel (Laurus nobilis) react to alantolactone
and isoalantolactone.52 People sensitized to Chrysanthemum also react to this lactone.53
3.3.5.1.10 Lactuca sativa L., Lettuce
Lactuca sativa L. is cultivated as a vegetable in several varieties. Vail and Mitchell54 and Friis et
al.55 reported cases of contact dermatitis owing to lettuce. Allergic reactions affect the face,
forearms, and hands in grocers and lettuce packers. Krook reported an occupational case and
immediate reaction confirmed by scratch tests.56 Lettuce dermatitis seems to be associated with
endive dermatitis without true cross sensitization. The allergen is probably a sesquiterpene lactone
(lactopicrin).
3.3.5.1.11 Parthenum hysterophorus
Parthenum hysterophorus L. (Congress grass, feverfew, and Santa Naria) is native to South America
and West India. This weed grows in South and North America. It was accidentally introduced into
India producing severe and sometimes fatal dermatitis.
In India, P. hysterophorus L. causes allergic diseases including asthma, fever, and dermatitis57
on the face and neck. Later, dermatitis spreads to other parts and may become generalized.58 In
Texas, contact dermatitis from P. hysterophorus L. is well known. Bhutani and Rao have evoked
photocontact dermatitis.59
Towers reviewed allergic contact dermatitis owing to P. hysterophorus L.60 Parthenin (a ses-
quiterpene lactone) contained in P. hysterophorus L. has been used by Lonkar and Yog for patch
testing at 0.1 percent in petrolatum.61 Hymenin and tetraneurin A, two other sesquiterpene lactones,
have been isolated. No cross-reaction between parthenin and hymenin exists in man62 or guinea
pigs.63 Sohi et al. have also studied the allergenic nature of P. hysterophorus.64
3.3.5.1.12 Saussurea costus
Saussurea costus (Falc) Lipsch, costus [synonym: S. lappa (Decne) Clarke] is 1 of the more than
200 species growing in temperate regions of Europe, Asia, and North America. Sometimes it is
cultivated in gardens. Costus root oil is used in cosmetics. Costus absolute is used in perfumes and
is a potent sensitizer. The haptens incriminated are the lactones costunolide and dehydrocostus
lactone.65 Guinea pigs sensitized with root oil react to these two sesquiterpene lactones. Cheminat
et al. removed these haptens with polyaminoethylstyrene.65 Patch tests can be performed with
costunolide and dehydrocostus lactone at 0.1 percent in petrolatum. Cross-reactions with other
Compositae plants and other sesquiterpene lactones have been reported.66

3.3.5.1.13 Miscellaneous Contact-Dermatitis-Causing Asteraceae
It is difficult to list all cases of contact dermatitis owing to all Compositae plants. Benezra et al.
listed those most commonly found in the medical literature: Achillea millefolium L., milfoil, yarrow;
Ambrosia bidentata Michx, lance-leaved ragweed; Chrysanthemum parthenium (L.) Bernh, fever-
few; Chrysanthemum cinerariaefolium (Trev) Vis, pyrethrum; Cynara cardunculus L., cardoon;
Franseria acanthicarpa (Hook.) Cov.; Gaillardia pulchella Foug., showy gaillardia; Helenium
autumnale L., sneezeweed; Helianthus annus L., common sunflower; Leucanthemum vulgare Lam.,
Chrysanthemum white-weed; Matricaria inodora L.; Matricaria chamomilla L., German camomile;
Tagetes minuta L., little flowered marigold; Tanacetum vulgare L.; Taraxacum officinale Weber,
dandelion; Xanthium spinosa L., spiny clotbur.67
3.3.6 PRIMULACEAE
This family has a cosmopolitan distribution. It is especially found in north temperate regions.
Primula is the more representative genus.
Primula obconica Hance., goblet-primrose, native to China, is very popular in Europe because
of its beauty, long flowering season and resilience.
Primula sinensis (Lindl) Sabine, Chinese primrose, is distinct from P. obconica Hance. Hjorth
reviewed primula dermatitis in Mitchell and Rook.68 The eyelids, face, neck, fingers, hands, and
arms are most often affected. P. obconica can also provoke conjunctivitis and an erythema-multi-
form-like eruption. The most important allergen is primin, a quinone present in the plant in highest
concentration from April to August.69 For Cairns, it is not certain that primin is the sole allergen.70
Fresh leaves can be used for patch testing. Agrup et al. proposed an extract of stem and leaves
harvested in spring. Synthetic primin is now available commercially.71 It is a powerful allergen
which must be tested at extremely low concentration (0.01 percent pet.) to avoid inducing sensiti-
zation. Fernandez de Corres observed active sensitization in 5 of 20 patients retested several months
later, after using an ether extract for patch testing.72
3.3.7 GINKGOACEAE
Ginkgo biloba L., ginkgo or ginkgo tree, is the sole survivor of the Ginkgoaceae order and can be
considered the world’s oldest living tree. Contact dermatitis from ginkgo tree fruit has been reported
in the area where female ginkgo trees grow. The ginkgo fruit is used in cooking and the children
play “marbles” with the fallen fruit. Lepoitevin et al. reported a study in guinea pigs tested with
anacardic acid and urushiol; no clear cross-reactions were observed.73
Sowers et al. reported a small epidemic of contact dermatitis among the students (35 cases) of
a preparatory school for girls, owing to contact with trampled fruit pods splashed onto the legs.74
Nakamura reported four cases with a history of contact dermatitis from ginkgo.75 Tombe et al.
reported three cases occurring in Strasbourg among Asiatic immigrants.76 Allergic reactions occur
only when the fruit is opened and the pulp extracted. The lesions consist of erythematous papules
and vesicles, with swelling in the more severe cases, affecting the face, forearms, and thighs.
Contact dermatitis can also involve the penis and scrotum.77 Ingestion of ginkgo fruit provokes
stomatitis, cheilitis, and proctitis. Becker and Skipworth recommended patch tests with fruit pulp
in 1 percent in acetone.78 Cross-reaction is possible between ginkgo fruit pulp and poison ivy, and
also between ginkgo and cashew nut.
3.3.8 LICHENS
Lichens as a class belong to the Thallophytes division. Lichens consist of a fungus and an alga in
symbiosis. Lichens are cosmopolitan and grow on walls, roofs, tree trunks, and rocks. Several species
are sensitizing. Champion described immediate allergy (asthma and urticaria) by inhalation or direct

contact with algae from lichens.79 The species most often found as causes of contact dermatitis are
Parmelia sp., Evernia prunastris (L.) Ach., Cladonia rangifera (L.) Web, and Usnea sp.
Dahlquist and Fregert reported cases of allergic contact dermatitis owing to perfumes containing
“oak moss” (a mixture of several lichens).80 Contact dermatitis usually affects foresters and lichen
pickers, and appears on the hands, forearms, and other exposed areas. Thune and Thune and Solberg
reported cases of contact dermatitis owing to lichen with a history of photosensitivity.81,82 Salo et
al. reviewed contact dermatitis from Cladonia alpestris (L.) Rab.83 Allergic reactions were seen in
nine subjects, three of whom also had positive photo patch test reactions from lichen allergens.
Airborne contact dermatitis simulating photodermatitis has been proposed as explaining the clinical
features seen in patients with lichen allergy. Lichens can be tested as is, but irritant reactions are
possible. Oak moss, present in the fragrance mix of the standard series, is a mixture of Evernia
prunastris (L.) Ach., Pseudovernia furfuraceae (L.) Zopf., and Parmelia furfuraceae (L.) Ach.
Several lichen acids (atranorin, usnic acid, evernic acid, etc.) can be tested at 0.1 percent pet. The
reality of cross sensitization is not clear. It is probably a concomitant sensitization.84,85
3.3.9 LIVERWORTS
The bryophites division comprises the Hepaticae class and Musci class (mosses). Among Hepaticae,
the order Jungermannilales comprises numerous families including Frullaniaceae.
Frullania dilatata (L.) Dum., Frullania tamarisci (L.) Dum., and F. tamarisci (L.) Dum. ss.
niqualensis, are the most aggressive species. Mitchell et al. listed 12 species in British Columbia:
only one gave a negative patch test.86 Frullania species grow on the trunk and branches of trees
(oak, beech, locust tree, poplar, etc.) and rocks. Suire and Ducombs described the method of
microscopic examination to identify the Frullania species.87
Le Coulant and Lopez first described the role of liverworts in forestry sensitization.88 Contact
dermatitis affects exposed areas of the face, neck, hands, forearms, and genitals. Sometimes
dermatitis can be generalized. Sometimes the eruption seems to be aggravated by sunlight. The
plant contains sesquiterpene lactones, among them (+) frullanolide was identified in F-dilatata (L.)
Dum., and (-) frullanolide in F. tamarisci(L.) Dum.89 Barbier and Benezra demonstrated the
stereospecificity of sensitization to one enantiomer in guinea pigs. Animals sensitized to the (+)
frullanolide do not cross-react to its mirror image (-) frullanolide and vice versa.90 Reactions to
both enantiomers in man can been explained by multiple concomitant sensitizations.91 On the other
hand, cross-reactions have been demonstrated between the sesquiterpene lactones of Laurus nobilis
L. (laurel) and Frullania.92,93
3.3.10 WOODS
3.3.10.1 Native Woods
Most of the literature on dermatosis due to wood gives greater emphasis to the importance of exotic
or foreign woods, with less mention of native woods as causes of allergic contact dermatitis. Weber
reported cutaneous sensitizations among forestry workers.94 Acacia, alder, ash, beech, birch, and
poplar are incriminated. Other trades, such as carpenters, joiners, cabinetmakers, polishers and
finishers, can be involved. It must be always be borne in mind that patients can also be in contact
with lichens or liverworts growing on the bark of trees. The mechanism of dermatitis owing to
wood can be irritant or allergic. Airborne contact dermatitis is possible with pollens borne by the
wind and also in joiners workshops from sawdust. Contact dermatitis begins on the dorsa of the
hands and forearms, eyelids, face, and neck, as well as the genitals. The scalp can be affected in
bald men. If the clothing gives poor protection, fine dust may drift inside and eczema involve the
sweaty areas of the axillae, waistband, groin, ankles, and dorsa of the feet.95 In Europe, two species
are the most often quoted: Piceae and Pinus.

Pinacea excelsa Lint. or Picea alba (L.) karst, Norway spruce, is an up to 50-m tree that grows
at altitudes of up to 2000 m in northern and central Europe, and it was introduced into North
America. It is useful for its resin and turpentine. The wood is used in the building and aircraft
industries and for heating. Contact dermatitis can occur in these different occupational or nonoc-
cupational circumstances. The face, neck, arms, hands, and forearms are affected by erythematove-
sicular lesions. Spruce can also provoke asthma. Fregert and Rorsman blame the presence of
stilboestrols in balsam of spruce.96 Patients positive to this balsam will also react to colophony and
turpentine.
Pinus p.p., the pine tree, comprises about 80 species spread throughout the northern hemisphere:
Pinus pinaster Soland or Pinus maritima Mill or cluster pine maritine pine grow in the Mediter-
ranean and Atlantic European coastal regions. Pinus pinea L., stone pine, is common in France.
Pines are known to cause dermatitis among foresters, woodcutters, and carpenters. Contact derma-
titis is often owing to contact with lichens, liverworts, or caterpillar hairs. Painters and workers in
the paper industry can also be affected.
Pine trees produce an oleoresin. A cut on the trunk yields pine resin from which turpentine
and colophony (rosin) are produced. Most dermatitis is owing to these derivatives.
3.3.10.1.1 Turpentine
Portugal, Spain, Mexico, China, and India are the major commercial sources of turpentine which
is used in the pottery industry, and in polishes, paints, varnishes, and liniments.97 Its sensitizing
power is due to its content of '3-carene, present only in the aged, oxidized oil.98 This compound
is not present in French turpentine, which is not sensitizing. Dermatitis owing to turpentine is
common in Finland and Italy. Pirilä et al.,99 Cronin,97 and Foussereau et al.100 reviewed turpentine
allergy. The face is often affected because turpentine is volatile.
3.3.10.1.2 Colophony
Colophony is the residue left after the distillation of the volatile oil from the oleoresin of the Pinus
species. There are several types: wood rosin, gum rosin, and tall oil rosin. The chemical constituents
vary considerably according to the origin.101 In most countries, Chinese colophony is mainly used
(50 percent of the market). Colophony contains resin acids (90 percent) and neutral matter
(10 percent). Of the resin acids, 90 percent are abietic acid and pimaric acid, and 10 percent are a
mixture of hydro and dehydroabietic acid.102 Abitol (hydroabietyl alcohol) has been incriminated
by Cronin and Calman103 in patch test tape dermatitis and by Dooms-Goossen et al.104 in mascara.
Foussereau et al. reported 13 cases of patients allergic to colophony with patch tests positive to
abietic acid (7/13), methyl abietate (6/13), and pimaric acid.105
Karlberg has summarized her studies based on several papers about contact allergy owing to
colophony. Clinical and chemical aspects, sources, and patch testing have been described.106
Sources of contact dermatitis from colophony are paper, surface coatings, printing inks, sol-
dering fluxes, cutting fluids, glues, adhesives, varnishes, polishes, wood wool, sawdust, tackifiers
to prevent slipping, dentistry products, cosmetics, brown soaps, violinist’s rosin and chewing gums,
and so on. Abietic acid, the classical colophony allergen, was found not to be allergenic, while its
oxidation products as well as those of abietic acid and dehydroabietic acid were identified as
allergens. The isolated allergens showed a pattern of cross-reactivity in animals experimentally as
well as among patients with known allergy to gum rosin. Hausen et al. studied the sensitization
capacity of commercial colophony products in guinea pigs.107-109 Tall oil colophony is the strongest
sensitizing material. Most of the modified products show a higher sensitizing capacity than the
resin acids themselves. Cross-reactions between the resin acids and the derivatives are uncommon.
Hausen proposed preparing a mixture containing 1 part of Chinese colophony and 2 parts of
modified colophony products (60 percent altogether). These two product derivatives should pref-
erably be a maleic-modified product and Abitol, as both possess proven sensitizing potency and

simultaneously show the highest number of positive reactions in patients with a known allergy to
modified colophony products. Hausen tested such a mixture in his standard series and confirmed
that patients with a relevant history of colophony allergy could be positive to the mix but negative
to Chinese colophony (20 percent) as usually tested in the standard series.
3.3.10.2 Tropical Woods
Hublet et al.,110 Oleffe at al.,111 Woods and Calnan,112 Cronin,113 Hausen,114 and Benezra et al.115
list and describe, with numerous references, irritation and allergy provoked by tropical woods. In
this book, Hausen also describes these effects. The skin can be damaged by the mechanical action
of bristles and splinters, by chemical irritation or sensitization, or by combinations of these
processes. Photosensitization has not been proven but may well occur in the Rutaceae and
Flindersiaceae.
The dermatitis resembles an airborne dermatitis and begins on the dorsa of the hands and
forearms, affecting the eyelids, face, and neck, as well as the genitals. Contact dermatitis affects
sawyers, carpenters and joiners, and polishers and finishers exposed to fine dust. Dermatitis from
the solid wood of finished articles is much less common, but prolonged contact with musical
instruments, bracelets, or knife handles made of rosewood can be followed by eczema. An erythema-
multiform-like reaction has also been described. Sawdust exposure can also provoke irritation of
mucous membranes, contact urticaria, nasal irritation, allergic rhinitis, conjunctivitis, systemic
syndromes, and asthma. Certain fine dusts from these woods are also responsible for nasal and
ethmoid cancers, specially in poorly ventilated workshops. Patch tests can be performed with
sawdust or extracts, or allergens when these are available.
3.3.10.2.1 Bignoniaceae
This family comprises wood sensitizing owing to the presence of quinones (lapachone, lapachol,
etc.). Peroba do campos [Paratecoma peroba (Record) Kuhlm.] and Lapacho wood [Tabebuia
avellanedae (Griseb.) Lor.] provoke eczema from contact with sawdust. See Chapter 20 by Binutu
and Cordell on Bignoniaceae.
3.3.10.2.2 Cupressaceae
Sawdust of the western (Canadian) red cedar (Thuya plicata D-Don.) causes respiratory symptoms
and contact dermatitis in wood workers. The red cedar is used for indoor and outdoor furnishings.
Thuya plicata D. Don. contains E-thujaplicin and 7-hydroxy-4-isopropyltropolone, giving pos-
itive patch tests. Reactions were also observed with thymoquinone and methylbenzoquinone.
3.3.10.2.3 Fabaceae (Papilionaceae)
Bowdichia nitida spruce, Sucupira, is used for building frameworks and joints, exterior construc-
tions, and railway sleepers. The bark and roots are used in medical products. Sucupira is known
as a sensitizer (quinones: 2,6-dimethoxybenzoquinone and bowdichione). Cross-reactions are pos-
sible with dalbergiones and also Primula.
Dalbergia latifolia Roxb., Dalbergia melanoxylon Guill. and Perr. African blackwood, and
Indian rosewood are woods that are used for making veneers for dining room and bedroom furniture,
desk accessories, walking sticks, paper knives, bracelets, necklaces, mouthpieces for flutes, and
so on.
3.3.10.2.4 Moraceae
Chlorophora excelsa (Welw) Benth and Hook., iroko (African teak), is used for general building
and railway sleepers. Dermatitis affects the hands, face, and eyelids. Chlorophorin is certainly
allergenic and may be used in petrolatum for patch testing, when available. Moist sawdust may
also be used.

3.3.10.2.5 Sapotaceae
Tieghemella heckelii (A. Chev.) Pierre, makore, is used in joinery, cabinet making, furniture, office
equipment, statuettes, the manufacture of skis, and so on. The wood is probably an irritant causing
both dermatitis and mucous membrane irritation.
3.3.10.2.6 Sterculiaceae
Mansonia altissima (A. Chev.), mansonia, is used in decoration, joinery, and cabinet making.
Workers involved in such activities can be affected by dermatitis, as well as nasal irritation and
sneezing. Sawdust is tested as is or in petrolatum. Mansonon may also be used (0.1 or 1 percent
in petrolatum).
3.3.10.2.7 Verbenaceae
Tectona grandis L. is known as Teak or Indian oak. Its timber is used in naval construction, outdoor
joineries, wheelwright works, containers for chemical products, and the wood of musical instru-
ments. Eczema and contact urticaria from teak has been described, involving the face, neck, eyelids,
arms, and genitals. Lapachol and deoxylapachol are the sensitizers, which can be tested at 1 percent
petrolatum, but moist teak and sawdust can also be tested.
Dalbergia latifolia Roxb. can provoke urticaria and eczema. Sawdust can be used for patch
testing. D. latifolia Roxb. and D. melanoxylon Guill. and Perr. contain dalbergiones which are
potent sensitizers.
Dalbergia nigra Allem., brazil rose wood or jacaranda, is used for cabinet making, woodware,
brushmaking, and so on. Allergic contact dermatitis is reported in forestry workers (in Brazil) and
also from contact with wooden objects made in Brazil. Sawdust or ethanol extracts and dalbergiones
can be patch tested.
Dalbergia retusa Hemsl., Cocobolo, is used for making boats, cutlery, tool handles, and music
and scientific instruments. Dermatitis can result from contact with objects made of this wood. Patch
tests are possible with sawdust, as is, or dalbergiones.
Machaerium scleroxylon Tul., Pao ferro or jacaranda, is used in fine furniture. Pao ferro can
cause eczema on the hands, face, and neck. An erythema-multiform-like eruption has also been
reported. A patch test with sawdust is possible, or R-3-4-dimethoxydalbergiones, if available (1
percent in petrolatum).
3.3.10.2.8 Meliaceae
Khaya anthotheca (Welw) DC, African mahogany, is used in joinery and cabinet making, in
veneering, and in boat building. Dermatitis of the face, eyelids, forearms, and dorsa of the hands
affects workers engaging in finishing operations. For patch testing, sawdust, as is, or in solvents
may be used. The wood contains anthothecol.
3.4 REFERENCES
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2. Oppenhein, M., Dermatitis bulbeuse striée consecutive aux bains de soleil dans les prés, Ann. Derm.
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(psoralens) in plants, J. Invest. Dermatol., 39, 225, 1962.
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and tulip, Arch. Dermatol. Forsch., 274, 117, 1973.

9. Papageorgiou, C., Corbet, J. P., Brandâo, F. M., Pecequeiro, M., and Benezra, C., Allergic contact
dermatitis due to garlic (Allium sativum L.). Identification of the allergens: the role of monodi-, and
trisulfide present in garlic. A comparative study in man and animal (guinea pig), Arch. Dermatol.
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11. Hausen, B. M., Prater, E., and Schuber, H., The sensitizing capacity of alstromeria cultivars in man
and guinea pig. Remarks on the occurrence quantity and irritants and sensitizing potency of their
constituents tuliposide A and tulipalin A (D-methylene J-butyrolactone) Contact Derm., 9, 46, 1983.
12. Santucci, B., Picardo, M., Iavarone, C., and Trogolo, C., Contact dermatitis to alstromeria, Contact
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1968.
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properties of daffodils (Narcissus pseudonarcissus L., Amaryllidaceae). A review of daffodil derma-
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15. Slob, A., Tulip allergens in Alstromeria and some other liliflorae, Phytochemistry, 12, 811, 1973.
16. Barbier, P. and Benezra, C., Allergic D-methylen-J-butyrolactones. Study to the capacity of E-acetoxy
E-hydroxy and D-methylene J-butyrolactones to induce allergic contact dermatitis in the guinea pig,
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tulip, Arch. Dermatol. Forsch., 247, 117, 1973.
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(Ambrosia species). The role of sesquiterpene lactones, Arch. Dermatol., 104, 73, 1971.
30. Fernandez de Corres, L., Leanizbarrutia, I., and Munoz, D., Contact dermatitis to Anthemis plant, in
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occupational contact dermatitis from Arnica longifolia Eaton., Contact Derm., 4, 3, 1978.
32. Willuhn, G. and Hermann, H. D., Zwei sesquiterpenlaktones aus den Blüten von Armica longifolia,
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33. Hausen, B. M., The sensitizing capacity of Compositae plants. III. Test results and cross-sensitizing
in Compositae-sensitive patients, Dermatologica, 159, 1, 1979.
34. Mitchell, J. C. and Rook, A., Botanical Dermatology: Plants and Plant Products Injurious to the
Skin, Greengrass, Vancouver, BC, 1979, 190.
35. Burry, J. N., Kurchel, R., Reid, J. K., and Kirk, J., Australian bush dermatitis. Compositae dermatitis
in south Australia, Med. J. Aust., 1, 110, 1973.

36. Mitchell, J. C., Geissman, T. A., Dupuis, G., and Towers, G. H. N., Allergic contact dermatitis caused
by Artemisia and Chrysanthemum species, J. Invest. Dermatol., 56, 98, 1971.
37. Hausen, B. M. and Schulz, K. H., Chrysanthemem-allergie.1. Mitteilung, Berufs Derm., 21, 199, 1973.
38. Bleumink, E., Mitchell, J. C., and Nater, J. P., Contact dermatitis due to chrysanthemum, Arch.
Dermatol., 108, 220, 1973.
39. Hausen, B. M. and Schulz, K. H., Chrysanthemum allergy. Identification of the allergens, Arch.
Dermatol. Res., 255, 111, 1976.
40. Frain-Bell, N., Hetherington, A., and Johnson, B. E., Contact allergic sensitivity to Chrysanthemum
and the photo sensitivity dermatitis and actinic reticuloid syndrome, Br. J. Dermatol., 101, 491, 1973.
41. Bleumink, E., Mitchell, J. C., Geissman, T. A., and Towers, G. H. N., Contact hypersensitivity to
sesquiterpene lactones in Chrysanthemum dermatitis, Contact Derm., 2, 81, 1976.
42. Krook, G., Occupational dermatitis from Lactuca sativa (lettuce) and Cichorium (endive). Simulta-
neous occurrence of immediate and delayed allergy as a cause of contact dermatitis, Contact Derm.,
3, 27, 1977.
43. Friis, B., Hjorth, N., Vail, J. T., Jr., and Mitchell, J. C., Occupational contact dermatitis from cichorium
(chicory, endive) and Lactuca (lettuce), Contact Derm., 1, 311, 1975.
44. Gougerot, H., Eczema professionnel par I’artichaut, Bull. Soc. Fr. Derm. Syph., 43, 1463, 1936.
45. Vallet, G., Allergie aux plantes maraichres—artichauts, celeris, persil, Concours Med. Paris, 86, 3603,
1964.
46. Burry, Y. N., Kuchel, R., Reid, J. G., and Kirk, J., Australian bush dermatitis. Compositae dermatitis
in south Australia, Med. J. Aust., 1, 110, 1973.
47. Calnan, C. D., Sensitivity to dahlia flowers, Contact Derm., 4, 168, 1978.
48. Vryman, L. H., Dahlien wurzelrinden, Derm. Arch. Derm. Syph., 168, 233, 1933.
49. Hjorth, N., Active sensitization with alantolactone, Contact Derm. Newsl., 8, 175, 1970.
50. Mitchell, J. C., Fritig, B., Singh, B., and Towers, G. H. N., Allergic contact dermatitis from Frullania
and Compositae. The role of sesquiterpene lactones, J. Invest. Dermatol., 54, 233, 1970.
51. Schelwer, G., Stampf, J. L., and Benezra, C., Synthesis of methylene butyrolactones: A structure
activity relationship of their allergenic power, J. Med. Chem., 23, 1031, 1980.
52. Stampf, J. L., Schelwer, G., Ducombs, G., Fousserau, J., and Benezra, C., Allergic contact dermatitis
due to sesquiterpene lactones. A comparative study of human and animal sensitivity to D-methylene-
J-butyrolactones and derivatives, Br. J. Dermatol., 98, 163, 1978.
53. Campolini, P., Sertoli, A., Fabbri, P., and Panconesi, E., Alantolactone sensitivity in Chrysanthemum
contact dermatitis, Contact Derm., 4, 93, 1978.
54. Vail, J. T. and Mitchell, J. C., Occupational dermatitis from Cichorum intybusc endiva and Lactuca
sativa var longifolia, Contact Derm. Newsl., 14, 413, 1973.
55. Friis, B., Hjorth, N., Vail, J. R., and Mitchell, J. C., Occupational contact dermatitis from Cichorium
(chicory, endive) and Lactuca (lettuce), Contact Derm., 1, 311, 1975.
56. Krook, G., Occupational contact dermatitis from Lactuca sativa (lettuce) and Cichorium (endive).
Simultaneous occurrence of immediate and delayed allergy as a cause of contact dermatitis, Contact
Derm., 3, 27, 1977.
57. Lonkar, A., Nascinpagi, B. A., Narayanan, C. R., Landge, A. B., and Sawaikar, D. D., An antigen
from P. hysterophorus, Contact Derm., 2, 151, 1976.
58. Behl, P. N. and Captain, R. Y., Skin-Irritant and Sensitizing Plants Found in India, Chand, S., and
Naga, R., Eds., S. Chand and Co., Ltd., RAM NAGAR, New Dehli, 1979, 39.
59. Bhutani, J. K. and Rao, D. S., Photo contact dermatitis caused by P. Hysterophorus, Dermatologica,
157, 206, 1978.
60. Towers, G. H. N. and Mitchell, J. C., The current status of the seed Parthenium hysterophorus L. as
a cause of allergic contact dermatitis, Contact Derm., 9, 465, 1983.
61. Lonkar, A. and Yog, M. K., “Epidemic” contact dermatitis due to Parthenium hysterophorus (Com-
positae family of plants), Reports of 350 cases, Contact Derm. Newsl., 11, 291, 1972.
62. Subba Rao, P. V., Mangala, A., Towers, G. H. N., and Rodriguez, E., Immunological activity of
parthenin and its diastereomer in persons sensitized by Parthenium hysterophorus L. Contact Derm.,
4, 199, 1978.
63. Picman, A. K., Picman, J., and Towers, G. H. N., Cross-reactivity between sesquiterpene lactones and
parthenin in parthenin sensitized guinea pigs, Contact Derm., 8, 294, 1982.

64. Sohi, A. S., Tiwari, V. D., Lonkar, A., Rangachar, S. K., and Naga, B. A., Allergenic nature of
Parthenium hysterophorus, Contact Derm., 5, 133, 1979.
65. Cheminat, A., Stampf, J. L., Benezra, C., Faffal, M. J., and Frecher, J. M. J., Allergic contact dermatitis
to costus. Removal of haptens with polymers. IV, Acta Dermatovenerol., 61, 525, 1981.
66. Mitchell, J. C., Contact sensitivity to costus-root oil (Saussurea), Arch. Dermatol., 109, 572, 1974.
67. Benezra, C., Ducombs, G., Sell, Y., and Foussereau, J., Plants Contact Dermatitis, Decker Mosby,
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69. Hjorth, N., Seasonal variations in contact dermatitis, Arch. Derm. Venereol., 47, 409, 1967.
70. Cairns, R. J., Plant dermatoses: some chemical aspects and results of patch testing with extracts of
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71. Agrup, G., Fregert, S., Hjorth, N., and Ourisson, S., Routine patch testing with ether extract of Primula
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74. Sowers, W. F., Weary, P. E., Collins, D. D., and Cawley, E. P., Ginkgo tree dermatitis, Arch. Dermatol.,
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4 Diagnosis and Patch Testing
of Plant Dermatitis
John C. Mitchell and Howard I. Maibach
CONTENTS
4.1 Introduction
4.2 Plant Samples
4.3 Identification
4.4 Value of Literature Search
4.5 Lack of a Diagnostic Test for Phytophoto-Toxic (Irritant) Dermatitis:
Plant Test vs. Patient Test
4.5.1 Photopatch Testing
4.5.2 Lack of Significant Patch Test in Suspect Poison Ivy–Oak Dermatitis
4.5.3 Patch Testing to Plants
4.6 Housecall and Garden Walk
4.7 Phytochemical Investigation
4.8 References
4.1 INTRODUCTION
We have often been asked for guidance by colleagues during their investigation of suspected plant
dermatitis, but a partial follow-up suggests that such investigations are not often brought to a
successful conclusion. Why is this so?
A difficulty in the investigation of phytodermatitis is that speed is necessary to achieve a
satisfactory result. In many instances, by the time the clinician is ready to perform testing, the
patient is no longer afflicted and has lost interest. The patient is only too glad to forget the whole
episode leaving the investigator, who is about to make a sparkling, maybe original finding, frustrated.
This experience deters some from further aspirations in botanical study and, consequently, some
interesting observations are not shared.
4.2 PLANT SAMPLES

To overcome some of these difficulties, we suggest that immediately after a diagnosis of phyto-
dermatitis is suspected, the clinician should obtain the plant and have it botanically identified. This
is often more easily said than done. On request, a cooperative patient will often bring in suspect
plants. Be careful not to handle the suspect plants personally.
The patient should be requested to be thorough and bring samples of all plants including those
that one would call “weeds” and, therefore, be inclined to overlook. Often one or two garbage bags
full of plants will arrive on the clinician’s desk.

We suggest the clinician immediately divide each plant in the collection into three parts. We
have become sensitized to many plants and wish now that we had utilized scissors, forceps, and
gloves to protect our skin when handling plant specimens.
One part of each plant is kept for identification (see below), one part is placed in the refrigerator
for possible patch testing, and one part is placed in a freezer for safekeeping. The plant part kept
for identification should include its flowering parts and can be pressed between sheets of paper
and allowed to dry. The plants for refrigeration and freezing can be placed in plastic food bags.
4.3 IDENTIFICATION
It is essential for meaningful scientific investigation of plant dermatitis that botanical names be
used. A colloquial or common name has no scientific validity and is useless for scientific reports.
Colloquial names for a plant species vary from one country to another and are misleading and
numerous. It is essential to have botanical identification by a taxonomist. A local nurseryman is
not recommended, but somewhere in each community is located a botanist who can provide what
is needed.
The challenge is to find this individual—try a botanical garden or a botanical department at a
college or university. Botanists are as subspecialized as we are, some interested in biochemistry,
plant physiology, and so on. We need the one who can provide a botanical name for a common
weed or garden specimen. This superior person will be glad to help but, when needed, may be off
plant collecting on the Himalayas or in Amazonia. We suggest that more than one authority be sought.
A botanical name permits a scientific literature search, the important next step. Refer to standard
sources such as those by Benezra et al.,1 Hausen,2 Lovell,3 or Mitchell and Rook.4 Is the named
plant reported to cause dermatitis or to contain psoralen? Is the plant a known irritant such as
Euphorbia?
4.4 VALUE OF A LITERATURE SEARCH

In the following case, patch testing was followed by a severe reaction. The sap of the plant Agave
americana, incorrectly named cactus juice and used as a hair restorer, evoked contact urticaria
followed by acute eczematous dermatitis of the scalp and forehead.5 Open patch tests with fresh
sap produced burning pain and follicular contact urticaria. Within hours, the appearance had changed
to an acute papulovesicular eczematous reaction. Even an open patch test to plant juice, unless
diluted, is inadvisable. Regular closed patch testing to such a plant might be disastrous. In such a
case, a search of the literature can reveal reports of irritancy by a plant or its close relatives.
Before performing photopatch or patch testing, consider whether such testing is likely to be
helpful or not.
4.5 LACK OF A DIAGNOSTIC TEST FOR PHYTOPHOTO-TOXIC

(IRRITANT) DERMATITIS: PLANT TEST VS. PATIENT TEST
In investigations of suspected phytophotodermatitis, there is a test for the plant but not for the
patient. The following show some examples. A produce worker presented striate hyperpigmentation
of the forearms after cutting celery (Apium graveolens) at work followed by a visit to a tanning
studio. On a sunny day, a child played with monstrous garden plant Heracleum mantegazzianum
and blisters appeared on the hands and face. A gardener who was treated for alleged impetigo
recollects handling the green leaves of parsnips (Pastinaca sativa) on a sunny day. Blisters appeared
on the neck of a tourist in Hawaii who wore a Mokihana neck garland (Pelea anisata). All these
plants contain psoralens.

In these and other instances, bullae accompanied by pain rather than itching and followed by
striate hyperpigmentation strongly suggest a diagnosis of phytophotodermatitis. The diagnosis is
made on circumstantial evidence that includes a characteristic clinical appearance and a history of
exposure to a phototoxic (photo-irritant) plant and of actinic exposure that evoked the reaction.
This is no clinical test to prove a diagnosis of phytophotodermatitis in contrast to the specificity
of a patch test in allergic contact dermatitis.
4.5.1 PHOTOPATCH TESTING

In phytophotodermatitis caused by a photochemical reaction mediated by psoralens and possibly
by other plant chemicals, no allergic mechanism is implicated.
A photopatch test can be performed using the juice of the plant and exposure of the skin test
site to UV. The investigator may well choose to carry out this test on him/herself so as not to
inconvenience the patient who is often a child.
Almost all normal subjects will show a positive response by photopatch test to a plant that
contains sufficient psoralen. If a plant is known to contain psoralen, a photopatch test with it is
unnecessary. Testing is only needed if the suspect plant is one not previously studied.
Volunteers for a photopatch test to a plant deserve careful explanation and warning. Besides a
painful blister like a burn, hyperpigmentation may ensue. An inconspicuous site covered by clothing
should be chosen so that the amount and duration of UV exposure can be controlled. A volunteer
will not appreciate hyperpigmentation lasting a year on a forearm flexure.
The test for phototoxicity described by Daniels involves growing Candica albicans on agar
plates.6 Plant material is placed on the agar and plates incubated under UVA and, as control, in the
dark. A zone of inhibition of yeast growth around plant material under UVA but not in the dark
indicates phototoxic activity by a plant. We have found this test useful for screening plants and
those showing phototoxicity can then be submitted to a phytochemist for detection and isolation
of the actual chemicals. By these procedures, for example, psoralen was found in Pelea confirming
the phototoxic nature of the Mokihana burn of Hawaii. An extensive discussion of the in vitro and
in vivo techniques for identifying phototoxic chemicals can be located in Marzulli and Maibach7
and Rougier et al.8
4.5.2 LACK OF SIGNIFICANT PATCH TEST IN SUSPECT POISON IVY–OAK

DERMATITIS
Lack of significant test to be carried out on a patient can pose a problem in the diagnosis of poison
ivy–oak dermatitis. A patient who has been camping out in locations where poison ivy or poison
oak are known to grow develops acute pruritic vesicular striate dermatitis of exposed skin surfaces.
Clinically, a diagnosis of phytodermatitis may appear likely. A significant cause in geographic areas
where plants are endemic and exposure is frequent, a proportion of individuals will show a positive
patch test reaction to the leaf from prior exposure. Therefore, it cannot be assumed that a positive
patch test reaction is relevant to an episode of acute dermatitis that a patient presents because the
patient might have been previously sensitized.
Note that it is unwise to perform a patch test to poison ivy or oak leaf for fear of active
sensitization of a previously unsensitized individual!
When poison ivy or poison oak dermatitis is clinically suspected on the basis of morphology
and history and there is no clear history of exposure, one should think of exposure to other plants.
Common ivy (Hedera helix) and in the United States southwest scorpion weed (Phacelia) can each
produce dermatitis closely resembling or indistinguishable from poison ivy or poison oak dermatitis.
In locations where poison ivy and oak dermatitis is common, dermatitis from Hedera and Phacelia
can be, and often is, misdiagnosed as the commoner poison ivy and oak dermatitis.

There is usually a good history of exposure to common ivy. The patients will often recollect
cutting back its exuberant growth and contact with its sap. Patients who have been exposed to
scorpion weed in the wild can rarely identify it, recalling only exposure to vegetation in general.
It is necessary to have knowledge of the presence of scorpion weed in one’s local geographic area
and also to know that some (Phacelia) species are cultivated in gardens.
4.5.3 PATCH TESTING TO PLANTS

The actual plants to which the patient was exposed should be used for patch testing. Rarely is it
possible to use dried herbarium specimens of identified species for this purpose.
In a case of suspected plant dermatitis, the patient can bring in plants from the house and
garden for testing but in some cases we have found it useful to donate a role of plastic tape to the
patient. The patient is asked to apply a piece of a plant to the forearm flexure, about 1 cm square,
and occlude the site with a piece of the tape. The patch is to be removed immediately after any
irritation or at 24 h. We have no controlled studies, but find that a 4 h patch test exposure to plant
material may be sufficient to give meaningful results. If any reaction is noted, the patient is asked
to show it to the physician for evaluation and more precise testing. We have often found that
enthusiastic patients will themselves suggest the procedure or have already initiated it, making one
wonder why patch testing was not considered a clinical tool before 1897. By this rough and ready
form of patch test, we have made some interesting findings. For example, a patient unexpectedly
discovered for himself contact allergy to certain lichens.
For patch testing in the office, the plants selected for the first set of patch tests should be those
recognized as causing dermatitis. If these first tests are negative, tests with the remaining plants
should be carried out. In some instances, repeated search may be required before the offending
plant can be detected.
Over 95 percent of all cases reported of patch test proven dermatitis have been caused by plants
in a small number of families. Time can be wasted by repeated testing with innocuous plants, but
judgment is required if an infrequently allergenic plant is not to be missed; for example, Tolmiea
(piggyback plant) yielded four positive and 89 negative reactions in 93 tests.
If there is a clinical suspicion of plant dermatitis but no clear lead is provided by the history,
it may be useful to limit the screening patch testing to plants within these commonly offending
families.1-4 Otherwise, patch tests with innocuous but popular plants may continue to be performed.
Worldwide only 100 species and their close relatives cause the majority of plant dermatitis.
Some plants are irritant and allergenic. When such plants are suspect, it is necessary to use
plant extracts diluted to a nonirritating level for patch testing.
If irritancy seems possible, patch test with caution. In all cases, patch tests to plants in a patient
suspected to be allergic should be accompanied by control patch tests in at least 5, preferably 20,
volunteer subjects. The literature abounds with invalid reports in which alleged allergenic plants
have not received the simple but crucial tests for irritancy in controls. No plant can be considered
proven allergenic unless tests are negative in a substantial number of controls.
False-positive reactions can result from testing during status eczematous. The back is more
sensitive than the extremities. Confusion may occur from discoloration of the skin at the test site
by the presence of a plant of a red dye that simulates an erythema. Any irritant patch test reaction
can never be reliably distinguished from an allergic patch test reaction on morphologic grounds alone.
To prepare a plant for patch testing, leaves and petals should be lightly crushed, stalks and
thick leaves should be cut into thin slices.
When patch testing more than one plant at one time, and especially when testing many plants
concomitantly, we have often observed an angry back; that is, the presence of many positive plant
test reactions, some of which, on sequential testing of one plant at a time, were found to be negative.
Some positive test reactions obtained by concomitant testing could not be reproduced by sequential
testing.

One should wait until acute dermatitis has subsided before patch testing to minimize the risk
of producing a focal or disseminated flare. The skin site selected for patch testing should be clear
of dermatitis for at least two weeks, preferably a month, before such testing is carried out—hence,
the usefulness of freezing plants. It is during this delay that a patient may lose interest in an
investigation.
4.6 HOUSECALL AND GARDEN WALK

A housecall to the patient’s home and garden has proved most useful for supplementing data. For
instance, a patient who had chrysanthemum dermatitis did not recover, despite avoidance of contact
with chrysanthemum. A visit to the patient’s garden revealed that he was pulling Tanacetum (tansy)
weed, which infested his flower beds. The dermatitis was perpetuated by exposure to tansy weed,
which is botanically and chemically related to Chrysanthemum.
A patient who shows a positive patch reaction to ragweed (Ambrosia) may never have been
exposed to this weed; he may actually have been sensitized to one of many other Compositae
plants. Cross-reactions between Compositae often are observed owing to several thousand cross-
reacting allergenic sesquiterpene lactones occurring in species of this family.
In our patch test unit, we have kept specimens of Primula obconica to show to patients asking
if they possess a plant that looks similar and have stimulated some recollections. Textbooks with
color photographs are also helpful.1,2
A house call to patients with suspect Primula obconica dermatitis can be rewarding. The patient,
when in the doctor’s office, may deny possession of the plant or indeed any knowledge of it, but
inspection of the home may reveal specimens of this species that the patient had forgotten about.
Some simply cannot believe that such a beautiful plant can cause so much human misery.
Garden or green house visits are strongly recommended. The investigator can soon train
himself/herself to recognize the common culprits. For example, the giant Heracleum mantegaz-
zianum is distinctive, as are its seedling. The gas plant can be recognized in a perennial border and
as rue in an herb garden.
4.7 PHYTOCHEMICAL INVESTIGATION

Having suspected and then incriminated an offending plant, it is tempting to try to find out the
allergenic plant chemical. Some idea of its nature can be gained by patch testing with aqueous and
organic solvent fractions of parts of the plant.
Plant extraction by any method is a time-consuming process during which it is necessary to
maintain the patient’s interest and cooperation. The patient who showed a positive patch test to a
plant must be ready, willing, and able to be patch tested again, to successive fractions of the plant
material in an attempt to identify and purify its allergens.
To pursue the matter, phytochemical expertise is required. Phytochemists are not plentiful and
it can be assumed that they and their junior staff are already committed to important research. A
dermatologist naturally feels that his patient-oriented inquiries are of vital importance, but a
phytochemist may be less enthused that efforts expended will lead to stamping out of disease. After
all, poison ivy dermatitis was recognized in 1609 and its allergenic chemicals identified early in
this century, but we have little in the way of an effective prevention and cure.9
The essential problem is that of funding. To identify an unknown chemical may take a junior
staff member, say a Postdoctoral Fellow of a Department of Botany, six months or more. For his
salary for a year and for chemicals and the use of sophisticated analytic equipment, a total expense
of $50,000 to 100,000 might be expected. If the chemical turns out to be already known to science,
the Postdoctoral Fellow has essentially wasted his time without career advancement. The next
problem consists of obtaining funds from a granting agency. The dermatologist, when he applies,

will need to state that he intends to turn over the funds, when he gets them, to a Department of
Botany for chemical studies and his only contribution will be to patch test one or more patients if
he can both find them and maintain their interest. This information does not always appeal to
granting agencies. Some agencies like to have a detailed breakdown of how the money will be
spent on equipment and supplies. Such requests passed on to phytochemical colleagues are likely
to induce hilarity rather than enthusiasm for completion of a grant application.
If successful in the grant application, the clinician may find to his dismay that the small amount
of plant material stored in the freezer, for example 100 g wet weight is considered insufficient by
the phytochemist who requests a larger amount, say 10 kg dry weight. The patient suffered his
dermatitis in the summer when plants were growing actively but when the grant money is received,
winter has arrived and the garden is bare and the suspect plants are now on the compost heap and
unidentifiable. Alternatively, the suspect plant is, say, a liverwort and the investigator must spend
his leisure hours and risk his neck climbing trees to harvest a supply. It is essential, therefore, to
store material as did the wise virgins and not run out of supplies as did the foolish virgins.10 A
steady and reliable source of supply of plant material must be ensured.
It cannot be assumed by the investigator that botanists will go out into the field to identify and
collect plants for dermatological research. They may feel that they have more important tasks to
undertake or in the case of lichens and liverworts refuse to collect substantial quantities of small
plants for fear of disturbing the ecology and balance of nature.
If the preceding difficulties are recognized, then they can be anticipated and overcome with
the result of rewarding and productive cooperative studies. One of us (Mitchell) consulted Professor
T. A. Geissman who had been studying sesquiterpene lactones for most of 40 years and, being
amazed and delighted that his knowledge was significant for health, he immediately donated time
and rare chemicals. A phytochemist, Professor Towers, suggested usnic acid as an allergen of
lichens and provided samples of lichen chemicals; he pointed out methylene groups attached to a
lactone as an immunochemical requisite of Compositae plants. Professor Towers and his staff have
investigated plants causing plant dermatitis and co-authored many other reports. We have received
chemicals and help from Professor Hausen of Hamburg who has made many studies of plant
dermatitis. With such expertise and requisite funding, satisfactory investigations can be carried out.
4.8 REFERENCES
1. Benezra, C., Ducombs, G., Sell, Y., and Foussereau, J., Plant Contact Dermatitis, Decker, Toronto,
1985.
2. Hausen, B. M., Allergiepflanzen-Pflanzenallergene: Handbuch und Atlas der allergie-induzierenden
Wild- und Kulturpflanzen, Ecomed Verlagsgesellschaft mbH, Landsberg/München, 1988.
3. Lovell, C., Plants and the Skin, Blackwell, London, 1993.
4. Mitchell, J. C. and Rook, A., Botanical Dermatology, Greengrass, Vancouver, 1979.
5. Kerner, J., Mitchell, J. C., and Maibach, H. I., Irritant contact dermatitis from Agave americana L.,
Arch. Dermatol., 108, 102, 1973.
6. Daniels, F. A., A simple microbiological method for demonstrating phototoxic compounds, J. Invest.
Dermatol., 44, 259, 1965.
7. Marzulli, F. and Maibach, H. I., Dermatotoxicology, 4th ed., Hemisphere Press, Washington, D.C.,
1991.
8. Rougier, O., Goldberg, A., and Maibach, H., In Vitro Skin Toxicology, Lieberg, NY, 1994.
9. Rostenberg, A., Jr., An anecdotal biographical history of poison ivy, Arch. Dermatol., 72, 438, 1955.
10. Matthew 25:1.

5 Prevention of Allergic Contact
Dermatitis to Plants
Hongbo Zhai and Howard I. Maibach
CONTENTS
5.1 Introduction
5.2 Plant Dermatitis
5.2.1 Immediate Contact Dermatitis (Urticaria)
5.2.3 Phytophotodermatitis (Photoirritation, Phototoxicity)
5.2.4 Allergic Contact Dermatitis
5.3 Prevention
5.3.1 Generic Prophylactics
5.3.2 Role of Hyposensitization
5.3.3 Protective Creams and Ointments
5.4 Conclusions
5.5 References
5.1 INTRODUCTION
Allergic contact dermatitis to plants is a significant problem worldwide. Poison ivy and poison oak
dermatitis, a typical plant allergic contact dermatitis, affects millions yearly.1-5 The severity of plant-
induced contact dermatitis not only depends on the plant’s irritant or allergic potential but also the
degree of exposure and the sensitivity of the individual. Even plants which rarely cause contact
dermatitis may produce severe eruptions in highly allergic patients.6
Avoiding such causative plants may not be practical for persons whose occupation or recre-
ational activities are outdoors, such as forest fire fighters, utility line workers, agricultural workers,
gardeners, outdoor enthusiasts, and so on. Therefore, prevention approaches play a critical role in
reducing the risk of developing allergic contact dermatitis to plants. Numerous articles have been
written on the prevention of allergic contact dermatitis to plants. Prevention by immunologic
modification through oral or parenteral hyposensitization is possible but not widely employed.1,2,6,7
Protective creams (or barrier creams) decrease such dermatitis.3-5,8,9 This chapter highlights the
personal prevention of allergic contact dermatitis to plants and, in particular, emphasizes the results
of recent studies.
5.2 PLANT DERMATITIS

Plant dermatitis usually occurs through at least four different mechanisms: immediate type contact
urticaria, irritant contact, phototoxicity, and allergic contact.7

5.2.1 IMMEDIATE CONTACT DERMATITIS (URTICARIA)
Some plants, for example, stinging nettle, stinging trees of Australia, spurge nettle, tomato, straw-
berry, and so on may cause contact urticaria. Those urticariogenic plants are common and especially
abundant in the tropics. An urticarial reaction, typified by an immediate but short-lived wheal and
flare, usually results. Most common type are nonimmunologic contact urticaria (NICU) without
previous sensitization.10 Parts of some urticariogenic plants are capable of causing an immune
response by direct contact alone, producing mild type I hypersensitivity reactions in patients who
have been sensitized previously. This is immunologic contact urticaria (ICU). Latex contact urticaria
syndrome (CUS) is the prime example.11

Skin may be traumatized either mechanically or chemically from contact with an offending plant
as well as hot peppers, garlic, rose, sharp grasses, barberry, borage, spurges, and tobacco, and so
on. Those plants exert their effect by direct chemical action or intense mechanical irritation with
sufficient contact. Some may cause a violent reaction on contact with mucous membranes or
sensitive locations, such as the nose and genitalia, even with the slightest contact.
5.2.3 PHYTOPHOTODERMATITIS (PHOTOIRRITATION, PHOTOTOXICITY)

When the skin is exposed to some plants, for example, angelica, bavachee, celery, fig, gas plant,
hogweed, Queen Anne’s lace, and so on and exposed to UVA photosensitivity reactions may occur.
An uncomfortable dermatitis, erythema, and vesiculation lasting 1 to 2 weeks may result, followed
by streaky hyperpigmentation. However, in phytophotodermatitis, the lesions develop only in sun-
exposed areas, are somewhat painful as well as pruritic, and leave a hyperpigmented residual that
may take months or years to resolve.

Poison ivy and its close relatives poison oak and poison sumac frequently cause plant dermatitis.
Urushiol, the major potent allergen, is responsible for sensitizing approximately 50 percent of
Americans. Cell-mediated immune response to plant contact occurs only in previously sensitized
persons who experience erythema, vesiculation, weeping, and pruritus on exposure. Dermatitis lasts
for up to several weeks but usually heals without pigmentary changes or scarring. Other plants as
well as cashew, mango, Japanese lacquer, and marking nut trees are from the same family as poison
ivy and can cross-react with it to produce similar lesions.
5.3 PREVENTION
5.3.1 GENERIC PROPHYLACTICS
The allergic component of the plant is so rapidly absorbed through the skin that highly sensitive
people must remove the antigen within minutes of exposure. Vigorously washing the skin with
water and soap are essential, but an organic solvent might be beneficial if done immediately.2,6,7
Rubber gloves may not protect the individual because the allergens can penetrate the rubber gloves
and produce dermatitis.2,6,7,12 Heavy-duty vinyl and cloth gloves may afford some protection.
Protective clothing limits contact with the allergen but may itself be a source of exposure if items
are not removed and cleaned with care.1,6,7 Wahlberg and Maibach12 summarized this field.

FIGURE 5.1 Protective value of all test preparations against urushiol, as compared with the control (100
percent). (From Epstein, Arch. Dermatol., 125, 499, 1989. With permission.)
5.3.2 ROLE OF HYPOSENSITIZATION

Hyposensitization, which attempts to induce a temporary tolerance by administering the causative
antigen orally or parenterally over many months in hypersensitive individuals, has been studied in
detail.1,2,6,7 Such treatment often leads to proctitis and pruritus ani. Hyposensitization products have
not been approved by the Food and Drug Administration for rhus hyposensitization.
5.3.3 PROTECTIVE CREAMS AND OINTMENTS

Orchard et al.3 assessed the ability of 156 different preparations (based on 22 different chemicals)
to prevent poison ivy dermatitis in 57 subjects. Protective substances were applied to the back of
volunteers. About 10 min later, the sites pretreated with protectants and unprotected were challenged
with 5 ml poison ivy extract for 48 h. Several polyamine salts of a linoleic acid dimer were able
to prevent the usual dermatitis in approximately 70 percent of the subjects.
Epstein8 examined the protective capacity of topical preparations against experimental poison
ivy/oak in 28 highly sensitive volunteers after testing with weak dilution’s urushiol in a rigorous
double-blind study. Organoclay preparation gave 95.3 percent protection against topical urushiol
application; bentonite, kaolin, and silicone gave 29.6, 37.9, and 32.9 percent protection, respectively,
in the same system (Figure 5.1).
Grevelink et al.4 evaluated seven different barrier creams against experimentally produced
Toxicodendron dermatitis in a randomized, double-blind study. Involved were 20 subjects with a
positive patch test to Toxicodendron extract. Test creams were applied on the forearm of each
subject (one area as a untreated control). After the drying of preparations for 20 min, a fresh

FIGURE 5.2 Effect of various barriers on the global severity of experimentally produced Toxicodendron
dermatitis. (From Grevelink et al., J. Am. Acad. Dermatol., 27, 182, 1992. With permission.)
FIGURE 5.3 Plot of mean reaction scores for quaternium-18 bentonite (Q18B) and control sites. (From Marks
et al., J. Am. Acad. Dermatol., 33, 212, 1995. With permission.)

FIGURE 5.4 Efficacy of protective materials against 3 percent Rhus. Results are expressed as the mean ±SE.
Statistical differences are shown in comparison with untreated skin site; *p<0.05; **p<0.01; N.S. = not
significant. (Modified from Zhai et al., Contact Derm., Submitted. With permission.)
Toxicodendron extract then was placed on the center of each target area and covered with a Finn
Chamber for 4 h. Assessment of Toxicodendron dermatitis was followed on days 1, 2, 3, 4, and 7
after application. The barrier creams Stokogard, Hollister Moisture Barrier, and Hydropel signifi-
cantly reduced the erythema, induration, and global severity of Toxicodendron dermatitis
(Figure 5.2).
Marks et al.5 investigated the effect of 5 percent quaternium-18 bentonite lotion in preventing
experimentally induced poison ivy and poison oak allergic contact dermatitis in 211 susceptible
volunteers. It was a single-blind, paired comparison, randomized, multicenter study. Both forearms
were patch tested with urushiol 1 h after applying the test lotion on one randomly selected forearm.
All test materials were removed 4 h later and the sites interpreted for reaction 2, 5, and 8 days
later. Results shown that the test sites pretreated with quaternium-18 bentonite lotion had absent
or significantly reduced reactions to the urushiol compared with untreated control sites (Figure 5.3).
Zhai et al.9 utilized an in vivo human model to examine the effect of potential protective
materials against two acute primary irritants (SLS and NH4OH plus urea) and one allergen (Rhus).
The putative protective materials and vehicle were applied to both ventral forearms of 10 subjects
in each group according to a randomized code. Test materials were spread over a marked 2.0 cm2
area, massaged in, allowed to dry for 30 min, and reapplied with another 30 min drying period.
The model irritants and allergen were then applied (0.025 ml) to an AL-test® occlusive patch that
in turn, was placed for 24 hours over each of the 8 designated sites. Inflammation was scored
according to a clinical scale 72 h post application. Paraffin wax in cetyl alcohol significantly
(p<0.01) decreased Rhus allergic contact dermatitis (Figure 5.4).

5.4 CONCLUSIONS
The best way to prevent allergic contact dermatitis to plants is to avoid the exposure to such
causative plants, but if that is impossible, personal protection measures are important. Persons with
known exposure to sensitizing plants should thoroughly wash with soap and water at the first
opportunity to remove any allergens remaining on the skin and thereby prevent the allergens from
being transferred to other parts of the body. Unfortunately, allergens readily adhere to many surfaces
as well as clothing and tools that then act as fomites to spread the allergens to man. Decontamination
is aided by suitable organic solvents, such as acetone, alcohol, and so on. Another crucial preventive
approach is blocking or retarding absorption of the antigen into the skin by barrier creams or
protective ointments. Barrier creams or protective ointments as protective agents have long been
used; their value in outdoor occupations and, especially, against poison ivy/oak is now established.
Some preparations have been demonstrated to prevent or limit experimentally produced allergic
contact dermatitis to poison ivy/oak. A combination approach (i.e., decontamination and barrier
creams) should be considered.
5.5 REFERENCES
1. Epstein, W. L., Occupational poison ivy and oak dermatitis, Dermatol. Clin., 12, 511, 1994.
2. Fisher, A. A., Poison ivy/oak dermatitis. Part I: Prevention—soap and water, topical barriers, hyposen-
sitization, Cutis, 57, 384, 1996.
3. Orchard, S., Fellman, J. H., and Storrs, F. J., Poison ivy/oak dermatitis. Use of polyamine salts of a
linoleic acid dimer for topical prophylaxis, Arch. Dermatol., 122, 783, 1986.
4. Grevelink, S. A., Murrell, D. F., and Olsen, E. A., Effectiveness of various barrier preparations in
preventing and/or ameliorating experimentally produced Toxicodendron dermatitis, J. Am. Acad.
Dermatol., 27, 182, 1992.
5. Marks, J. G., Jr., Fowler, J. F., Jr., Sherertz, E., and Rietschel, R. L., Prevention of poison ivy and
poison oak allergic contact dermatitis by quaternium-18 bentonite, J. Am. Acad. Dermatol., 33, 212,
1995.
6. Guin, J. D., Plant dermatitis, in Practical Contact Dermatitis, Guin, J. D., Ed., McGraw-Hill, New
York, 1995, 497.
7. Juckett, G., Plant dermatitis, Postgrad. Med., 100, 159, 1996.
8. Epstein, W. L., Topical prevention of poison ivy/oak dermatitis, Arch. Dermatol., 125, 499, 1989.
9. Zhai, H., Willard, P., and Maibach, H. I., Evaluating protective materials against irritants and allergens:
an in vivo screening human model, Contact Derm., submitted, 1998.
10. Lahti, A., Nonimmunologic contact urticaria, in Contact Urticaria Syndrome, Amin, S., Lahti, A., and
Maibach, H. I., Eds., CRC Press, Boca Raton, FL, 1997, 5.
11. Amin, S. and Maibach, H. I., Immunologic contact urticaria definition, in Contact Urticaria Syndrome,
Amin, S., Lahti, A., and Maibach, H. I., Eds., CRC Press, Boca Raton, FL, 1997, 11.
12. Wahlberg, J. E. and Maibach, H. I., Prevention of contact dermatitis, in Protective Gloves for Occu-
pational Use, Mellström, G. A., Wahlberg, J. E., and Maibach, H. I., Eds., CRC Press, Boca Raton,
FL, 1994, 7.

6 Phytophotodermatoses
Christopher Roland Lovell
CONTENTS
6.1 Introduction—Historical Aspects

6.2 Molecular Aspects of Phototoxicity
6.3 Clinical Presentation
6.4 Plant Species Causing Phototoxic Reactions
6.5 Treatment and Prevention
6.6 References
6.1 INTRODUCTION—HISTORICAL ASPECTS

In 1942, Klaber coined the term phytophotodermatitis to describe a toxic skin eruption induced
by contact with plants, followed by sun exposure.1 Such reactions are common, especially in
children, and sometimes misdiagnosed. In man the principal phototoxins are linear furocoumarins
(psoralens 5) (Figure 6.1) which are found in biologically significant amounts in a few plant families.
In common with other toxic phenomena, phototoxic reactions can occur in any individual given
sufficient exposure to the substance and to long-wave ultraviolet light (UVA). Although psoralens
are occasional sensitizers, photoallergic reactions to plants occur rarely, if ever. Exposure to airborne
plant allergens, such as Compositae, can result in a pattern of allergic contact dermatitis which
mimics photosensitivity. Indeed, such patients may subsequently develop a true photosensitivity
dermatitis (chronic actinic dermatitis/actinic reticuloid)2; however, the Compositae allergens appear
not to be photosensitizers per se.
Phototoxic reactions are often distinctive. A streaky erythema with or without blistering occurs
on light-exposed areas. The lesions are painful rather than itching and they resolve with hyperpig-
mentation. This hyperpigmentary reaction has been exploited in folk medicine since approximately
1500 to 2000 B.C. In Ayurvedic medicine and in Chinese and Egyptian culture, the juice of genera
such as Angelica and Ammi was rubbed on lesions of vitiligo and the patient was encouraged to
lie in the sun. This forms the basis of photochemotherapy (PUVA) used in the treatment of psoriasis,
cutaneous T-cell lymphoma, and other disorders including photosensitivity secondary to allergic
contact dermatitis to Compositae.4
For several centuries, authors have noted the toxic effects of plants such as rue and parsnip
although the importance of sunlight was not recognized. In 1932, Oppenheim described dermatosis
bullosa striata pratensis, attributing the linear bullous eruption to contact with meadow grass while
sunbathing. Behçet et al.3 found that the active wavelength of light lay in the long-wave ultraviolet
spectrum and Klaber1 confirmed it to be between 320–400 nm. Psoralens were identified as the
major phototoxins by Kuske in 1940.5 Although other potential phototoxins occur naturally in
plants, they appear not to be relevant clinically.

O O O
FIGURE 6.1 Psoralen, a linear furocoumarin.
OCH3
O O
FIGURE 6.2 Khellin (furanochrome).
6.2 MOLECULAR ASPECTS OF PHOTOTOXICITY

The chemical basis of phototoxic reactions has been succinctly reviewed by Johnson.6 In brief,
psoralens bind weakly by cycloaddition with thymine residues on DNA to form monoadducts. When
cycloaddition occurs with the 4¢5¢bond of the furan, exposure to UVA gives rise to cross-links.
These interstrand cross-links with pyrimidine bases in DNA lead to the characteristic acute bullous
lesions.6,7 The mechanism for the hyperpigmentation is less clear and may occur independently of
the acute inflammatory reaction. Thus, khellin (furanochrome) (Figure 6.2) induces hyperpigmen-
tation without prior erythema.6 The major phototoxic psoralens are illustrated in Figure 6.3.
Photoallergic reactions have been reported rarely for psoralens.8,9 The major allergens appear
to be the relatively poorly phototoxic molecules sphondin and isobergapten (Figure 6.4).10
Distribution of psoralens varies widely between plant species and may even vary in one species
according to geographical location and climate. Fungal attack may induce an increase in psoralens11
that have antifungal properties in the plant. The development of disease-resistant cultivars of
vegetables such as celery and parsnip has resulted in increased concentration of psoralens in these
plants and, hence, a greater risk of phototoxicity.
6.3 CLINICAL PRESENTATION

The typical linear lesions occur often in mid- to late summer in temperate climates, when the skin
is unprotected by clothing and the levels of psoralens are highest in the plants. In the United States,
in particular, the eruption can be confused with allergic contact dermatitis due to poison ivy. The
chief points of difference are noted in Table 6.1. Characteristic phototoxic reactions and post-
inflammatory hyperpigmentation are illustrated in Figures 6.5 and 6.6.* Even in atypical cases, the
eruption is restricted to areas of light exposure (Figure 6.7).
Children are especially at risk of phototoxicity when playing outdoors near plants (Table 6.2).
The resultant linear streaks can lead to misdiagnosis of child abuse (e.g. see Reference 12). Children
have used the hollow stems of Heracleum mantegazzianum as pea shooters and trumpets, with
resultant perioral blisters.13
Walkers, ramblers, and joggers are at risk of photodermatitis after brushing against plants
(Table 6.2, e.g., Cneoridium dumosum).14 Application of rue to the skin as an insect repellent may
induce a more diffuse erythema and blistering.15
* All color figures appear after page 142.

O O O
psoralen
OCH3
O O O
8-methoxypsoralen
O O O
5-methoxypsoralen
OCH3
O O O
5,6-dimethoxyisopsoralen
H3CO
OCH3
FIGURE 6.3 The major phototoxic psoralens, psoralen, 8-methyoxypsoralen, 5-methoxypsoralen, and
5,6-dimethoxyisopsoralen.
sphondin
O O O
H3CO
O O O
OCH3
FIGURE 6.4 Potentially photo-allergenic psoralens, sphondin (6-methoxyisopsoralen) and isobergapten

(5-methoxyisopsoralen).
Gardeners are clearly at risk, chiefly from rue (Ruta graveolens) and (in the United States)
from the burning bush (Dictamnus albus). Modern power tools such as string trimmers (Figure 6.8)
are used to trim areas of scrub and rank weeks; unfortunately, these tools deliver a buckshot spray17
of plant sap to the skin. The scantily clad operator develops bright red irregular macules and papules

TABLE 6.1
Distinctions between Phototoxicity and Allergic Contact Dermatitis Owing to Plants
Phototoxicity Allergic Contact Dermatitis
Onset Within hours of contact Typically 1–2 days before onset

Evolution All lesions develop simultaneously Evolution may be more gradual
Symptoms Pain, may be severe Pruritus
Morphology Linear streaks, often bullous; restricted to May be linear; erythema and oedema with
areas of light exposure; sharply demarcated vesicles and bullae in severe cases; borders
margins; subsequent hyperpigmentation may be less distinct; not restricted to areas
of light exposure; no hyperpigmentation
FIGURE 6.5 Phototoxic reaction caused by Heracleum sp.
on the anterior chest wall and arms within 12–24 h of exposure, the so-called strimmer dermatitis18
or weed-wacker’s dermatitis.19 The eruption may superficially resemble pityriasis lichenoides,
although its distribution is distinct (Figure 6.9). Histology reveals a dermal capillaritis with a
pericapillary lymphocytic infiltrate.19 Garlands containing fruit capsules of Pelea anisata have
induced bullous phototoxic reactions, particularly when the garlands (lei) are worn for the celebra-
tion of Kamehameha Day in early June in Hawaii.20 Laboratory workers handling psoralen-con-
taining materials may develop bullae following spillage.21 Similarly, operatives harvesting or can-
ning vegetables such as celery and parsnip are at risk of phototoxic reactions.22

FIGURE 6.6 Hyperpigmentation following a phototoxic reaction.
The term berlock (breloque) dermatitis (Figure 6.10) was first coined by Rosenthal in 192523
taking its name from the German work berlock, meaning a charm or trinket (breloque in French).
The pendant-like streaks of hyperpigmentation10 occur on the neck, face, arms, or trunk in areas
of light exposure and were subsequently attributed to psoralens in bergamot oil that was derived
from the rind of Citrus bergamia fruit. Many cases were described subsequently, although it has
become much rarer since the introduction of artificial bergamot oil.24 In a recent Italian survey,
bergamot oil is still implicated in patients with photodermatitis.25 It has been used as a suntanning
agent for many years. Phototoxicity has followed its use in aromatherapy26,27 and the use of lemon
oil in a sauna room.28 Both oils are rich in 5-methoxypsoralen.
Patients receiving PUVA therapy either ingest psoralens or apply them topically before exposure
to UVA. Toxic reactions occur due to overdosage with psoralen or UVA or accidental exposure to
additional UVA, for example, from a sunbed or natural sun. Topical application of psoralens is
more likely to induce phototoxic reactions.29 Second degree skin burns have been reported in two
women who received PUVA.30
Ingestion of plant material is an important cause of phototoxic reactions in animals. Several
naturally occurring molecules, such as icterogenic and rehmannic acid, induce cholestasis prevent-
ing the excretion of phylloerythrin, a porphyrin metabolite of chlorophyll.31 Other plant pigments,
including hypericin, are direct causes of photosensitivity.32 Similarly, phototoxicity has been
reported in five Japanese who ingested a preparation containing the alga Chlorella as a natural
health food! The photosensitiser appears to be a chlorophyll derivative, pheophorbide A.33 Recent
case reports confirm that ingestion of vegetables rich in psoralens is capable of inducing phototox-
icity in individuals who subsequently lie under UVA sunbeds.34-36 Sunbed exposure can also induce
phototoxic reactions in individuals who handle vegetables such as parsnips.37

FIGURE 6.7 Phototoxic reaction to rue. The affected individual was wearing shorts while decorating his
house, inadvertently leaning against a rue bush. His lower legs were protected by ankle-length boots.
TABLE 6.2
Phototoxicity: ‘At Risk’ Activities
Gardening – brushing against plants, e.g, rue, Dictamnus
– harvesting vegetables, e.g., parsnip or fruits, e.g., figs
– using string trimmers
Rambling/jogging/rolling in the hay
Play – making pea shooters, fighting with vegetables
Swimming
Canning or processing vegetables
Medication – use of rue as insect repellent
– PUVA toxicity
Cosmetic – tan promoters
– breloque/berlock reactions from cosmetics
– wearing lei/garlands of Pelea anisata
Ingestion – chlorella
– psoralen-rich foods

FIGURE 6.8 A string trimmer power tool.
FIGURE 6.9 String trimmer dermatitis; lesions are restricted to areas of light exposure and contact with plant
sap (typically, the back is spared).

FIGURE 6.10 Berlock (breloque) dermatitis.
6.4 PLANT SPECIES CAUSING PHOTOTOXIC REACTIONS

The important plant families responsible for phototoxicity are listed in Table 6.3. Other plant
families have been suspected and implicated in earlier reports. Several families, such as Ranuncu-
laceae, are irritants; irritant reactions from Euphorbia spp., including the poinsettia (E. pulcherrima)
may simulate phototoxicity.38
Herbs and vegetables belonging to the Umbelliferae (Apiaceae) are major causes of phototox-
icity (Table 6.3). Many species are characteristically aromatic. Wild carrot (Daucus carota)
(Figure 6.11) has the much-divided leaves and umbrella-like inflorescence that gives the family its
name. Some species, such as Ammi majus (Queen Anne’s lace) are grown as ornamentals
(Figure 6.12). Members of the family are common roadside and hedgerow weeds in temperate areas
worldwide, often favoring moist areas. Heracleum mantegazzianum is a giant plant from the
Caucasus, occurring on river banks and damp waste ground in northern Europe as a naturalized
escape (Figure 6.13). It is a cause of severe phototoxic reactions in children.13
The rue family (Rutaceae) includes citrus fruit such as lime, lemon, and bergamot orange.
Essential oils from these fruit are used as insect repellents, tanning agents, and in perfumery. The
Ruta species, including the common rue (R. graveolens) (Figure 6.14) is probably the major cause
of phototoxicity in Britain.42 Dictamnus albus, a beautiful Mediterranean subshrub (Figure 6.15)
is thought to be the burning bush encountered by Moses (Exodus, Chapter 3). On a hot, calm day,
the aromatic oil which exudes from the plant can be ignited without harm to the plant. It is a
common yard plant in the United States and Canada.16 8-Methoxypsoralen and 5-methoxypsoralen
are found in highest concentrations in the seed pods.44 Only one species in the Moraceae, Ficus,
appears to be responsible for phototoxicity (Figures 6.16 and 6.17) especially in Mediterranean
areas; the psoralens are found chiefly in the leaves and unripe fruit.40
6.5 TREATMENT AND PREVENTION

Phototoxic reactions should be entirely preventable. The Horticultural Trades Association (HTA)
in Britain is encouraging adequate hazard warnings of toxic plants such as rue. Accurate identifi-
cation of plants is essential, and may prevent unnecessary and potentially hazardous patch testing.
Computer-based identification programs have been developed.45,46 Phototoxic plants should not be

TABLE 6.3
Important Plant Causes of Phototoxic Reactions
Family Genus/Species Common Name Comments/References
Umbelliferae Ammi majus Queen Anne’s lace, Mediterranean, grown as ornamental

bishop’s weed
Angelica archangelica Angelica European; naturalized on river banks; used
in confectionery
Angelica sylvestris Wild angelica Common in moist places in Europe
Anthrisus sylvestris Cow parsley, wild Common in fields, hedgerows, and waste
chervil ground; important cause of strimmer rash
in Europe (References 17–19)
Anthrisus cereifolium Chervil Garden herb
Apium graveolens Celery Skin reactions after handling and ingestion
(References 11, 34–36)
Cachrys libanotis — Mediterranean; common in meadows in
(Hippomarathrum) Sardinia (Reference 21)
Daucus carota Carrot Common in northern temperate areas
Foeniculum vulgare Fennel Mediterranean; a common garden herb
Heracleum sphondylium Cow parsnip Common on roadsides and hedgerows in
Hogweed Europe; large, coarse plant, important cause
of strimmer rash (References 17–19)
Heracleum Giant Russian hogweed Caucasus, introduced as an ornamental to
mantegazzianum Europe and now naturalized by rivers; a
massive spectacular plant (Reference 13)
Heracleum laciniatum Tromsø palm Common in Scandinavia (Reference 10)
Heracleum lanatum — United States/Japan
Heracleum dulce, —
giganteum persicum, etc.
Levisticum officinale Lovage May cause phototoxic reactions when
harvested (Reference 39)
Pastinaca sativa Parsnip Europe; cultivated vegetable, causes reaction
when handled or ingested (References 12,
22, and 37)
Petroselinum crispum Parsley Europe, naturalized in temperate areas
Peucedanum ostruthium Masterwort Europe, Asia
Peucedanum galbanum Blister bush South Africa, esp., Table Mountain; an
important cause of phototoxicity
Peucedanum other spp.
(?) Phellopteris littoralis United Sstates
(?) Pimpinella spp. Burnet saxifrage Europe, Asia, North and South America
Moraceae Ficus carica Fig Asia, naturalized in temperate areas;
Psoralens are found chiefly in the leaves and
unripe fruit (Reference 40)
Legummosae Psoralea corylifolia Bavchi, scurf pea Tropics and subtropics; used in folk medicine
for vitiligo
Rutaceae Citrus spp. including
C. aurantium v. bergamia Bergamot Mediterranean, widely cultivated; breloque
dermatitis (Reference 23)
C. aurantifolia Lime Aromatherapy oils (References 27 and 28);

used as insect repellent
Cneoridium dumosum United States (Reference 14)

TABLE 6.3 (CONTINUED)
Important Plant Causes of Phototoxic Reactions
Family Genus/Species Common Name Comments/References
Rutaceae Dictamnus albus Burning bush, gas plant Mediterranean; a popular border plant in
(continued) United States (Reference 16)
Pelea anisata Mokihana Hawaii (Reference 20)
Phlebalium argenteum Blister plant Western Australia, cultivated in California
Ruta graveolens Rue Mediterranean, cultivated herb; important
cause of phototoxicity (Reference 42)
Ruta chalepensis
Ruta corsica Endemic to Corsica, Sardinia (Reference 43)
Algae Chlorella spp Ingestion in Japan (Reference 33)
FIGURE 6.11 Daucus carota (wild carrot).
planted in play areas or near pools or sun terraces. The use of string trimmers and other power
tools should be avoided at midday and operatives should be clothed and wear gloves. Sunscreens,
which protect against UVA as well as UVB may help to protect plant handlers when protective
clothing and gloves are impracticable.47

FIGURE 6.12 Ammi majus, grown at Oxford Botanic Garden.
FIGURE 6.13 Heracleum mantegazzianum naturalized on river banks at Charmouth, South Dorset.

FIGURE 6.14 Ruta Graveolens, rue, growing wild in Crete.
FIGURE 6.15 Dictamnus albus, growing wild in the Pindus Mountains, Greece.

FIGURE 6.16 Ficus carica, the fig.
FIGURE 6.17 Phototoxic reaction after handling figs; the reaction spares the area protected by a ring (courtesy
of Dr. John Cook).

6.6 REFERENCES
1. Klaber, R., Phyto-photo-dermatitis, Br. J. Dermatol., 54, 193, 1942.
2. Frain-Bell, W. and Johnson, B. E., Contact allergic sensitivity to plants and the photosensitivity
dermatitis and actinic reticuloid syndrome, Br. J. Dermatol., 101, 503, 1979.
3. Behçet, H., Ottenstein, B., Lion, K., et al. Les dermatites des figues. Recherches des influences
cliniques, physiques et allergiques pouvant provoquer la dermatitie des figues, Ann. Derm. Syph., 32,
125, 1939.
4. Burke, D. A., Corey, W., and Storrs, F. J., Psoralen plus UVA protocol for Compositae photosensitivity,
Am. J. Cont. Derm., 7, 171, 1996.
5. Kuske, H., Perkutane Photosensibilisierung durch pflanzliche Wirkstoffe, Dermatologica, 82, 273,
1940.
6. Johnson, B. E., The naturally occurring psoralens and other plant photosensitizers and their mode of
action, in Plants and the Skin, Lovell, C. R., Ed., Blackwell Scientific, Oxford, 1993, 66.
7. Averbeck, D., Recent advances in psoralen phototoxicity mechanism, Photochem. Photobiol., 50, 859,
1989.
8. Ljunggren, B., Psoralen photoallergy caused by plant contact, Contact Derma., 3, 85, 1977.
9. Ortiz-Frutos, F. J., Sanchez. B., Garcia, B., et al., Photocontact dermatitis from rue (Ruta montana
L.), Contact Derm., 33, 284, 1995.
10. Kavli, G., Volden, G., and Raa, J., Accidental induction of photocontact allergy to Heracleum lacin-
iatum, Acta Dermat., 62, 435, 1987.
11. Wu, C. M., Koehler, P. E., and Ayres, J. C., Isolation and identification of xanthotoxin (8-methoxyp-
soralen) and bergapten (5-methoxypsoralen) from celery infected with Sclerotina sclerotium, App.
Microbiol., 23, 852, 1972.
12. Campbell, A. N., Cooper, C. E., and Dahl, M. G. C., “Non-accidental injury” and wild parsnips, Br.
Med. J., 284, 708, 1982.
13. Drever, J. C. and Hunter, J. A. A., Giant hogweed dermatitis, Scot. Med. J., 15, 315, 1970.
14. Tunget, C. L., Turchen, S. G., Manoguerra, A. S., et al., Sunlight and the plant: a toxic combination:
severe phytophotodermatitis from Cneoridium dumosum, Cutis, 54, 400, 1994.
15. Lovell, C. R., Plants and the Skin, Blackwell Scientific, Oxford, 1993, 81.
16. Egan, C. L. and Sterling, G., Phytophotodermatitis: a visit to Margaritaville, Cutis, 51, 41, 1993.
17. Oakley, A. M. M., Ive, F. A., and Harrison, M. A., String trimmer’s dermatitis, J. Soc. Occup. Med.,
36, 143, 1986.
18. Freeman, K., Hubbard, S. H. C., and Warin, A. P., Strimmer rash, Contact Derm., 10, 117, 1984.
19. Reynolds, N. J., Burton, J. L., Bradfield, J. W. B., and Matthews, C. N. A., Weed wacker dermatitis
(letter), Arch. Derm., 127, 1419, 1991.
20. Elpern, D. J. and Mitchell, J. C., Phytophotodermatitis from mokihana fruits (Pelea anisata H. Mann,
fam. Rutaceae) in Hawaiian lei, Contact Derm., 10, 224, 1984.
21. Ena, P., Cerri, R., Dessi, G., et al., Phototoxicity due to Cachrys libanotis, Contact Derm., 24, 1, 1991.
22. Aberer, W., Occupational dermatitis from organically grown parsnip (Pastinaca sativa L), Contact
Derm., 26, 62, 1992.
23. Rosenthal, O., Breloque dermatitis, Berliner Dermatologische Gesellschaft, Dermatol. Zeitsch., 42,
295, 1925.
24. Pathak, M. A., Phytophotodermatitis, Clin. Dermatol., 4, 103, 1986.
25. Pigatto, P. D., Legori, A., Bigardi, A. S., et al., Gruppo Italiano Ricerca Dermatitis da Contatto ed
Ambientali. Italian Multicenter Study of Allergic Contact Photodermatitis: Epidemiological Aspects,
Am. J. Contact Derm., 7, 158, 1996.
26. Tisserand, R. and Balacs, T., Essential Oil Safety: A Guide for Health Professionals, Churchill
Livingstone, London, 1995.
27. Clark, S. M. and Wilkinson, S. M., Phototoxic contact dermatitis from 5-methoxypsoralen in aroma-
therapy oil, Contact Derm., 38, 289, 1998.
28. Anon., Lemon burn warning, Int. J. Aromather., 4, 4, 1992.
29. Fulton, J. R. and Willis, I., Photoallergy to methoxsalen, Arch. Dermatol., 98, 445, 1968.
30. Boucaud, C. and Latarjet, J., Brulure par photosensibilisation lors d’usage cosmétique de méthoxalène,
Pres. Méd., 20, 1945, 1991.

31. Rimington, C. and Quin, J. I., Dikoor or geeldikhop on grassveld pastures, J. S. Afr. Vet. Med. Assoc.,
8, 141, 1937.
32. Brockmann, H., Kluge, F., and Muxfeldt, U., Total synthese des hypericins, Chem. Berichte, 90, 2302,
1957.
33. Jitsukawa, K., Suizu, R., and Hidano, A., Chlorella photosensitization. New phytophotodermatosis,
Int. J. Dermatol., 23, 263, 1984.
34. Ljunggren, B., Severe phototoxic burn following celery ingestion, Arch. Derm., 126, 1334, 1990.
35. Dijkstra, J. W. E. and Chang, L., Severe phototoxic burn following celery ingestion, Arch. Derm.,
128, 1277, 1992.
36. Puig, L. and de Moragas, J. M., Enhancement of PUVA phototoxic effects from celery ingestion; cool
broth also can burn, Arch. Dermatol., 130, 809, 1994.
37. Pedersen, N. B. and Arlés, U.-B.P., Phototoxic reaction to parsnip and UV-A sunbed, Contact Derm.,
39, 97, 1998.
38. Massmanian, A., Contact dermatitis due to Euphorbia pulcherrima Willa, simulating a phototoxic
reaction, Contact Derm., 38, 113, 1998.
39. Ashwood-Smith, M. J., Ceska, O., et al., Photosensitivity from harvesting lovage, Contact Derm., 26,
356, 1992.
40. Zaynoun, S. T., Aftimos, B. G., Abi Abi, L., et al., Ficus carica: isolation and quantification of the
photoactive components, Contact Derm., 11, 21, 1984.
41. Henderson, J. A. and Groseilliers, J. P., Gas plant Dictamnus albus phytophotodermatitis simulating
poison ivy, Canad. Med. Assoc. J., 130, 889, 1984.
42. Gawkrodger, D. J. and Savin, J. A., Phytophotodermatitis due to common rue (Ruta graveolens),
Contact Derm., 9, 224, 1983.
43. Ena, P. and Camarda, I., Phytophotodermatitis from Ruta corsica, Contact Derm., 22, 63, 1990.
44. Moller, H., Phototoxicity of Dictamnus albus, Contact Derm., 4, 264, 1978.
45. Callihan, R. H., Dobbins, R. T., Carson, S. L., et al., TOXPLANT, University of Idaho, 1995.
46. Dauncey, E. A. and Leon, C. J., Plant identification for medical professionals: a computerized solution,
Semin. Derm., 15, 124, 1996.
47. Vale, P. T., Prevention of phytophotodermatitis from celery, Contact Derm., 29, 108, 1993.

Section II
Clinical and Botanical Investigations

7 Phytochemical Procedures
Jean-Pierre Lepoittevin
CONTENTS
7.1 Introduction
7.1.1 Testing with Plants
7.1.2 Identifying the Allergen
7.2 Preparation of Plant Extracts
7.2.1 Solid–Liquid Extraction
7.2.2 Liquid–Liquid Extraction
7.3 Isolation and Purification of the Allergen
7.3.1 Thin Layer Chromatography (TLC)
7.3.2 Liquid Chromatography (LC)
7.3.3 Gas Chromatography (GC)
7.3.4 High Performance Liquid Chromatography (HPLC)
7.4 Identification of the Chemical Structure of the Allergen
7.4.1 Mass Spectrometry (MS)
7.4.2 Spectroscopic Techniques
7.4.3 Infrared (IR)
7.4.4 Ultraviolet—Visible (UV)
7.4.5 Nuclear Magnetic Resonance (NMR)
7.4.6 Determination of the Structure
7.5 Conclusion
7.6 References
7.1 INTRODUCTION
Because of the multitude of substances they contain, plants are responsible for many types of
dermatosis or phytodermatosis.1 This study is rendered difficult by the very large number of plant
species, with more than 300,000 identified and classified at the present time. In addition, the plant’s
chemical composition can be highly variable and depends, to a great extent, on the site and climate.
Phytodermatoses are, therefore, often regional phenomena highly dependent on the patient’s occu-
pation. The very high geographic mobility of people and goods makes the problem even more
complex owing to the presence in our environment of plants or objects of plant origin originating
in the four quarters of the globe.
7.1.1 TESTING WITH PLANTS

During allergological exploration, there can be a great temptation for the dermatologist to test parts
of the plant brought by the patient. This can only be done safely if the plant has been previously
identified so as to avoid any risk of active sensitization. Certain plant allergens are especially active

and many cases of sensitization have been reported during tests performed using plants or plant
extracts. In 1926, Bloch2 reported sensitization of several patients tested with a Primula extract
and, more recently, Tomb3 described active sensitization during tests using Frullania. It should also
be borne in mind that the allergen concentration can vary greatly from one part of a plant to another
and that completely different results can be obtained when testing with a sample of fruit, flower,
leaf, stalk, and so on.
In addition, a positive test is not proof of phytodermatosis, because many plants can be infested
with fungi or yeasts or simply contaminated with herbicides, pesticides, fertilizers or other phy-
tosanitary products.
It is, therefore, preferable, whenever possible, to test with the allergizing molecule(s) at a
precisely defined concentration.
7.1.2 IDENTIFYING THE ALLERGEN

Even today, the structure of many plant allergens is still unknown. The main reason for this is the
complexity of the identification process that requires a succession of events of low probability.
These can be summarized as follows.
First, the sensitized patient must consult a dermatologist. This is rarely the case in regions
where the risk is greatest. Second, the dermatologist consulted must have a strong interest in botany
and this type of problem. Finally, he or she must find a laboratory that can carry out the various
operations required to isolate and identify the allergen. This is a multistep, and often long, process
that consists of three main stages:
• Preparation of the plant extract

• Isolation and purification of the active molecules(s)
• Identification of the structure
Following each stage of purification, the different fractions must be tested on the patient (or
on previously sensitized animals) in order to follow the biological activity through the purification
process. This especially cumbersome assay method is a further major hindrance to the identification
of plant allergens.
7.2 PREPARATION OF EXTRACTS

The chief aim during the preparation of an extract is to obtain as much of the allergizing substance
as possible while avoiding any modifications that could change the chemical structure of the
allergen. This is even more important when one considers that many natural substances are heat-
and/or photo-sensitive and can, therefore, be modified during the extraction process. Experience
has shown that the majority of plant haptens are relatively lipophilic molecules that can cross the
stratum corneum. Extracts are, therefore, generally prepared using organic solvents such as ethyl
ether, acetone, or methanol.
7.2.1 SOLID–LIQUID EXTRACTION

The plant is subjected to extraction either with vigorous agitation in a mixer or in a Soxhlet
apparatus. The material to be extracted, normally dried, and reduced to a powder is placed in a
porous cartridge in the extractor. Then the bottom of the extractor is connected to a round-bottomed
flask and the top to a condenser. When boiled using a heating mantle, the solvent condenses,
refluxing continuously through the cartridge, and the soluble material is, thus, concentrated in the
round-bottomed flask. After evaporation of the solvent under vacuum, a crude extract is obtained
that can be tested after dilution. If this proves active, fractionation and purification can be continued.

FIGURE 7.1 General scheme of liquid–liquid extraction.
7.2.2 LIQUID-LIQUID EXTRACTION

This is a method that is especially useful in the analysis of the highly complex mixtures obtained
from natural products such as crude extracts. It is based on differences in solubility of the molecules
in a mixture of two nonmiscible solvents. The final concentration of a molecule in each of the two
solvents is determined by the partition coefficient. In the case of complex mixtures, it is possible
to perform a series of liquid–liquid extractions resulting in different fractions, the content of which
is a function of the physico–chemical characteristics of the molecules (Figure 7.1). The different
fractions can then be tested on the patient or on animals sensitized to the crude extract.
7.3 ISOLATION AND PURIFICATION OF THE ALLERGEN

The isolation and purification of organic molecules4 mainly involves chromatographic techniques
that rely on differences in the distribution of the molecules between a mobile phase (liquid or gas)
and a stationary phase (liquid or solid). Various combinations of these different phases result in
the main chromatographic techniques used.
7.3.1 THIN LAYER CHROMATOGRAPHY (TLC)

A glass or aluminium plate covered with a thin layer (0.25 mm) of a stationary phase is generally
used. The substance to be analyzed is deposited, using a capillary tube, at points at the bottom of
the plate that is then placed in a closed tank containing the mobile phase (developing solvent). The
mobile phase ascends the plate by capillary action and the different molecules are displaced to
different extents depending on their affinity for the mobile and stationary phases (Figure 7.2). The

FIGURE 7.2 Thin layer chromatography (TLC) principle.
various substances can be detected directly (colored substances), under UV light (UV absorbing
materials) or by staining using specific or nonspecific chemical reagents. Each substance is char-
acterized by its frontal retention defined as:
Rf = Migration distance of the substance / distance of the front from start
This value is characteristic of a given product in a given solvent. Thin layer chromatography
is a highly sensitive method that can be applied to very small amount of material. It is, therefore,
of great analytical use for the qualitative analysis of a mixture of products or to check the purity
of a compound.
The main stationary phases used are silica, alumina, and cellulose. It is also possible to use
phases chemically modified for particular needs; for example, to analyze highly lipophilic products,
it is possible to use stationary phases of silica to which have been bonded to lipophilic 18 carbon
chains (reverse-phase C-18).
The chief mobile phases, in order of increasing polarity, are the hydrocarbons (hexane and
pentane), ethyl ether, ethyl acetate, and methanol.
7.3.2 LIQUID CHROMATOGRAPHY (LC)

This is a preparative version of thin layer chromatography, applicable to large amounts of material.
The stationary phase is packed into a glass column, the material to be separated applied to the top
of the column, and chromatography performed by the passage of a solvent (mobile phase) of
constant or increasing polarity (Figure 7.3). Successive fractions are collected on leaving the column
and their content analyzed by TLC.
7.3.3 GAS CHROMATOGRAPHY (GC)

In this case, the mobile phase is an inert gas (helium, nitrogen, or argon) and the stationary phase
a solid coated with a layer of a nonvolatile liquid. The column is placed in a variable temperature
oven and separation performed (Figure 7.4). This is dependent on both the affinity of the product
for the stationary phase and its vapor pressure. Using gas chromatography, it is, therefore, possible
to separate molecules with the same polarity, but with different molecular weights and, therefore,
different boiling points. On leaving the column, the material enters a detector (thermal conductivity
or flame ionization) and the signal is recorded. This method can be used either analytically or
preparatively, as long as the products to be analyzed are sufficiently volatile.
7.3.4 HIGH PERFORMANCE LIQUID CHROMATOGRAPHY (HPLC)

This method uses the same principle as column chromatography, but the stationary phase is
extremely thin. A better separation is, therefore, obtained because of the increased area of the

FIGURE 7.3 Principles of liquid chromatography (LC).
FIGURE 7.4 Principle of gas chromatography (GC).
stationary phase, but the solvent must be circulated at high pressure to compensate for the loss of
charge. This is currently the most powerful chromatographic method for separation and analysis.
A very large variety of stationary phases (direct or reverse) can be used and partition or ion-exchange
chromatography performed.
7.4 IDENTIFICATION OF THE CHEMICAL STRUCTURE OF THE

ALLERGEN
7.4.1 MASS SPECTROMETRY (MS)
The first problem encountered with a compound of unknown structure is to determine its molecular
weight. The best method for this is mass spectrometry which records the damage caused to
molecules when they are bombarded in the gas phase by a stream of electrons or ions. During the
collision between the molecule and an accelerated electron, the energy of the latter is transferred
to the molecule which can dissipate the excess energy acquired by ejecting an electron (Figure 7.5).
When the now positively charged molecule is accelerated in an intense electric field, then passed

FIGURE 7.5 Principles of mass spectrometry (MS).
into a magnetic field, the ionized molecules deviate from their trajectory to an extent depending
on their mass/charge ratio. Knowing the charge of the molecule, it is then possible to calculate the
molecular weight with great precision.
Mass spectrometry also provides other information. During electronic bombardment, the trans-
ferred energy is usually sufficient to cause fragmentation of the molecules. Splitting does not occur
randomly and certain ions are preferentially formed. Analysis of the mass of these fragments yields
valuable information about the structure of the molecule.
7.4.2 SPECTROSCOPIC TECHNIQUES

When excited by electromagnetic radiation of a given wavelength, molecules absorb energy depend-
ing on the type of atoms and groups of atoms they contain. Absorption in the ultraviolet and visible
range results from electronic excitation, while, in the infrared spectrum, it results from the mode
of molecular vibration. Nuclear magnetic resonance involves nuclear spin transitions and provides
information on the number, type, and relative positions of all the protons in the molecule.
7.4.3 INFRARED (IR)

This is an energy absorption method that affects chemical bonds. The wavelengths used are between
2.5 and 15 mm and the unit most frequently used to describe infrared absorption spectra is the wave
number (cm–1) which is inversely related to the wave length:
cm–1 = 1/mm · 104
The infrared radiation is absorbed and converted into rotational and vibrational energy. The
absorption frequencies depend on the relative masses of the atoms, the binding force constants, and
the geometry of the atoms. Each molecule, therefore, gives absorption bands characteristic of its
constituent bonds. The absorption bands are particularly strong and characteristic when they involve
atoms of different types and/or multiple bonds. It is, therefore, a very good method for detecting
the presence of single or multiple C–O bonds, such as alcohols, ketones, aldehydes, esters, amides,
or acids, and also C–N bonds (single or multiple) and certain multiple-bonded forms of carbon.

7.4.4 ULTRAVIOLET—VISIBLE (UV)
This is an energy absorption method that affects the energy level of the electrons. The wavelengths
involved are between 150 and 400 nm for the ultraviolet and between 400 and 800 nm for the
visible. Ultraviolet absorption involves the movement of electrons from the resting state (funda-
mental) to an excited state. These transitions are determined by quantum mechanics and are
characteristic of certain systems or chromophores. This method is mainly useful for characterizing
carbon–carbon or carbon–heteroatom double bonds, especially if conjugated with other unsaturated
systems such as aromatics.
7.4.5 NUCLEAR MAGNETIC RESONANCE (NMR)

All nuclei have a charge and a mass. Those with an odd mass number also have a spin, that is, an
angular moment. Such nuclei can, therefore, be considered analogous to small magnetic stirrers
and be studied using nuclear magnetic resonance. When an external magnetic field is applied, these
magnetic stirrers have a tendency to align themselves with the direction of the field in the same
way as the needle of a compass aligns itself with the earth’s magnetic field. For the hydrogen
nucleus with a spin of 1/2 , there are two possible orientations, parallel and antiparallel to the direction
of the field. These two states have different energies and it is possible to make the nuclei pass from
the most stable state to the excited state using a radio frequency. The frequency required is
proportional to the magnetic field applied to the sample. For example, it is 200 MHz in a 47,000
gauss field. The magnetic field created by the electronic environment of the nucleus then superim-
poses itself on the field of the equipment and the resonance frequency of each nucleus is a reflection
of the neighboring atoms.
In order to compare information obtained on different machines, the values are expressed as
chemical shift (d ppm) defined as:
d = resonance frequency of the nucleus · 106 / frequency of the spectrometer
The chemical shift value makes it possible to obtain valuable information regarding the direct
environment of each atom studied.
When the magnetic moments tend to align themselves with the external magnetic field, they
produce between themselves interactions called spin–spin coupling. This effect is transmitted to
neighboring nuclei by the bonding electrons and results in signal multiplicity which depends on
the number of neighbors, with the distance between two bands depending on the dihedral angle
between the neighbors. This information, even if it complicates the reading of the spectrum, is very
important because it makes it possible to piece together how the different atoms are connected and
to have an idea of their respective orientations.
By means of certain NMR manipulations, it is also possible to demonstrate interactions across
the space between the atoms. This information makes it possible to build up the three-dimensional
structure of the molecule.
7.4.6 DETERMINATION OF THE STRUCTURE

As a general rule, it is not the use of a single method that allows the complete structure of a
molecule to be determined, but a combination of different methods:
• Mass spectrometry gives the molecular weight and certain information regarding the
molecule fragments. It is, thus, possible to have access to certain known and identifiable
fragments.

• Infrared and ultraviolet spectroscopy indicate the presence of chemical groups (alcohols,
ketones, esters, aromatics, etc), but give no information on their localization on the
molecule.
• Nuclear magnetic resonance first allows the primary structure of the molecule, that is,
the connection of atoms in the molecule, to be determined and the different groups
previously detected to be positioned. Second, it makes it possible, if necessary, to
determine the tertiary structure of the molecule, that is, its spatial conformation.
7.5 CONCLUSION
The identification of a natural allergen is never a simple routine operation but requires the use of
sophisticated methods generally involving several months of work.
7.6 REFERENCES
1. Benezra, C., Ducombs, G., Sell, Y., and Foussereau, J., Plant Contact Dermatitis, Mosby, St. Louis,
1985.
2. Bloch, B. and Steiner-Wourlisch, A., Die willkürliche Erzeugung der Primel über Empfindlichkeit
beim Menschen und ihre Bedeutung für das Idiosynkrasieproblem, Arch. Derm. Syph. (Berlin), 152,
283, 1926.
3. Tomb, R., Patch testing with frullania during a 10-year period: hazards and complications, Contact
Derm., 26, 220, 1992.
4. Gäfvert, E. and Karlberg, A.-T. Isolation and identification of contact allergens, in Allergic Contact
Dermatitis: The Molecular Basis, Lepoittevin, J.-P., et al., Eds., Springer, Berlin, 1997, 43.

8 Botanical Photoallergy
Ai-Lean Chew and Howard I. Maibach
CONTENTS
8.1 Photoallergy and Botanical Photoallergy

8.2 Methodology of Photopatch Testing
8.3 Materials for Photopatch Testing
8.3.1 Light Source
8.3.2 Chemicals
8.3.3 Vehicles
8.3.4 Concentration
8.3.5 Tape
8.4 Recording of Results
8.5 Interpretation of Results
8.6 Hazards of Photopatch Testing
8.7 Conclusion
8.8 References
8.1 PHOTOALLERGY AND BOTANICAL PHOTOALLERGY

Photoallergic contact dermatitis (PACD) describes the eczematous skin reaction caused by the
interaction of UV radiation and a photosensitizing substance. It is a delayed (Type IV) T-cell
mediated immunologic reaction. The effects of UV radiation on photosensitizers induce their
transformation into photoallergens and the formation of specific T-lymphocytes. On repeated expo-
sure to the photosensitizer and UV light, an inflammatory reaction occurs, which is restricted to
exposed skin areas.
Botanical photoallergy, or photoallergic contact dermatitis caused by plants or their industrial
derivatives, is an infrequent phenomenon and has not been well documented,1-4 although the
potential exists, as demonstrated by the photomaximization test for coumarins.5
Review of the literature revealed only four studies in which plants were thought to be photo-
sensitizers.
The first case is a 70 year old retired agricultural worker in India who exhibited a typical
photosensitive eruption, with circumocular and retroauricular sparing, to Parthenium hysteropho-
rus,1,6 commonly known as wild feverfew or congress grass. Closed patch testing and photopatch
testing with the sesquiterpene lactone, parthenin (in acetone and aqueous solutions) were negative,
but subsequent photopatch testing with paste prepared from the fresh plant yielded a positive
reaction. Unfortunately, no controls were performed in this case.
In the United States, Epstein reported suspected photoallergic contact dermatitis caused by
ragweed pollen.7 He presents a case of a 48 year old woman with a chronic facial dermatitis.
Photopatch testing produced weeping and crusting, a stronger reaction than the covered patch test,

which also showed a positive reaction. However, this could still indicate pure allergic contact
dermatitis and the issue is confused by lack of adequate controls.
The third report of Compositae-related photoallergy is described by Burry et al., who coined
the term Australian bush dermatitis, to describe several cases of chronic dermatitis in men living
in the Australian bush. The men all demonstrated sensitivity to the Compositae family on conven-
tional patch testing.8 Of these men, three also had positive photopatch tests to ragweed. Once again,
there were no controls performed, and there was no suggestion in the clinical description of any
circumocular or retroauricular sparing.
In the preceding three cases, the plants belonged to the Compositae family. This complicates
interpretation of the results because members of the Compositae plants are known to cause signif-
icant amounts of both irritant and allergic contact dermatitis (ACD)—the allergen in ACD being
the sesquiterpene lactones that are produced in hair-like structures (trichomes) on the plant surface.
The clinical picture of ACD caused by Compositae commonly mimics photodermatitis, that is, a
chronic erythematous lichenified eruption on exposed skin. Hence, it is difficult to differentiate the
two conditions. In photodermatitis, the upper eyelids, retroauricular areas, and submental skin are
usually spared.
The final presumed report of PACD is concomitant photoallergy and allergic contact dermatitis
in lichens.9 Lichens consist of algae and fungi living in symbiosis. Lichens, like the Compositae,
are also known to cause ACD, simulating a photosensitive eruption. In this Norwegian study,
patients with photosensitive-like eruptions were patch tested and photopatch tested using a series
of aromatic lichen substances. Positive reactions to the various lichens were shown by 16 patients
and, in 6 of them, the reactions were thought to be stronger after irradiation. This could be interpreted
as co-existing photoallergy or wholly allergic contact dermatitis.
8.2 METHODOLOGY OF PHOTOPATCH TESTING

Photopatch testing is a simple and sensitive office procedure, essential in confirming the diagnosis
of photoallergic contact dermatitis, as well as identifying the exogenous photosensitizer.
Techniques in photopatch testing vary—no universal standard exists, although Scandinavian
dermatologists have utilized a standard procedure since 198010 and the German study group has
provided detailed background.11,12 A typical photopatch testing method is outlined next.
Each potential photosensitizer is incorporated into a suitable vehicle (e.g., petrolatum) in a
nonirritating concentration. Duplicate sets of substances are prepared and applied in aluminum
chambers on two patches. These duplicate patches are placed on symmetrical sites on the back,
and sealed with light-opaque material. After 24 to 48 h, one set is uncovered, evaluated and
irradiated, then resealed. At 72 and/or 96 h, both sets are uncovered and evaluated.
8.3 MATERIALS FOR PHOTOPATCH TESTING

8.3.1 LIGHT SOURCE
The most important equipment for photopatch testing is an artificial light source with good spectral
irradiance in the UVA range. The most suitable light sources for photopatch testing in the office are
the high pressure (hot quartz) mercury vapor lamp, fluorescent tubes (Blacklight), and Wood’s light
(Black ray).13 All have adequate irradiance in the longer wavelength UVA range (320 to 400 nm).
The dose of UVA utilized is 5–10 J/cm2 or 50 percent of MED. Photoallergy with UVB has rarely
been demonstrated, but should be considered when a suspected case is negative with UVA exposure.14

TABLE 8.1
Recording of Photopatch Test Results*
Ph – Negative reaction
Ph ?+ Doubtful reaction; faint or macular erythema only
Ph + Weak positive; erythema and infiltration, possibly papules
Ph ++ Strong positive; edematous or vesicular
Ph +++ Extreme bullous or ulcerative reaction
Ph T Phototoxic reaction
Ph NT Not photopatch tested
* International Contact Dermatitis group accepted designations—table

modified from Emmett.18
8.3.2 CHEMICALS
Recommended screening batteries of photoallergenic chemicals are available. These differ from
country to country, and may be modified according to the patient’s history. When botanical pho-
toallergy is suspected, the patient should bring in all suspected plants with which there has been
contact. Portions of the plant, for example, the stem, leaf, root, and petal may be gently crushed
and applied under tape for photopatch testing. For some plants, the specific photoallergen may be
available commercially for patch testing. Irritant plants, for example, psoralens-containing plants
should not be photopatch tested because a photoirritant reaction can be predicted.
8.3.3 VEHICLES
Each chemical or portion of the plant to be tested should be incorporated into a suitable vehicle,
for example, petrolatum, in aluminum chambers.15 When a suspected case is negative with petro-
latum as the vehicle, consider alternative solvents such as ethanol.
8.3.4 CONCENTRATION
A concentration of 1 percent was previously thought to be ideal. However, photoallergenic com-
pounds are frequently phototoxic as well, therefore, in photopatch testing the potential allergen is
diluted to a level where phototoxic reactions are not seen.
8.3.5 TAPE
The sites must be quickly and rigorously covered with opaque material to prevent stray radiation.
Water-resistant tape, such as Scanpor, is frequently used.
8.4 RECORDING OF RESULTS

There are two main schemes utilized for recording of photopatch test results. Both are similar and,
therefore, a source of confusion. The accepted scheme of the International Contact Dermatitis
Group is shown in Table 8.1.

TABLE 8.2
Interpretation of Photopatch Testing Results
Diagnosis Irradiated Site Nonirradiated Site
Normal (no photosensitivity) – –

Photoallergic contact dermatitis + –
Allergic contact dermatitis + +
Dual sensitivity +++ > +
8.5 INTERPRETATION OF RESULTS

Although the photopatch testing procedure is relatively simple, interpretation of results may be
difficult.
Photoallergic contact dermatitis is confirmed by a positive reaction at the irradiated site, coupled
with a negative reaction at the nonirradiated site. Allergic contact dermatitis is seen as equally
positive reactions at both sites. If both sites show positive reactions, with a stronger reaction at the
irradiated site, this suggests dual sensitivity, that is, concomitant allergic contact dermatitis and
photoallergic contact dermatitis (Table 8.2).
8.6 HAZARDS OF PHOTOPATCH TESTING

The following are hazards and complications of photopatch testing:13,19
• Inadvertent sensitization to test materials.

• Mechanical or radiation injury—due to improper use of a light source.
• False positives or negatives—due to inappropriate amount of light, inappropriate con-
centration, angry back syndrome,16 and so on.
• Inaccurate interpretation of data—differentiation from photoirritant dermatitis demands
particular attention, as many plants contain phototoxic agents, for example, psoralens.
Plants of the Compositae species are also known photoirritants.1 For plants of unknown
irritancy, control patch tests on normal subjects are recommended for the accurate
interpretation of results.
• Masked photopatch test17—if inadequately opaque tape is used, then inadvertent irradia-
tion may occur and trigger a reaction in unirradiated patch sites in sensitive individuals
leading to the erroneous diagnosis of photoallergic contact dermatitis.
• Persistent hyperpigmentation at test sites.
8.7 CONCLUSION
Although photomaximization tests have shown that plants are potentially potent photosensitizers,
this does not translate well in practice—few well-documented cases of photosensitizing plants exist.
Insufficient controls and variations in photopatch testing procedures, materials, recording, and
interpretation of results hinder identification of true photosensitizers. Standardization of the pro-
cedure and, in particular, incorporating normal controls when appropriate, may lead to more plants
being identified as photosensitizers in the future.

8.8 REFERENCES
1. Lovell, C. R. Plants and the Skin, Blackwell Scientific, Oxford, 1993.
2. Benezra, C., Ducombs, G., Sell, Y., and Foussereau, J., Plant Contact Dermatitis, Decker, Philadel-
phia/Toronto, 1985.
3. Mitchell, J. and Rook, A., Botanical Dermatology: Plants and Plant Products Injurious to the Human
Skin, Greengrass, Vancouver, BC, 1979.
4. Frosch, P. J., Johansen, J. D., and White, I. R. Eds., Fragrances: Beneficial and Adverse Effects,
Springer-Verlag, Berlin, 1998.
5. Marzulli, F. N. and Maibach, H. I., Dermatotoxicology, Taylor and Francis, Washington, D.C., 1991.
6. Bhutani, J. K. and Rao, D. S., Photocontact dermatitis caused by Parthenium hysterophorus, Derma-
tologica, 157:206, 1978.
7. Epstein, S., Role of dermal sensitivity in ragweed contact dermatitis, Arch. Dermatol., 82, 48, 1960.
8. Burry, J. M., Kuchel, R., Reid, J. G., and Kirk, J., Australian bush dermatitis: Compositae dermatitis
in South Australia, Med. J. Aust., 1, 110, 1973.
9. Thune, P. O. and Solberg Y J. Photosensitivity and allergy to aromatic lichen acids, Compositae
oleoresins and other plant substances, Contact Derm., 6, 81, 1980.
10. Jansen, C. T., Wennersten, G., Rystedt, I., Thune, P., and Brodthagen, H., The Scandinavian standard
photopatch test procedure, Contact Derm., 8, 155, 1982.
11. Rünger, T. M., Lehmann, P., Neumann, N. J., Matthies, C., Schauder, S., Ortel, B., Münzberger, C.,
and Hölzle, E., Recommendations for a photo-patch test standard series by the German speaking study
group “Photopatch-Test,” Hautarzt, 46(4), 240, 1995.
12. Lehmann, P., The German study group photopatch test, Hautarzt, 41(5), 295, 1990.
13. Harber, L. C. and Bickers, D. R., Photosensitivity Diseases: Principles of Diagnosis and Treatment,
2nd ed., Decker, Philadelphia, 1989.
14. Horio, T., Allergic and photoallergic dermatitis from diphenhydramine, Arch. Dermatol., 112(8), 1124,
1976.
15. Tanglertsampan, C. and Maibach, H. I., The role of vehicles in diagnostic patch testing. A reappraisal,
Contact Derm., 29(4), 169, 1993.
16. Bruynzeel, D. P. and Maibach, H. I., Excited skin syndrome (angry back), Arch. Dermatol., 122(3),
323, 1986.
17. Epstein, S, “Masked” photopatch test, J. Invest. Dermatol., 41, 369, 1963.
18. Emmett, E A., Phototoxicity and photosensitivity reactions, in Adam’s Occupational Skin Disease,
Adams, R. M., Ed., W.B. Saunders Company, Philadelphia, 1990, 184.
19. Rietschel, R. L. and Fowler, J. F., Jr., Fisher’s Contact Dermatitis, Williams and Wilkins, Baltimore,
MD, 1995.

Section III
Plant Families Responsible for the
Majority of Dermatologic Reactions
9 Toxic Anacardiaceae
Jere D. Guin, John H. Beaman, and Harold Baer
CONTENTS
9.1 Introduction
9.2 Toxic Anacardiaceae (Anacardium)
9.2.1 Overview
9.2.2 Description
9.2.3 Clinical
9.2.4 Chemistry
9.3 Buchanania
9.3.1 Overview
9.3.2 Description
9.3.3 Clinical
9.4 Campnosperma
9.4.1 Description
9.4.2 Clinical
9.4.3 Chemistry
9.5 Comocladia
9.5.1 Overview
9.5.2 Description
9.5.3 Clinical
9.5.4 Chemistry
9.6 Drimycarpus
9.6.1 Overview
9.6.2 Description
9.6.3 Clinical
9.7 Gluta
9.7.1 Overview
9.7.2 Description
9.7.3 Clinical
9.7.4 Chemistry
9.8 Holigarna
9.8.1 Overview
9.8.2 Description
9.8.3 Clinical
9.9 Lithraea
9.9.1 Overview
9.9.2 Clinical
9.9.3 Chemistry

9.9.4 Lithraea caustica (Mold.) Hook. et Am. (Litre)
9.9.5 Clinical
9.9.6 Lithraea molleoides (Veil.) Engler and Lithraea brasiliensis March
9.10 Loxopterigium
9.10.1 Overview
9.10.2 Clinical
9.11 Mangifera
9.11.1 Overview
9.11.2 Description
9.11.3 Clinical
9.11.4 Chemistry
9.12 Mauria
9.12.1 Overview
9.12.2 Description
9.12.3 Clinical
9.12.4 Chemistry
9.13 Melanochyla
9.13.1 Overview
9.13.2 Description
9.13.3 Clinical
9.14 Metopium
9.14.1 Overview
9.14.2 Description
9.14.3 Clinical
9.14.4 Chemistry
9.15 Nothopegia
9.15.1 Overview
9.15.2 Description
9.15.3 Clinical
9.16 Parishia
9.16.1 Overview
9.16.2 Description
9.16.3 Clinical
9.17 Pentaspadon
9.17.1 Overview
9.17.2 Description
9.18 Pseudosmodingium
9.18.1 Overview
9.18.2 Description
9.18.3 Clinical
9.18.4 Chemistry
9.19 Rhus
9.19.1 Overview
9.20 Schinus
9.20.1 Overview
9.20.2 Description
9.20.3 Clinical
9.20.4 Chemistry
9.21 Semecarpus
9.21.1 Overview

9.21.2 Description
9.21.3 Clinical
9.21.4 Chemistry
9.22 Smodingium
9.22.1 Overview
9.22.2 Description
9.22.3 Clinical
9.22.4 Chemistry
9.23 Spondias
9.23.1 Overview
9.23.2 Description
9.23.3 Clinical
9.24 Swintonia
9.24.1 Overview
9.24.2 Description
9.24.3 Clinical
9.25 Tapirira Aubl
9.25.1 Description
9.25.2 Clinical
9.26 Toxicodendron
9.26.1 Overview
9.26.2 Description
9.26.3 The Black Spot Test
9.26.4 Poison Ivy, Poison Oak, and Poison Sumac
9.27 Toxicodendron rydbergii (Rydberg’s Poison Ivy)
9.28 Toxicodendron radicans (Poison Ivy)
9.28.1 Toxicodendron radicans ssp. negundo
9.28.2 Toxicodendron radicans ssp. pubens
9.28.3 Toxicodendron radicans ssp. verrucosum
9.28.4 Toxicodendron radicans ssp. eximium
9.28.5 Toxicodendron radicans ssp. divaricatum
9.28.6 Toxicodendron radicans ssp. orientale
9.28.7 Toxicodendron radicans ssp. hispidum
9.28.8 Toxicodendron radicans ssp. barkleyi
9.28.9 Toxicodendron vernix (Poison Sumac)
9.28.10 Field Recognition of Toxicodendrons in Winter
9.28.11 Toxicodendron striatum
9.28.12 Toxicodendron in Asia
9.28.12.1 Clinical
9.28.12.2 Chemistry
9.28.13 Effect of Structures on Irritancy and Sensitization
9.29 Immunology of Toxicodendron Dermatitis
9.30 Toxicodendron Dermatitis
9.30.1 Black Spot Poison Ivy Dermatitis
9.31 Sources of the Antigens
9.32 Patch Testing
9.33 Treatment of Toxicodendron Dermatitis
9.34 References

9.1 INTRODUCTION
The Anacardiaceae are well known for the toxic properties of some members of the family,
especially poison ivy (Toxicodendron radicans) in North America. Some of the more toxic genera
are indigenous to the Caribbean and Asia, but these are less well studied and, consequently, are
less well known to the medical community. The nomenclature is subject to change, and this has
forced those reviewing the literature on the subject to be able to recognize both old and new names.
At one time, poison ivy, poison oak, and poison sumac were included in the genus Rhus, but
they now classed as Toxicodendron. Many scientific manuscripts continue to use Rhus to classify
poison ivy and poison oak, which is understandable because Linnaeus put them in that genus, so
it is traditional. However, Toxicodendron originated with Tournefort, who preceded Linnaeus.
Therefore, it is hardly new. There are compelling reasons to separate poison ivy, poison oak, and
poison sumac from Rhus, which is a benign genus. However, doing this broke with tradition, so it
was not often done until Barkley and, later, Gillis wrote classic treatises on the Anacardiaceae and
Toxicodendron respectively. More recently, the scientific publications have shown a shift toward
the use of Toxicodendron for these plants.
The true Rhus is a benign genus which rarely causes contact dermatitis. The family Anacardi-
aceae, however, contains numerous allergenic taxons other than Toxicodendron, so the separation
is not only based on the allergenic principle, but on a multiplicity of botanical features, including
many used in field recognition. Such properties are important when one considers that avoidance
of contact must include plants in all stages of development and in all four seasons. The traditional
use of leaf recognition only by many weekend campers and gardeners has led to many prominent
clinical reactions. Unfortunately, accurate and reliable field identification will necessarily require
one to know something of the typical presentation of plants in one’s own geographic area, but there
are the number of characteristic features that separate benign from toxic taxons. We shall discuss
some of the better known members of this family, clinical features of the cutaneous reaction, plant
chemistry where it is well known and, in the case of Toxicodendron, a brief mention of the
immunology, as a detailed discussion is beyond the scope of this chapter.
The listing of dermatitis-producing Anacardiaceae from the Caribbean and Central America
should not be considered complete, as expected plants are missing from floras of certain locations
(e.g., Dominica) because of agricultural practices. There are also far fewer reports of plant dermatitis
than one might expect from Central America and the Caribbean, as anyone familiar with problems
experienced by American servicemen stationed in Panama. In many cases, our sources are limited
to oral comments by botanists or from annotations on herbarium specimens or in floras.
9.2 TOXIC ANACARDIACEAE (ANACARDIUM)

9.2.1 OVERVIEW
The cashew, A. occidentale, was a pre-Columbian introduction from Brazil into the West Indies.
Its entry into Central America is thought to have been accomplished by the early Spanish governors.
It is too cold-sensitive to tolerate the occasional cold snaps in southern Florida, and it is not grown
in the Bahamas. The cashew nutshell oil is of considerable economic importance. It is used for the
production of friction dusts for use in brake linings and clutch facings. Other uses include epoxy
resins and laminates, paints, varnishes, and foundry core oil.1
9.2.2 DESCRIPTION
The cashew is a small tree, sometimes shrub-like, with a trunk rarely exceeding 6 in. in diameter
and a height of 12–24 feet. It has a dense, irregular crown. The bark is light gray-brown, smooth
to lightly fissured. There is a whitish to reddish-brown inner bark that contains the milky latex.
The twigs are yellowish-green and fuzzy when newly formed. The simple, leathery, elliptic leaves

are a dull blue-green, about 2.5–6 in. long and 2–3 in. broad. Fragrant pink flowers are formed on
a panicle that may be 19 in. long.
The cashew apple (hypocarp) and the roasted seed are both edible parts of the plant. The
hypocarp of Anacardium (Semecarpus is the only other member of the Anacardiaceae with a
hypocarp) is perhaps the most distinctive feature.
The (edible) cashew nut is contained singly in a nutshell. The shell (pericarp) is three-layered.
The outer layer (epicarp) is leathery. The inner layer (endocarp) is thin and hard. In between is a
honeycombed section (mesocarp) filled with an oily liquid. As the nut matures, the stalk at its base
(receptacle) swells rapidly over a few days to form a fleshy, pear-shaped yellow or reddish structure
known as the fruit or cashew apple. This is astringent when green, but may be eaten uncooked
when mature and is used locally for the production of wine and vinegar.2
9.2.3 CLINICAL
Although the cashew plant contains phenols producing allergic contact dermatitis, their concentra-
tion in the nutshell is such that, if undiluted, they induce an immediate vesicant action.3,4 Indeed,
oil oozing from damaged nutshells has been used in Africa to produce ritual scarification and keloid
formation,5 and it has been employed medically for the removal of warts.6
Chronic irritant dermatoses of the palmar surface of the hand are produced in unprotected
agricultural workers.7 The fumes from roasting nuts during processing are very irritating. In a
processing plant in India, (ostensibly irritant) blackish crusting was noted in almost all of the
workers examined, but allergic reactions were much less common.8
Dock workers unloading unprocessed nuts have experienced contact dermatitis. Because the
phenols oxidize in air to produce a shiny black varnish, at one time vanilla beans were coated with
cashew nutshell oil to increase their attractiveness leading to the so-called vanilla bean dermatitis
in dock workers and food handlers.5 Workers in a cashew-nutshell oil processing plant may
experience allergic contact dermatitis, but after continuing to work they seem to develop hardening
so that they are less sensitive or even patch-test negative. Only 2 of 19 workers tested in one study
reacted,9 and persons allergic to poison ivy may see a diminution of the level of sensitivity.10
Eating cashew nut butter contaminated with cashew nutshell-oil caused acute contact dermatitis
involving the perianal area,11 and systemic contact dermatitis involving the flexures and buttocks
has been reported from eating cashew nuts.12 A pesto sauce containing cashew nuts contaminated
by cashew nutshell oil caused systemic contact dermatitis with flexural accentuation, usually 1 to
3 d after ingestion.13
An unusual source of cashew nut dermatitis in children was imported toys made with unroasted
nuts.14 Similarly, adults may be affected from native-crafted jewelry or from party favors, such as
novelty swizzle sticks.15 The recent interest in unprocessed foods in health food stores has resulted
in reports of generalized dermal eruptions in poison ivy sensitized patients who consume large
quantities of raw cashew nuts.16,17 Although most attention is given to dermatitis caused by the
nutshell liquid, the latex also is present in vesicant concentrations in the tree bark.3,5
9.2.4 CHEMISTRY
During World War II, cashew nutshell phenols were used to form resins with electrical insulating
properties for military equipment. Considerable effort was expended on studying the cause and
nature of the dermatitis because of the strategic importance of these resins. Keil and Dawson4
demonstrated cross sensitivity between the cashew and poison ivy. These investigators determined
the nature of the sensitizing phenols and conducted some of the earliest structure-activity rela-
tionship studies in contact dermatitis. They established the importance of the ring position of the
alkyl side chain, its degree of unsaturation, its chain length, and the necessity of the free phenolic
group. They also investigated the relative sensitizing potency of the various phenolic cashew
components.

The principal phenols are anacardic acid, cardol, 2-methylcardol, and cardanol.18,19 Various
processing methods are used.1 The modern industrial method is to convey humidified nuts through
a bath of heated preformed cashew nutshell oil. This bursts the epicarp, releasing the liquid from
the mesocarp, and, simultaneously, decarboxylating the anacardic acids into the desired cardanols.
The roasted nuts, with the endocarp still intact, are centrifuged or rolled in sawdust to remove
residual phenols and then shelled to yield the edible nut.
9.3 BUCHANANIA
9.3.1 OVERVIEW
Buchanania is likely a benign genus because it is common, but reports of toxicity are not common.
Beaman, in 1986, examined the genus in Sabah and found no reactions and no black spots in the
plant press.20 The genus, named for the Scottish botanist, F. Buchanan-Hamilton (1762–1829),
includes about 25 species of trees. These are largely distributed in tropical Asia, Australia, and the
South Pacific.21
9.3.2 DESCRIPTION
The taxon has simple leaves and the bisexual 5-merous flowers, with 5 petals and 10 stamens. The
presence of four to six free carpels rather than the single carpel or compound pistil (as found in
all but one other genus of Anacardiaceae) is the most distinctive feature of the genus.
9.3.3 CLINICAL
There is a report by Altschul,22 of a herbarium specimen of Buchanania lucida Bi. (B. arborescens)
collected in Sabah by Leandro that was labeled juice itchy and was called rengas. This suggests
some question about the potential for toxicity and, therefore, a need for further study.
9.4 CAMPNOSPERMA
The name for Campnosperma comes from Greek and means bent seed. The genus comprises about
10 species of trees of tropical America, Madagascar, and Asia.21,23 An oil from some species of
Campnosperma has been used to prevent parasitosis.20 Timber of C. auriculatum is used for making
canoes, and the exudate from the wood is called terentang-oji. The genus seems to have no English
common name, but one of the more commonly applied vernacular names in Malaysia and Indonesia
is terentang. Campnmosperma has also been reported in Africa (Madagascar).24
9.4.1 DESCRIPTION
Campnosperma has simple leaves, mostly unisexual flowers, stamens twice the number of the
petals, a 1-loculed ovary, and only one stigma and style.20 Campnosperma aurnculaturn (B 1.)
Hook.f. can be found in coastal peat swamps, as well as on well-drained soils up to 1600 m
(5200 ft).20
9.4.2 CLINICAL
This genus is not often reported to be allergenic, but Ding Hou21 mentioned that C. auriculatum
induced “a bad attack of irritation similar to that of rengas,” and Corner25 and Burgess26 have also
implicated the sap in causing allergy in some persons.

9.4.3 CHEMISTRY
Camnosperma is said to contain a 3-nonadecyl, 1,4-dihydroxybenzene.27
9.5 COMOCLADIA
9.5.1 OVERVIEW
This genus essentially is confined to the Caribbean islands, although there are four species along
the southwestern coast of Mexico, one of which extends into Guatemala. None is present in the
United States or South America. There are perhaps 20 species in all, but the genus is in need of
taxonomic revision. A number of published species may represent immature forms or local variants.
Only one species will be described and only a few selected species will be discussed.
9.5.2 DESCRIPTION
Comocladia glabra is representative of this genus. It grows as a small tree to about 20 ft tall at
sea level. At higher elevations, it becomes more shrub-like, and it is vine-like on cliff faces. The
characteristic of this genus is that the leaflets of the pinnately compound leaves have spine-tipped
dentate margins. (This characteristic is particularly pronounced in C. dodonaea.) The plant contains
a whitish latex that turns black on exposure to air. The minute red flowers are borne on a panicle.
The fruit is a small drupe bearing a single seed.
9.5.3 CLINICAL
The latex turns black on exposure to air and a drop leaves a black spot on the skin28 (similar black
spots on the skin are a rare consequence of poison ivy exposure).29 An early and detailed description
of the course of Comociadia dermatitis is given by Pardo-Castello.30 Comocladia dentata (Figure
9.1), known to the populace on Grand Cayman as maiden plum, is avoided by the local population
because of its reputation as a toxic plant.
9.5.4 CHEMISTRY
The chemistry of the sensitizing phenols from this genus has not been explored. Their concentration
in the latex is sufficiently great that it has been used in medicine for the removal of warts and
corns.28,31
9.6 DRIMYCARPUS
9.6.1 OVERVIEW
Drimycarpus (from Greek, pungent fruit) is an unfamiliar genus of trees of southern Asia. It was
long considered to have only a single species, Drimycarpus racemosus (Roxb.) Hook.f. ex March.,
but a second species was added by Ding Hou in 1978 by the transfer of Drimycarpus luridus
Hook.!. Ding Hou, formerly included in both Semecarpus and Swintonia.
9.6.2 DESCRIPTION
Leaves of Drimycarpus are simple, with a distinct marginal nerve.20 Flowers are mostly unisexual
and are especially distinctive and have an inferior ovary (which is quite distinctive). There is a
single style with three stigmas. In the field, these plants look very much like Mangifera, Mel-
anochyla, and Semecarpus.21

FIGURE 9.1 Comocladia dentata on Grand Cayman Island. (From Clinics in Dermatology, 1986, with
permission.)
9.6.3 CLINICAL
Beaman states that he had “seen no explicit statement about allergenic properties of Drirnycarpus;
however, as a member of the tribe Semecarpeae, it must be suspected”20 as all of the other three
genera in the tribe are allergenic, especially Semecarpus. In addition, the common names are also
somewhat incriminating.
9.7 GLUTA
9.7.1 OVERVIEW
The name Gluta comes from the Latin word for glue. This genus comprises about 30 species of
trees or sometimes large shrubs found throughout most of Southeast Asia. The capacity of this
genus to cause dermatitis is well established.
9.7.2 DESCRIPTION
Ding Hou21 combined the genus Melanorrhoea, a name much used in the literature on Southeast
Asian Anacardiaceae, with Gluta, because the known variations between the taxons does not allow
clear separation. Gluta has simple leaves and bisexual flowers. It also has a calyptriform calyx and,
frequently, numerous stamens, absence of a disk, and a single stigma and style. There is considerable
variation in flower structure, however, which makes it difficult to make sharp distinctions of the
genus. Some species of Gluta are found in peat swamps and along rivers where they may be a
dominant vegetation. Individual trees also are found widely throughout much of the lowland tropical
forest in Borneo.

Despite a beautiful deep red heartwood, (sometimes with black streaks or bands), the timber
is seldom used because of its propensity to cause allergy. Sometimes, the logs are left in the forest
to weather before attempting removal.21 Burmese20 and Thai32 lacquer comes from Gluta (Melan-
orrhea) usitata (Wall.). Ding Hou21 states that the lacquer of Cambodia comes from Mellanorrhea
laccifera.33
9.7.3 CLINICAL
Beaman20 describes a collection of Gluta wallichii (Hook.!.) Ding Hou in lowland primary forest
of the Malaysian state of Sabah. His party used a rope thrown over a limb to secure fruiting material,
and all four in the party developed a severe dermatitis despite attempted precautions. He also woke
up one morning on an expedition there to find black sap on the bunk where he had slept. His guides
had made a bed with poles of rengas for use as a bed on the rocky terrain. This was probably a
species of Gluta. The resultant dermatitis appeared within 15–20 h of contact and the sleeping bags
have black spots from these poles to this day.20 He describes a worker who had used a chain saw
to cut down a tree and had developed severe contact dermatitis over most of his upper body, probably
also from Gluta. A similar example was given by Gimlette.34
Dermatitis may be seen in Southeast Asia from gathering firewood as well as producing and
wearing lacquerware.32
Beaman20 also describes a vindictive poison made by mixing sap of Gluta with setae of the
bristleworm and crystals from the decayed fruit of Raphidophora giganteum (Araceae). This poison
is administered by smearing it on the clothes or sleeping mat of the victim.34 Where Gluta occurs,
it is commonly called rengas (or renghas), but many other vernacular names are also used, especially
jitong.34 According to Burgess,26 the name rengas is used for many trees in the Anacardiaceae that
have a black sap, sometimes wrongly. However, the black varnish is an excellent screen to use for
the allergenic species.35
This genus has also been known to be transmitted to persons wading in water as discussed in
Upwich and cited by Senear.36
9.7.4 CHEMISTRY
The fruit sap of Gluta renghas L. reportedly contains the monoethenoid alkyl catechol, glutareng-
hol.37 G. usitata contains thitsol, 4-heptadec(en)ylcatechol (MW 344).32
9.8 HOLIGARNA
9.8.1 OVERVIEW
Holigarna (from hulgeri, a local Deccan name) comprises approximately eight species of trees,
found in India, Thailand, and Vietnam, but the range does not extend as far as Malaysia.38-40
9.8.2 DESCRIPTION
Holigarna has simple, evergreen leaves that are distinctive because the petiole has 1–2 pairs of
deciduous spur-like appendages. The flowers are unisexual, with valvate petals, inferior ovary, and
three styles and stigmas.20
9.8.3 CLINICAL
Holigarna arnottiana Hook. f. ostensibly contains an acrid black juice7 in quantity that appears at
sites of plant injury. Because not all exposed break out, it is thought to be an allergic reaction.37,38
Both the fruit and the bark are said to have been used (with caution) medicinally.20

9.9 LITHRAEA
9.9.1 OVERVIEW
There are three indigenous South American species of Lithraea: L. caustica (Mold.) Hook. et Am.
(Litre), L. brasiliensis and L. molleoides41 all confined to the southern part of the continent.42,43
Perhaps the best known source of information on L. caustica is a monograph by Reyes.42
L. caustica grows in Chile at 30-39 degrees south lat. The word litre, derived from an aboriginal
mapuche word, is now popularly used for both L. caustica and the dermatitis it causes.41 Litre has
become part of the lore of the culture of Chile according to Hurtado.41 Despite its toxic properties,
because its wood is hard and resistant to moisture and decay, Lithraea is used commercially as a
source of heat and energy, for the manufacture of a beautiful reddish wood, for home construction,
and shipbuilding. It has also been used medically as a vesicant. Litre tends to stand out from the
surrounding vegetation in old forests because of its thick foliage and large stature, and it is said to
be a beautiful tree.41
9.9.2 CLINICAL
The genus was first reported to be medically important in 1877, when a facial dermatitis was caused
by introduction of litre leaves into the oral cavity to alleviate toothache.41 In experimental exposure
of 10 volunteers who rubbed leaves of the plant on their arms, only 5 developed reactions on the
rubbed site. One was accompanied by an enormous swelling of the face.42 The resultant skin lesions
reportedly are delayed, are usually vesicular or bullous, and are often accompanied by swelling of
the skin of exposed sites.42
9.9.3 CHEMISTRY
The chemistry of Lithraea is said to be somewhat similar to poison ivy comprising 3-penta and 3-
heptadec(en)ylcatechols.44 Guinea pigs sensitized to L. molleoides were also reactive to T. radi-
cans,45 and persons known to be allergic to litre are also sensitive to poison oak urushiol,44 and T.
striatum46 on patch testing.
9.9.4 LITHRAEA CAUSTICA (MOLD.) HOOK. ET AM. (LITRE)

L. caustica is one of the three indigenous South American species of the genus that are all confined
to the southern part of the continent. (see Ref. 10–28.) (The other two are L. brasiliensis and L.
molleoides.) L. caustica is known outside Chile through the monograph of Reyes,42 from whom most
of the information in this review has been drawn. The plant grows abundantly in Chile at 30–39° south
lat. Curiously enough, its long synonymy, as cited by Reyes, includes Rhus caustica and Mauria
simplicifolia, both classifications as of 1825. As stated previously, the word litre is derived from an
aboriginal mapuche word and now is used to designate both L. caustica and L. caustica dermatitis.
Litre so dominates the botanic world of Chile that, among Chileans, the family Anacardiaceae is
synonymous with litre. It has been the subject of many poems and essays that elaborate on its dangerous
yet inviting shade. Litre is economically important to Chileans. Although they know that its smoke
may cause dermatitis, they burn it as a source of heat and energy. They use the beautiful reddish wood
for construction of houses and ships because it is hard and very resistant to moisture and decay. Another
of its many uses is as a medicinal vesicant. Litre itself, because of its thick foliage and large stature,
is a particularly beautiful tree that stands out from the surrounding vegetation in old forests.
9.9.5 CLINICAL
The first medical report on litre dates from 1877. It states that facial dermatitis was caused by the
introduction of litre leaves into the oral cavity to alleviate toothache. Reyes42 experimented with
10 volunteers who agreed to rub litre leaves on their arms. Only five had delayed skin reactions

on the rubbed site that, in one volunteer, was accompanied by an enormous swelling of the face.
Reyes has reviewed 17 cases of acute litre dermatitis. He noticed that the skin lesions appeared
some time after contact, that they were usually vesicular or frankly bullous, and that many times
they were accompanied by swelling of the face and often of the external genitalia. He states that
the patients had a lowered blood pressure, high eosinophil counts, and leukopenia. Liquid taken
from the skin lesions was rich in eosinophils. It probably is related to that of the toxicodendrons
because guinea pigs sensitized to L. molleoides showed positive reactions to T. radicans.45 Further-
more, in subjects with a past history of litre dermatitis, T. striatum (patch tests) elicited positive
skin reactions.47
9.9.6 LITHRAEA MOLLEOIDES (VEIL.) ENGLER AND LITHRAEA BRASILIENSIS MARCH

The Lithraea molleoides (Veil.) Engler and Lithraea brasiliensis March (Aroeiras, aroeira brava)
species, indigenous to Brazil, extend into Argentina and Uruguay.42,48,49 Their name, aroeira, means
mastic tree; the suffix brava translates into harmful or dangerous. Wood from L. mollcoides is used
for the construction of houses and as a dye.48 Aroeiras are known to be poisonous, and cause aroeira
dermatitis that does not differ essentially from litre dermatitis. Symmetric swelling of the face and
other parts of the body may develop and systemic symptoms, such as fever, may accompany the
dermatitis.48,49 L. molleoides extracts have been shown to sensitize guinea pigs for a skin response
to L. caustica, L. brasiliensis, and T. radicans.45
9.10 LOXOPTERIGIUM
9.10.1 OVERVIEW
Loxopterigium sogotii is popularly called picatón, meaning that it itches and suggesting that it has
allergenic properties. There are a few voucher specimens of L. sagotii Hook., collected in eastern
Venezuela, available at the National Herbarium in Caracas. L. sagotii also has been found in British
Guiana150 and Suriname.51 L. lorentzii has the common name of mal de quebracho.37
9.10.2 CLINICAL
The juices of picatón have been called an irritant to the skin.52
9.11 MANGIFERA
9.11.1 OVERVIEW
North Americans often tend to think of Mangifera (from the vernacular, mango, and Latin, to bear)
as including a single species, Mangifera indica L. (mango). However, Mangifera is a large genus
of trees comprising about 35 species widely distributed throughout Southeast Asia. It is perhaps
most diverse in the region of the Malay Peninsula, Sumatra, and Borneo. The mango has been
cultivated in India for over 4000 years and is said to have over 1000 cultivars.20
The mango, a native of Asia, has become a popular fruit tree in tropical America. It was
introduced into the West Indies in 1742, but it was brought into Mexico and Brazil in the late
seventeenth century.2 It is also cultivated in southern Florida and, on a smaller scale, in Texas and
southern California. However, mango is planted everywhere in both Central America and the
Caribbean, and it has, naturally, escaped from cultivation. This plant is somewhat cold-sensitive,
so it tends not to thrive at altitudes greater than 4000 ft.2 Although the trees are not generally
common, Mangifera is sometimes used for lumber, going under the Malay common name
machang.20 Mango fruit can be eaten raw or dried and made into jams, jellies, pickles, and
chutneys.21

9.11.2 DESCRIPTION
Mangifera indica can reach a height of 60 ft. However most plants in cultivation are kept to about
20–25 ft to facilitate harvesting.2 The trunk and many branches are typically thick, and the typical
crown is dense and rounded. Leaves are deciduous simple, and alternate. They typically are about
6–12 in. long and 1.5–3 in. wide with black spots on sites of injury on older leaves. The latex
reaches the surface3 and oxidizes following adequate trauma from multiple sources.20 The plentiful
erect panicles of yellowish-orange flowers reportedly have an unpleasant fragrance.20 The fruit is
a pendulous ellipsoid or reniform drupe. About 3–6 in. (or more) long, it contains a single, large,
flat, fiber-covered seed set in a firm orange pulp.2 The rind of the fruit becomes greenish-yellow
to reddish-purple at maturity, depending upon the variety.2 The genus has simple leaves, petals
often with glands forming thickened ridges on the inside, one or two fertile stamens and the others
much shorter and sterile, the ovary 1-loculed, and a single style and stigma.20
9.11.3 CLINICAL
Mango is not thought of as being toxic because it is eaten in much of the world. However, allergy
to this plant is well known.53-56 However, reports of reactions to this plant are less common from
tropical regions where consumption is commonplace. This has prompted some to postulate that
consumption of mango early in infancy and thereafter may cause a form of tolerance. The sensitizing
principle is contained in lactiferous ducts within the stem attached to the fruit.2 Patch tests are
positive to sap, leaf, stem, and fruit skin.57 If the fruit is picked, about 1 ml of latex may spill onto
the skin of the fruit. This oxidizes to a shiny varnish. However, the fruit, when peeled, may be
eaten safely by persons who might otherwise be allergic. When the fruit is eaten whole without
removal of the skin, the most common pattern, a circumoral dermatitis and cheilitis, may also be
seen. Stomatitis is less common.2,55 Some agricultural workers develop a more widespread hand-
transfer dermatitis of the face, neck, and genitals.2 Persons allergic to poison ivy or poison oak
tend to be cross sensitive to the mango.2
Mango dermatitis may be less common in those who grew up eating mango. In a study in
Hawaii, the natives of the Islands comprised only 12 percent of the patient population with mango
dermatitis, but they represented 72.5 percent of those with phytophotodermatitis.58 This has been
attributed to their first exposure being oral rather than cutaneous.58
Burgess26 included sap from the bark, smoke from bonfires of Mangifera leaves, and raindrops
from tree crowns among sources of exposure. He notes that timber cutters are reluctant to cut the
trees because of their irritant sap.
While most reactions to this genus are to Mangifera indica, other members of the genus
reportedly can also cause dermatitis. These include M. lagenifera, M. caesia, M. foetida, M.
kemanga, and M. odorata.37
9.11.4 CHEMISTRY
The major component of mango latex is 5-2(Z)-heptadec(en)yl] resorcinol.59 The toxic principle is
mainly in the fruit rind, but it can also be found in other parts of the tree. Allergenic species include
Mangifera caesia Jack, M. foetida Lour., M. lagenifera Griff., and M. odorata Griff.20
9.12 MAURIA
9.12.1 OVERVIEW
Hurtado et al.60 reported the toxic properties of Mauria puberula in 1982, but according to Lampe,2
M. puberula may be only a variant of M. heterophylla. There are, perhaps, 10–20 species in the
genus Mauria, mostly in Venezuela and Peru. According to Blackwell and Dodson61 Mauria glauca
J.D. Sm. and M. birnngo Tulasne are synonymous with M. heterophylla H.B.K., so this may be

the only species in Central America where its range extends from Costa Rica, Honduras, and El
Salvador into Ecuador and northern Peru.2 If Blackwell and Dodson61 are correct in considering
M. glauca J.D. Sm. and M. birnngo Tulasne to be synonymous with M. heterophylla H.B.K.,
perhaps only this single species exists in Central America. Its range extends from Costa Rica,
Honduras, and El Salvador into Ecuador and northern Peru. Standley was not certain that M.
sessiliflora was sufficiently different from M. heterophylla to rank it as a distinct species.62 Ramirez
Goyena63 did not include Mauria in the flora of Nicaragua, but, according to Lampe,2 its presence
there may be assumed, but this needs to be confirmed.
9.12.2 DESCRIPTION
Mauria heterophylla is a small tree some 12–25 ft high, located in the humid upland forests of
Central America, Peru, and Colombia.2,41 Its pinnately compound leaves have 5–7 leaflets. The
white or yellow flowers and the fruit (a drupe) are small and borne in panicles. Hurtado equates
this taxon to M. simplicifolia, and separates it from M. puberula saying that it is a less well-known
species found not only in Venezuela but extending into Colombia and Peru and it is also toxic.41
9.12.3 CLINICAL
Dermatologic reactions to only a few of the South American species, have been described in the
medical literature.60 Mauria puberula is quite similar to M. heterophylla and may be only a variety.2
The only references to such a response for M. heterophylla are in a botanic monograph and on
herbarium sheets, the first of which (as M. glauca) states, “poisonous to some persons, producing
dermatitis and fever.”64 The herbarium annotations read (as M. biringo in Panama), “ ‘Siguella’ is
claimed to be poisonous by the natives;” (as M. heterophylla in Peru) “Produces skin eruptions in
some persons.”22
M. jaramubi, a new Colombian species, called tatacoa (a name meaning poisonous animal) is
also toxic, causing lesions similar to those produced by exposure to T. striatum.41
9.12.4 CHEMISTRY
No chemical studies have been conducted on this genus; however, it was shown that the South
American species, M. puberula, produces dermatitis in 3-pentadecylcatechol-sensitized guinea pigs
and in patients previously sensitized to other genera of Anacardiaceae.41,60
9.13 MELANOCHYLA
9.13.1 OVERVIEW
Melanochyla (from Greek, black sap) is a somewhat unfamiliar genus comprising 17 species of
trees in the Malay Peninsula, Borneo, Sumatra, and Java. Trees of this genus are found almost
exclusively at low levels of primary forests in either swamps or uplands.
9.13.2 DESCRIPTION
This genus has simple leaves, usually papillose beneath. Flowers are mostly unisexual, with the
petals villous or woolly inside. The filaments also are villous. The ovary is deeply set in the
hypanthium, 1-loculed, with a single style and three stigmas.21
9.13.3 CLINICAL
Most species are commonly called rengas, probably because the natives do not distinguish Mel-
anochyla from Gluta and Semecarpus. The economic value of Melanochyla is little mentioned
except for its use as timber. However, it is not usually cut for timber because of the irritant sap.26

Similarly, Mitchell says that M. auriculata (swamp rengas) is not harvested because of its reputation
of producing dermatitis.37 M. beccanana and M. elmeri can also cause dermatitis.25
9.14 METOPIUM
9.14.1 OVERVIEW
There are three species of Metopium found from subtropical Florida, through the Caribbean, to the
Netherlands Antilles, and to the mainland of Central America including southern Mexico, Belize,
and Guatemala. Metopium toxiferum, which is the only species of Metopium found in the continental
United States, grows in the southern tip of Florida. Where it is protected from fire, it may reach
40 ft in height.
9.14.2 DESCRIPTION
All three species are trees, differing in leaflet shape and in the structure of the flower and bud. The
odd-pinnate compound leaves may have three to seven leaflets, but usually have five. Leaflets are
3–4 in. long, leathery, and somewhat shiny on the upper surface. With time, the leaf tends to develop
black spots at the sites of mechanical or insect injury. Natives often recognize the tree from its
thin, reddish bark, that flakes to exude a clear, sticky resin that blackens with exposure. The long-
stalked panicles of flowers, seen only on new growth have five minute, yellowish-green petals and
are relatively inconspicuous. The fruit, tan or orange at maturity, is a small drupe, about 1/2 in.
long, containing a single seed.2
9.14.3 CLINICAL
Each of the species is associated with dermatitis65-67 from the sensitizing catechols in exterior parts
of the tree. The wood68 and pollen69 are not toxic.
9.14.4 CHEMISTRY
Chemical analysis of Metopium toxiferum shows mostly C-15 catechols similar to that of poison
ivy. The content is about equally divided between the C-8 monoene and the C-11 diene with a
small quantity of saturated 3-pentadecylcatechol. There are perhaps 5 percent with unsaturated
heptadec(en)yl sidechains and a trace (less than 0.2 percent) with nonyl substituted catechols.70
The sensitizing catechols70 are similar to those of poison ivy, but this plant is quite toxic in all
exterior parts of the tree, producing strong black spots on specimens collected and causing dermatitis
in persons who normally do not react to poison ivy.
9.15 NOTHOPEGIA
9.15.1 OVERVIEW
Nothopegia (from Greek, a false Pegia, another genus of Anacardiaceae) is a genus comprising
about six species of shrubs and trees found in India and Ceylon. The plants occur in semi-evergreen
or deciduous forests.40 They are not on record to be economically important. A common name in
Sri Lanka (Ceylon) is bala.23
9.15.2 DESCRIPTION
Leaves are simple and flowers are usually unisexual (but sometimes bisexual) and are 4-merous,
with a single style and a barely 3-lobed stigma.20

9.15.3 CLINICAL
Beaman20 found only one literature report23 that the resin is toxic, but he reasoned that the genus
is in the tribe Semecarpeae, and all other genera of Semecarpus are allergenic. Nothopegia seems
to be related to Melanochyla, and its inner bark has a (clear?) latex, which turns black upon drying.23
Beaman concluded that taxononomic and chemical studies of the genus were needed.
9.16 PARISHIA
9.16.1 OVERVIEW
Parishia (for C. S. P. Parish, 1822–1897, an English botanist) comprises five species of deciduous
trees that are distributed from Burma and Thailand to the Malay Peninsula, Borneo, and the
Philippines.
9.16.2 DESCRIPTION
Leaves are pinnately compound and deciduous. The flowers are 4-merous, unisexual, and the 4-
lobed calyx is much enlarged in fruit, forming wings. The ovary is 1-loculed, the style 3-parted,
and the drupe densely pubescent.
9.16.3 CLINICAL
Mitchell and Rook37 attribute a report of dermatitis from Parishia wood to Senear,36 but Beaman
could find no mention of the genus in that paper.20 It is possible that there was confusion of Parishia
maingayi Hook. f. with Melanorrhoea maingayi Hook. f. (equivalent to Gluta wallichii) that was
mentioned by Senear. Burgess26 considered the sap to be nonpoisonous. Although the common name
rengas susu has been applied to P. maingayi, many common names have been used for this and the
other species.21,26 It seems that the allergenic properties of Parishia remain to be demonstrated.
9.17 PENTASPADON
9.17.1 OVERVIEW
Pentaspadon comes from the Greek, five and eunuch, to indicate the five sterile stamens. The genus
comprises six species of large deciduous trees found in the region of Thailand and Vietnam to the
Malay Peninsula, Sumatra, Borneo, the Moluccas, New Guinea, and the Solomon Islands. A black
resin from the tree has been used to treat parasitic itches, but the severity of the skin irritation of
the skin limits that.20
9.17.2 DESCRIPTION
Leaves are compound, and flowers are bisexual, 5-merous, and usually with 5 stami nodes in
addition to the 5 stamens. There is a single style and stigma (which is sometimes slightly 2-lobed),
and a 1-loculed ovary.
9.18 PSEUDOSMODINGIUM
9.18.1 OVERVIEW
Pseudosmodingium comprises five species, but some are not well defined.71-73 All are restricted to
Mexico. The gummy exudate from the trunk is said to be acrid37 and to have a carrion odor.2

9.18.2 DESCRIPTION
Pseudosmodingiun perniciosum, the best known species, is usually a small tree (up to 26 ft in
height) with smooth exfoliative leaves that are pinnately compound with 9 or 11 pale green, oval
leaflets. Flowers are inconspicuous and borne on an erect panicle and the fruit is a flattened, glossy
drupe.71-73
9.18.3 CLINICAL
These plants produce a poison ivy-like dermatitis.71-73
9.18.4 CHEMISTRY
The chemistry of the plant is not well-known.
9.19 RHUS
9.19.1 OVERVIEW
We have previously stated many reasons that Rhus is separate from Toxicodendron. Mitchell and
Rook37 list several species of Rhus as causing dermatitis, but the problem may be one of nomen-
clature because several of the taxons mentioned are known to be misclassified as Rhus in those
reports. For example, Rhus juglandifolia and R. striata are Toxicodendron striata, R. metopium is
Metopium toxiferum, and R. punjabensis was mistaken for Toxicodendron wallichii.74 There is one
report of R. typhina, staghorn sumac, possibly causing dermatitis. If this plant ever causes a problem,
we have never seen it. The plant produces a negative black spot test, and no specimen of Rhus that
we have collected has caused black spots on the paper. Therefore, any allergic reaction would have
to be to a component other than a substituted catechol or resorcinol. In short, true Rhus is a benign
genus.
9.20 SCHINUS
9.20.1 OVERVIEW
Schinus comprises some 28 species, mostly indigenous to South America, with some that range
into Mexico. Perhaps the best known for its problems is the Brazilian pepper-tree, Schinus
terebinthifolius, which since it was introduced into Florida, has become something of a pest. In
Florida, it is known as Florida holly where it has escaped cultivation and become a part of the
flora. The worst part is that it has seemingly resisted all efforts at eradication. The plant is said to
be controlled where the land reverts to swampland, but the economics of the area do not allow
that methodology.
9.20.2 DESCRIPTION
Schinus terebinthifolius is a small tree reaching some 25–30 ft.2 Leaves are compound odd pinnate
with five, seven, or nine leaflets often toothed and attached directly to a winged rachis. The injured
specimen when collected has a peppery-turpentine odor.2
9.20.3 CLINICAL
Dermatologists in Florida generally consider this plant to cross-react with poison ivy,75 although
this remains to be proven. The latex from bark and crushed berries is said to cause allergic contact
dermatitis,6 and has been called the most common cause of allergic contact dermatitis in South

FIGURE 9.2 Dr. John H. Beaman in Sabah pictured with what is likely a new species of Semecarpus collected
there. (From Beaman, H., Allergenic Asian Anacardiaceae, Clinics in Dermatology, 4, 191, 1986, with permission.)
Florida.75 It was also the cause of the pink peppercorn caper, when its use as a seasoning was
followed by outbreaks of diarrhea and perianal dermatitis.
9.20.4 CHEMISTRY
Schinus terebinthifolius contains a number of terpenes, but the sensitizing fraction is said to be a
3-pentadec-8-enyl phenol,203 also known as cardanol and present in cashew. Unfortunately, the
chemical study cited used only the fruit and other chemists who have attempted isolation of the
toxic fraction have found inconsistent data. Dr. Jerry McLaughlin at Purdue University isolated a
nonadecyl phenolic from one specimen from the Florida Keys (collected by George Avery) and
could not duplicate this with subsequent collections (also collected by Avery) later the same year.
Brian Lawrence also told one of us (Guin) that he had also experienced problems in consistently
isolating a toxic principle from this plant.
9.21 SEMECARPUS
9.21.1 OVERVIEW
Semecarpus comprises many species, all of which are probably allergenic.20 One is illustrated in
Figure 9.2. The best known example is Dhobi-mark dermatitis as reported by Livingood and
FitzHugh (see below). Many of these species are found in a limited geographic area and to this
day all species may not be well known. The name for the genus, Semecarpus, comes from Greek,
referring to the juice of the fruit used for marking cloth. The taxon includes some 60 species ranging
from India to Ceylon, Burma, Thailand, Indochina, Taiwan, Australia, Micronesia, the Solomon
Islands, New Caledonia, and Fiji.20
9.21.2 DESCRIPTION
The individual species may be trees, treelets, or shrubs. The genus has simple leaves that are often
papillose on the lower surface. The leaves vary greatly in size, as may be seen in Semecarpus
borneensis Merr. with relatively small leaves, and the Semecarpus sp. shown in Figure 9.2 with
very large leaves. The latter plants are treelets with a rosette of leaves near the summit of a slender

trunk 2–6 m (6.5–20 ft.) high.20 The flowers, mostly unisexual and 5-merous, have three styles and
stigmas and a 1-loculed ovary. As with Mangifera, the fleshy hypocarp at the base of the drupe is
a distinctive feature.21
9.21.3 CLINICAL
Semecarpus anacardium, the Indian marking-nut tree, is also called Dhobi’s nut. The bhilawa oil
from the ripe pericarp is used in a mixture with lime water or lum25 or the green nut76 as an ink
to mark laundry. S. orientale also induced dermatitis in a laboratory worker cutting the fruit.77
Mitchell and Rook37 give numerous examples of contact dermatitis caused by clothing marked with
this substance, and they provide a list of other species of Semecarpus that cause contact dermatitis.
Apparently, there are two patterns in those using the nut for a laundry mark and two other patterns
in those wearing the marked clothing.
The persons making the laundry marking ink typically break out on the hands or face but may
break out on the legs if the nut is crushed in a mortar and pestle held between the knees.37 A
different pattern is seen in those wearing clothing marked with the plant extract. In 1943, Livingood
and FitzHugh evaluated an epidemic of contact dermatitis in military personnel of the 20th General
Hospital in the China Burma India Theater. Of the population exposed, 11 of 55 officers and 41
of 344 (enlisted) men developed contact dermatitis. The eruption was seen directly under the marked
spot on the individual’s clothing and in some of the more sensitive, eczema was found elsewhere.
The eruption responded promptly after contaminated clothing was avoided with the worst cases
sometimes taking two weeks. Re-exposure caused a return of the eruption. Some of the natives
believed that the rash occurred only in some because the tree had a like or dislike for certain
individuals.
Livingood and FitzHugh’s description76 of the marking procedure is somewhat different from
that of Mitchell and Rook. They saw the natives stick the (green) nut with a pin that was then
contaminated with a dark fluid that could be used to mark clothing. Patch tests to the ripe nut were
negative in 8 of 41 allergic subjects, but all of the 8 reacted to an extract of the green nut that was
said to have stronger allergenic properties.76 The marks were indelible, not removed by washing,
boiling, solvents, or sun exposure. Livingood and FitzHugh felt that there was some evidence that
repeated washing tended to diminish the allergic effect, but they recommended that the marks be
removed (excised) from the clothing of those affected.
Despite the numerous species of Semecarpus, relatively few commercial uses are recorded for
the genus, perhaps because it is such a potent contact allergen. The hypocarp of S. anacardium is
edible after roasting,25 and that of S. cassuvium is also said to be edible.21 The very young, white
(before chlorophyll is formed) leaves are said to be eaten raw,21 and the sap of this species is also
used as a black dye. The juice of the fruit wall is sometimes used as a treatment for ringworm and
has been called a cure for a rather heroic nature.78
9.21.4 CHEMISTRY
The allergenic chemical of Semecarpus anacardium L.f., called bhilawanol by some authors, is
reported by Loev79 as a mixture of cis and trans isomers of urushenol. Mitchell and Rook say that
S. heterophylla contains renghol, a pentadec(en)yl catechol with one unsaturated bond in the side
chain. It is unlikely that examination of multiple clones will reveal only one chemical because this
would be unusual for the more modern studies of the various Anacardiaceae. S. australiensis
contains a principle similar to poison ivy.80 Mitchell and Rook list S. vernicifera (used to make
Formosa lacquer) and S. travancorica among species containing Laccol, a catechol with a dienoic
3-heptadec(en)yl substitution.

9.22 SMODINGIUM
9.22.1 OVERVIEW
Smodingium argutum is a toxic species found in the eastern Cape and Natal of South Africa, but
is not indigenous to any other part of the African continent.81 In 1963, this plant was first reported
to cause a rash similar to that produced by T. radicans,82 it was recognized as toxic by tribal members
of the native population, botanists, horticulturalists, and amateur gardeners for a long time.81 The
plant, like many of the Anacardiaceae, has been cultivated for its beautiful red foliage in the fall,
so it may be seen growing as a shrub or climbing vine in parks and recreational areas.83 The species
has been known since 1832.82
9.22.2 DESCRIPTION
The plant can be seen growing as a shrub, a tree up to 20 ft tall or as a climbing vine.81 The leaves
are trifoliate81 or ternate. The plant, similar to many of the Anacardiaceae, may demonstrate brilliant
autumnal colors for which it has been planted.
9.22.3 CLINICAL
The clinical dermatitis is caused by contact with sap from the injured plant, much like poison ivy,
and the presentation of the rash is similar. Contact may occur in private gardens or less typically
in public parks and playgrounds.81 This species cross reacts in much the same way as (western)
poison oak, which it mimics in its chemistry.81
9.22.4 CHEMISTRY
The toxic material, which tends to contain heptadec(en)yl catechols as mono- or diolefins, is carried
in resin canals,84 similar to T. radicans.
9.23 SPONDIAS
9.23.1 OVERVIEW
Spondias (Greek name for plum) comprises 10 species found in the Indo-Malesian and American
tropics.21 Three species of Spondias are Malesian, while two others are American. Spondias mombin
L. and S. purpurea L. are cultivated widely in the Asiatic tropics. S. mombin is cultivated as a shade
tree, but its fruits are inedible. S. purpurea, however, is grown for the fruit (which is said to taste
like plums in turpentine).25
9.23.2 DESCRIPTION
The pinnate compound leaves have leaflets with a distinct vein running near the margin. The four
or five petals are valvate. Usually there are 10 stamens. The ovary can be from 5- to 1-loculed,
and there are from one to five styles.
9.23.3 CLINICAL
Spondias is generally considered an unlikely source of dermatologic problems.20 However, Mitchell
and Rook37 quote Woods and Calnan who had a sawyer with contact dermatitis and a strong positive
patch test to the sawdust of S. mombin. The bark of S. pinnata has been said to be an irritant.38

9.24 SWINTONIA
9.24.1 OVERVIEW
Swintonia, named for G. Swinton, a government official in Bengal about 1840, comprises approx-
imately 12 species of trees in southeast Asia and the Malay Archipelago.
9.24.2 DESCRIPTION
The simple leaves have a marginal nerve, and the lower leaf surface of some species is distinctly papillate.
A distinctive feature of the genus is that the five petals are persistent and become much enlarged with
fruit. Beaman20 describes their functioning like helicopter blades to disperse the fruit, a situation similar
to that in some species of Gluta. The ovary is 1-loculed and there is a single style and stigma.
9.24.3 CLINICAL
Although Burgess26 considered the sap of the genus to be nonpoisonous, members of the genus have
black sap and their common name is rengas, suggesting that they may possess allergenic properties.
Foxworthy85 listed Swintonia along with Gluta, Holigarna, Melanorrhea, and Semecarpus as
the principle poisonous woods of Indo-Malaysia. Beaman points out, however, that some species
that were formerly included in Swintonia have been transferred to Gluta, however, so the status of
Swintonia as an allergen remains uncertain.
9.25 TAPIRIRA AUBL.

Tapirira guianensis Aubl. (Jobillo, pau pombo), a native of tropical South America, according to
Hurtado is found in Venezuela.41 It reportedly roots so easily that limbs are used in fence building.
The wood is sometimes used for construction, and the fruit is edible.50,51,86,87
9.25.1 DESCRIPTION
Members of this taxon are shrubs to large trees with evergreen leaves. Leaves are alternate, pinnately
compound usually petiolulate, with approximately 5–9 leaflets, and secondary veins are joined
together in a series of marginal loops. The inflorescence is axillary or terminal, paniculate. Flowers
are pedicellate or sessile, cream colored to yellow or greenish yellow, 5-merous, petals imbricate,
usually with 10 stamens inserted below the intrastaminal disk; ovary densely pubescent, 1–3 locular.
The fruit is a fleshy drupe, reddish purple or black, and edible when ripe, stone without an
operculum. In tropical America seven or eight species are distributed from Mexico southward
through Central America and northern South America to Bolivia and Paraguay.88
9.25.2 CLINICAL
Exudate from this species is said on botanical records to be caustic and to cause dermatitis,41 and
freshly crushed leaves have been used as a vesicant.89 Dr. Tom Wendt, who has collected the
Mexican taxons, climbed them and eaten the fruit without ill effect. However, some of the local
people have complained of some burning of the mouth (personal communication from Tom Wendt,
Ph.D., Curator of Herbarium, University of Texas, Austin, TX).
9.26 TOXICODENDRON
9.26.1 OVERVIEW
Although the genus Toxicodendron is not considered by all taxonomists to be distinct from Rhus, the
evidence reviewed by Gillis74 strongly supports separation of these genera. Toxicodendron includes
about 30 species widely distributed in Asia and America in temperate areas and tropical mountains.

FIGURE 9.3 Toxicodendron succedanea, the Japanese wax tree. (From Clinics in Dermatology, 1986, with
permission.)
9.26.2 DESCRIPTION
Toxicodendron is a genus of small trees, shrubs, and vines with compound leaves except for T.
borneense (Stapf) Gillis with simple leaves. The flowers are unisexual and 5-merous, with five
sepals (or calyx lobes), five petals, and five stamens. The ovary is 1-loculed with a short style and
three stigmas. Toxicodendron has 15 species in China,90 and probably 8 species in the Malay
Archipelago. Only T. succedanea (L.) Moldenke (Figure 9.3) occurs in both areas. There are only
six species in the western hemisphere, so the diversity of poison ivy relatives is considerably greater
in the Old World. The chemistry of the allergenic compounds in Toxicodendron varies with the
taxon and is covered under the specific species.
Leaves of Toxicodendron species that have three leaflets per leaf are said to be ternate, while
those with more than three leaflets are odd pinnate. Toxicodendrons usually do not develop flowers
and fruit for three or more years, and until they do, one cannot separate male from female plants.
Flowering and fruiting structures arise between the leaf and the twig, so they are said to arise in
the axillary position (Figure 9.4). The petiole, which supports the three leaflets, is enlarged toward
its origin (Figures 9.4 and 9.5), and there is a groove on the distal surface through which the
flowering and fruiting structures arise (Figure 9.5). In North America, this feature can be observed
even during winter months when no leaves are present because the leaf scar left at the season’s
end is U- or V-shaped (Figure 9.5). The (terminal) flowering and fruiting structures of Rhus arise
at the end of the branch. Both Rhus and Toxicodendron are dioecious, that is, there are both male
and female plants. The male flowers (Figure 9.6) tend to have prominent stamens and are more
fragrant than female flowers (Figure 9.7). This often attracts bees and other insects during the
flowering season.
Individual fruits (Figure 9.4) are drupes. These are borne in panicles (Figures 9.4 to 9.7). The
female flowers when pollinated develop into fruits that are green during the growing season
(Figure 9.4) and become off-white in the fall of the year. The off-white exocarp often peels away
during winter exposing a chalk-white mesocarp with black lines (Figure 9.5) representing toxic
oleoresin within secretory canals within the mesocarp. The lines are oriented like longitudinal
divisions on a globe (Figure 9.5). The fruits found on mature female plants are helpful in winter
recognition, often allowing identification of small specimens of T. rydbergii that protrude above
the snow. Fruit, when heavy, tends to be pendant. This is especially true of T. diversilobum.

FIGURE 9.4 T. radicans ssp. radicans showing the fruit on a female specimen during the growing season.
Another distinguishing feature is the tendency for Rhus to have hairs on the surface that are
glandular. Toxicodendron may or may not have hair (tricomes) on the surface, but in either case
the tricomes present do not contain glands. The tricomes in Rhus tend to be glandular. Pollen grains
of Toxicodendron are smaller, usually less than 32 mm in length. Toxicodendron also demonstrates
brown root hairs.
The sap of Toxicodendron tends to darken in the air, and one may see black spots that resemble
black enamel paint in areas of previous injury. This can often be helpful in field recognition. In
Malaysia and the Caribbean where even more toxic plants are found, the black stains on the trunk
of trees is often used to identify rengas and poisonwood (Metopium). Self-melanization of alk(en)yl
catechols is also the basis for the black-spots test, used to confirm the identification of toxic
Anacardiaceae in the field.
9.26.3 THE BLACK SPOT TEST

To do a black spot test, one needs to transfer sap from poison ivy leaves to a sheet of white paper.
Using vinyl gloves, three or four leaves can be collected. These are placed in a folded sheet of
white paper and crushed against a hard surface, such as concrete or asphalt, using a disposable
object such as a stone, brick, or rock. For a positive test, there must be enough sap to create a wet
spot on the paper.
The leaves are discarded and the paper is checked at 5-min intervals. The positive test should
begin to turn dark after 10 or 15 min and black after 24 h. Other toxic Anacardiaceae will also
produce this pattern, and some more allergenic taxons such as Metopium produce dark spots more
quickly. A positive test is not absolute proof but can be very helpful in questionable cases of field
recognition.
9.26.4 POISON IVY, POISON OAK, AND POISON SUMAC

There two species of poison ivy, two species of poison oak, and, in the United States, one species
of poison sumac. One species of poison ivy, Toxicodendron radicans that tends to climb trees and
other objects, has nine recognized subspecies, six of which can be found in the United States. The
term subspecies is normally used to separate plants of the same species with distinct characteristics
found in a specific geographic range. The other species of poison ivy, T. rydbergii (Figure 9.8), is

FIGURE 9.5 Drawing of poison ivy (T. radicans) to illustrate some of the characteristic features. (1) Buds are
not terminal, so new growth is in a different direction each growing season. (2) Petioles are enlarged at the points
of attachment and grooved on the dorsal surface. (3) Leaf scar left where a leaf has dropped off ar U- or V-
shaped. (4) Fruit arising in the axillary position. (5) Trichomes are present on the fruits of poison oak and some
species of poison ivy. (6) The exocarp, which is off-white when mature in the fall, tends to peel away during
winter, leaving the chalk-white mesocarp. (7) Fruits showing the chalk-white mesocarp often demonstrate black
lines like longitude lines on a globe. These represent the (toxic) resin canals. (8) Female specimens may show
empty fruit stalks when fruits have been harvested by birds. (9) Lenticles, tiny holes in the bark, are valuable
aids in recognition of mature plants, especially in winter. (From Clinics in Dermatology, 1986, with permission.)

FIGURE 9.6 Male flowers of T. radicans ssp. negundo. (From Clinics in Dermatology, 1986, with permission.)
FIGURE 9.7 Female flowers of T. radicans ssp. negundo. (From Clinics in Dermatology, 1986, with
permission.)
a nonclimbing small shrub found from southwestern Texas to the northern tier of the United States
and Canada north of the 44th parallel and west of the region that has 29 or more inches of annual
rainfall.74
Western poison oak, T. diversilobum (Figure 9.9), unlike its eastern counterpart, grows in many
types of soils provided water is present in adequate quantity. The fruit on female plants is the largest
of the domestic toxicodendrons, and because of its weight, tends to be pendant. T. diversilobum,

FIGURE 9.8 T. rydbergii in the Indiana Dunes. This is a nonclimbing species of poison ivy.
FIGURE 9.9 T. diversilobum, western poison oak.
or western poison oak, can be found from Baja California in Mexico to the lower latitudes of British
Colombia (Figures 9.10 a, b). It is mostly contained by the Rocky Mountains, but some local
dermatologists have found it in the mountainous regions of Nevada. This species, which is much
larger than eastern poison oak, has one of the widest ranges and the most varied soil type of any
California shrub.74 This species is commonly seen as a shrub, but it may develop aerial rootlets and
climb. Hair may be seen on the fruit as well as the bark of the branch.74,91
The fruit, a drupe that is largest among domestic toxicodendrons74 (up to 7.5 mm), is pendant74,91
and similar to ripe cherries. Lobes on leaflets are rounded but seem to be less stiff than those of
T. toxicarium. The shape of the leaflets, like T. toxicarium, has been likened to leaves of white oak,
but it is perhaps closer to those of live oak (Quercus agrifolia).92
T. toxicarium (Figure 9.11), eastern poison oak, is a small shrub found in sandy soil of poor
nutritional and low calcium content and, in the ridge and valley areas over sandstone outcroppings.
The range is shown in Figure 9.12. It tends to grow slowly so that plants less than 1 ft tall can

FIGURE 9.10a Range of T. diversilobum.
FIGURE 9.10b Range of T. rydbergii.
sometimes be seen producing flowers and fruit. Eastern poison oak, unlike T. radicans and T.
diversilobum (western poison oak), does not produce aerial rootlets and does not climb trees. It is
commonly seen in a savannah woodland (less than 50 years old) together with scrub oak trees such
as turkey oak, and pine, sassafras and bunch grasses. Gillis considered the habitat to be so distinctive
that it could be recognized from a moving automobile. Poison ivy and poison oak prefer different
soils, but in the southeastern United States they are still sometimes found rather close to each other.
They do not tend to hybridize because they do not flower at the same time, but this can be done
artificially and putative hybrids are occasionally seen in the field.
In locations where poison ivy [T. radicans ssp. radicans (Figures 9.13 to 9.15)] and poison
oak [T. toxicarium (Figures 9.11 and 9.12)] are both found, there are several characteristics that

FIGURE 9.11 T. toxicarium, eastern poison oak.
FIGURE 9.12 Range of T. toxicarium.
can be used to distinguish them. Poison oak has hair (pubescence) on the leaves, petioles and fruit,
while T. radicans ssp. radicans tends to have tufts of hair in leaf axils (Figure 9.15). T. radicans
ssp. radicans tends to form aerial rootlets, while T. toxicarium does not. The morphology of leaflets
tends to depend somewhat on the maturity of the plant.
The archetype leaflets of poison oak resemble those of white oak (Quercus alba) so closely
that an experienced botanist has to be careful to look before grasping what seems to be a white
oak sapling in the woods, but leaf morphology of T. toxicarium is so variable that it is often
unreliable as a recognition feature.93 Lobes on leaflets are rounded, but leaflet morphology of eastern
poison oak is greatly variable with some clones essentially unlobed and many intermediate grada-
tions.93 The leaves on T. toxicarium arise fairly close together from the stem of the plant so the
foliage is said to be pseudoverticillate.
Plant chemistry is also somewhat different. The toxic principle in poison ivy comprises mostly
pentadec(en)yl catechols, while the oleoresin of poison oak contains mostly heptadec(en)yl catechols.

FIGURE 9.13 T. radicans ssp. radicans.
FIGURE 9.14 Range of T. radicans ssp. radicans.
9.27 TOXICODENDRON RYDBERGII (RYDBERG’S POISON IVY)

In the northern tier of the United States and Canada (Figure 9.8), north of the 44th parallel and
west of the region that has 29 or more inches of annual rainfall (Figure 9.10b),74 poison ivy grows
as a small shrub that does not climb trees because it lacks aerial rootlets.74,91,94 It often produces
upright branches74,91 that in winter can resemble tines on a fork (Figure 9.8).74,95 Typically leaflets
are quite broad and petioles are long and glabrous.91 While the fruit and petiole lack hair, but hair
sometimes can be found on the under surface of the leaflets.74 These small, slow growing plants,
may be sufficiently mature to produce fruit and flowers when only 8–10 in. above the ground.95
The petioles of the leaves tend to arise closely together giving a pseudoverticillate appearance.
Where the range of T. rydbergii overlaps the range of T. diversilobum (along the Klickitat River in
Washington and the Hood River in Oregon), the two species have been known to hybridize.74

FIGURE 9.15 Hair in vein axils that tends to be straw-colored on the under surface of a leaf of T. radicans
ssp. radicans. Hair is also present in the two oriental taxons, T. radicans ssp. hispidum and T. radicans ssp.
orientale, but the color is slightly different.
FIGURE 9.16 T. radicans ssp. negundo.
9.28 TOXICODENDRON RADICANS (POISON IVY)

The range is presented in Figure 9.14. Along the East Coast of the United States, T. radicans ssp.
radicans (Figure 9.13) has pubescence on fruit although the plants in southern Florida lack this
feature.74,91 The leaflets also have straw-colored tufts of hair in vein axils; (Figure 9.15) This taxon
tends to form aerial rootlets, and it frequently climbs trees, utility poles, fence posts, and other
structures.74,91,94 Mature leaflets typically are ovate (widest below the center), and they are unlobed
(entire) or have a single lobe.74,96 In the herbarium, leaflets from this subspesies can be separated
from those of the oriental subspecies whose leaflets have reddish tufts of hair in vein axils and
obovate leaflets (wider distal to or above the center).74

FIGURE 9.17 Range of T. radicans ssp. negundo.
9.28.1 TOXICODENDRON RADICANS SSP. NEGUNDO
Toxicodendron radicans ssp. negundo (Figure 9.16), the dominant taxon of poison ivy in the
midwestern United States, is so named because its leaves can greatly resemble those of boxelder
(Acer negundo).74,91,97 Leaflets and fruit lack pubescence except some along veins on the leaflet
undersurface, but petioles show this.74 The lateral leaflets often have single lobes laterally that
resemble the thumbs of mittens with the palms upward.94,97 The range of this taxon (Figure 9.17)
overlaps many other U.S. subspecies (exceptions are T. radicans ssp. eximium and divaricatum),74,98
and hybridization is likely where there is geographic overlap.74
9.28.2 TOXICODENDRON RADICANS SSP. PUBENS
Toxicodendron radicans ssp. pubens (Figure 9.18), a plant of the fertile soil of the Delta region of
the Mississippi River and its tributaries, has glabrous fruit but broad, densely pubescent leaflets
with a dentate margin and prominent veins.74,91 The terminal leaflet is quite wide, often wider than
it is long. The foliage has a dull appearance caused by the dense pubescence.91 While the subspecies
archetype is found near the Mississippi River (Figure 9.19), this subspecies tends to contribute its
characteristics to putative hybrids in overlap areas.
9.28.3 TOXICODENDRON RADICANS SSP. VERRUCOSUM
Toxicodendron radicans ssp. verrucosum (Figure 9.20) grows in the limey soil74,91 southward from
the Arbuckle Mountains of Oklahoma along the Edwards Plateau of Oklahoma and Texas
(Figure 9.21).74 While some have confused this plant with poison oak because of the deeply lobed
leaflets, it is very different. T. radicans ssp. verrucosurn does not have pubescence on fruit and
leaflets. It is found in high-calcium (as opposed to low-calcium) soil, it develops aerial rootlets, it
is a large plant when mature, and it tends to produce sharply pointed lobes on its leaflets—all
different from poison oak.74,91

FIGURE 9.18 T. radicans ssp. pubens.
FIGURE 9.19 Range of T. radicans ssp. pubens.
9.28.4 TOXICODENDRON RADICANS SSP. EXIMIUM
Toxicodendron radicans ssp. eximium (Figure 9.22) is a rare plant found in Big Bend National Park
and sometimes in tributaries of the Rio Grande River (Figure 9.23). It has unusual foliage with
lobing of the leaflets so deep and rounded that one might not suspect its toxic nature. Both the
leaves (Figure 9.24) and fruit have a soft, pubescent surface.74,91 The individual leaflets have a
deeply lobed configuration (Figures 9.22 and 9.24) that has been compared with that of a club on
playing cards.74

FIGURE 9.20 T. radicans ssp. verrucosum.
FIGURE 9.21 Range of T. radicans ssp. verrucosum.
Because of the lobing and pubescence, some might try to classify this as a form of poison oak.
However, its large size, its range, its inclination to climb with aerial rootlets, its lack of a pseudover-
ticillate leaf pattern, and its rocky (higher calcium) habitat, all help to distinguish it from (eastern)
poison oak.74 While it has been reported rarely in other locations, it can be found regularly in Oak

FIGURE 9.22 T. radicans ssp. eximium. (From: Guin, J.D., Beaman, J.H., Gillis, W.T., Recognizing the
toxicodendrons, J. Am. Acad. Dermatol., 4, 99–114, 1981. With permission.)
FIGURE 9.23 Range of T. radicans ssp. eximium.
Canyon in the Chisos Mountains of Big Bend National Park.74,91 There a small stream provides
adequate moisture in what is otherwise a largely desert terrain.

FIGURE 9.24 Pubescence on a leaflet of T. radicans ssp. eximium. (From: Guin, J.D., Beaman, J.H., Gillis,
W.T., Recognizing the toxicodendrons, J. Am. Acad. Dermatol., 4, 99–114, 1981. With permission.).
FIGURE 9.25 T. radicans ssp. divaricatum. (From: Guin, J.D., Beaman, J.H., Gillis, W.T., Recognizing the
toxicodendrons, J. Am. Acad. Dermatol., 4, 99–114, 1981. With permission.).
9.28.5 TOXICODENDRON RADICANS SSP. DIVARICATUM
Toxicodendron radicans ssp. divaricatum (Figure 9.25) is primarily a Mexican taxon. Its range is
in Mexico along the western slope of the Rocky Mountains (Figure 9.26), but to the north it extends
into the mountains of southern Arizona.74,91 Its leaflets tend to be long and narrow, but they are
somewhat variable in the field. Leaflets may be either lobed or unlobed, the fruit is glabrous, and
the leaves are usually glabrous.74,91 Although both this subspecies and T. rydbergii are found in the
mountains of Arizona, this taxon does not extend to the mountains of northern Arizona where
T. rydbergii is found.74,91

FIGURE 9.26 Range of T. radicans ssp. divaricatum.
9.28.6 TOXICODENDRON RADICANS SSP. ORIENTALE
Toxicodendron radicans ssp. orientale is distributed in Japan and the Kurile Islands and Sakhalin
in Russia (Figure 9.27). The plant grows in dense forests in Japan as part of the natural flora rather
than appearing in a weedy form after the ecology is disturbed as we see with American forms of
poison ivy.74 However, where a disturbance occurs, the plant becomes more abundant.
This subspecies is distinguished by its leaflets bearing tufts of hair in vein axils similar to T.
radicans ssp. radicans, but in T. radicans ssp. orientale the color is light colored to red brown.
Leaflets are entire but widest at or above the middle (obovate). The blade of the terminal leaflet is
1.2–1.7 times as long as it is broad and is 5–20 cm long and 3–12 cm wide. The base is cuneate.
Petioles are 1.5–11 cm long and petiolules are 0.5–3 cm long. The fruits are a flattened drupe,
5–6.5 mm broad, and the surface is papillose to short hairy.74 The northern form, said by some to
be nonclimbing, was regarded by Gillis to be the same except it had been too inadequately collected
to separate on this basis.74
9.28.7 TOXICODENDRON RADICANS SSP. HISPIDUM
This subspecies of T. radicans is indigenous to China and Taiwan (Figure 9.28), but some have
considered it to be the same subspecies as T. radicans ssp. orientale. However, Gillis separated it
because of the hispid nature of the fruit and the leaf measurements, both of which are somewhat
different. One might also argue that its montane nature is a bit different, as this subspecies grows
at elevations of 1150–3400 m, while T. radicans ssp. orientale is found at elevations as low as sea

FIGURE 9.27 Range of T. radicans ssp. orientale.
level and as high as 1800 m. Only the two ssp. indigenous to Mexico which are found as high as
2500 and 2800 meters, are close to T. radicans ssp. hispidum.74
This subspecies also has the widest part of the leaflet at or above the middle (obovate). It is
attenuated at the base and is nearly twice as long as it is broad. Tufts of hair in vein axils are
hyaline to red brown. The fruit is a flattened drupe that is obliquely deltoid, some 5–6.5 mm wide.
The fruit surface is hispid with hairs almost 1 mm in length.74
9.28.8 TOXICODENDRON RADICANS SSP. BARKLEYI
Toxicodendron radicans ssp. barkleyi (Figure 9.29) is a Mexican taxon of T. radicans found in
eastern Mexico and Guatemala (Figure 9.30). It grows in very high calcium soil, with a calcium
content sometimes as high as 5700 ppm,74 and at elevations ranging from moderate to 2800 m,
second only to T. radicans ssp. hispidum.
The plant is either a shrub or climbing vine with aerial rootlets. Leaflets are entire or subentire
or with occasional notches. Leaflets are ovate to elliptic or elliptic-lanceolate. The upper leaf surface
is glabrate to velutinous, while the lower leaf surface is strigose, tomentose, or deeply pilose. The
terminal leaflet is 3–14 cm long and 1–10 cm broad. The petiole is 2–12 cm long and the terminal
petiolule is 0.5–5 cm long. Fruits are glabrous or puberulent and about 3–5 mm broad. The stem
of the growing season is pilose to wooly.74

FIGURE 9.28 Range of T. radicans ssp. hispidum.
FIGURE 9.29 T. radicans ssp. Barkleyi.
9.28.9 TOXICODENDRON VERNIX (POISON SUMAC)

Poison sumac, T. vernix (Figure 9.31), can be seen as either a large shrub or a small tree. Its range
is the eastern United States and extreme southeastern Canada (Figure 9.32). It is found in peat bogs
in the north and swampy areas of the south, but it may also be seen where there is a high water
table.91 Its leaves are odd-pinnate, with 7–13 unlobed leaflets. The leaflets arise from the rachis at

FIGURE 9.30 Range of T. radicans ssp. Barkleyi.
FIGURE 9.31 T. vernix, poison sumac.
an angle, like rabbit ears. Flowers and fruit are borne in the axillary position and leaf scars are U-
or V-shaped similar to that seen with poison ivy. The glabrous fruit is green when unripe and off-
white at maturity similar to that seen with poison ivy.91
Although T. vernix has traditionally been considered Rhus, it is certainly Toxicodendron.
Because the genera Rhus and Toxicodendron are closely related, it is not surprising that the two
are often confused. Plants with odd-pinnate leaves to be distinguished from poison sumac include

FIGURE 9.32 Range of T. vernix, poison sumac.
Rhus copallina (winged sumac), that unlike T. vernix has a winged rachis and terminal fruits that
are red or almost purple.98 R. typhina or staghorn sumac has 9–27 leaflets, pubescent branches,
serrated leaflets, and red, terminal fruit91; and R. glabra, which has 11–31 leaflets with serrated
borders, and red, terminal fruit.91 Certain benign sumacs in Rhus, for example, R. trilobata and R.
aromatica have leaves with three leaflets similar to poison oak. Distinguishing features include
short or absent petiolules, terminal fruiting structures, and reddish fruit.
9.28.10 FIELD RECOGNITION OF TOXICODENDRONS IN WINTER

Perhaps the most distinctive winter feature of mature Toxicodendrons is the clusters of fruit found
on female specimens. The fruit, a small drupe, is green in the growing season, off-white in the fall,
and during winter it tends to become chalk white as the exocarp peels away, exposing the underlying
mesocarp (Figure 9.5).74,95 Even the remaining empty stalks distal to a leaf scar (after birds have
removed the fruits) are almost as good for identification. The typical U- or V-shaped leaf scars
(Figure 9.5),74,95 tell the observer the shape of the petiole that preceded them, and holes in the bark
called lenticels (Figure 9.5),95 and aerial rootlets are found on both male and female plants of T.
radicans and sometimes T. diversilobum.74,95
For many lay persons, the chief source of confusion for T. radicans is often Virginia creeper
or Parthinocissus quinquefolia, a member of the grape family.91 However, Virginia creeper clings
by tendrils rather than aerial rootlets. Furthermore, its fruit is borne opposite a leaf scar (at the
same node).95 The winter silhouette of poison ivy on fence posts, which resembles a medusa head,95
(Figure 9.33) is so characteristic that it can be identified from a moving automobile.
One should be suspicious of any vine clinging by aerial rootlets to a larger object. Very small
specimens and rootlets in soil can be almost impossible to identify, but one should suspect the soil
to contain rootlets if there is a mature vine climbing a nearby structure such as a tree or a utility
pole. T. rydbergii is usually so small that it can be difficult to see in northern states when there is
deep snow. However, the branching upward (Figure 9.34) with fruit on female specimens can be
diagnostic.95
T. vernix (poison sumac) has, as distinguishing winter features, the whitish fruiting structure
and gnarled appearance of the twigs caused by the different direction with each growing season.
Lenticels in the twigs and typical leaf scars can be invaluable.
The location of these plants also is important because they tend to prefer locations with certain
special features. Poison ivy will grow in a many soil types, especially moist, fertile soil that is well,

FIGURE 9.33 Winter silhouette of T. radicans ssp. negundo growing on a fence post at the edge of an Indiana
farm.
FIGURE 9.34 Branches of T. rydbergii showing above the snow resemble the tines of a fork as seen during
winter in the Indiana Dunes region.

FIGURE 9.35 Toxicodendron striatum, a montane sumac growing in the hill country of Venezuela. (From
Clinics in Dermatology, 1986, with permission.)
but not excessively, drained.74 Eastern poison oak prefers sandy soil of poor nutritional quality,74
and western poison oak is especially common in canyons where the shrub can find water. Poison
sumac is more likely to be in standing water in peat bogs and swamps, while most benign sumacs
grow in dryer soils. Unlike poison ivy and poison oak that are more common in disturbed sites,
poison sumac seems more abundant in remote, undisturbed locations, and it rapidly disappears
when the area is drained.
Winter recognition is more difficult, but it is still important because the nonleaf parts of these
plants can still induce dermatitis.99
The transition between the Caribbean and North American continent is abrupt with relatively
little overlap in plant taxons. Exceptions are the location of T. radicans in both Florida and the
extreme northwestern Bahamas and poisonwood (Metopium toxiferum) in the freeze-free zone of
the tip of Florida and the Keys as well as the Caribbean.
Mexico is another matter because that nation has two subspecies of T. radicans whose range
extends a very short distance into the southern counties of Texas and Arizona, while a third is self-
contained. Western poison oak, T. diversilobum, is predominantly found in the United States west
of the Rocky Mountains, but it extends for a very short distance into both British Columbia to the
north and Baja California in Mexico to the south.
9.28.11 TOXICODENDRON STRIATUM
Toxicodendron striatum (Figure 9.35) is a montane shrub or small tree, usually found at about 3000
ft. It is common in the Cobán region of Guatemala and south of Cartago in Costa Rica.2 Of the
reactive Anacardiaceae that are found in Central America, the montane Toxicodendron striatum is
the only Toxicodendron.
Leaves are pinnately compound with 11–15 leaflets, with those newly formed a bright red,
giving the tree a distinctive and recognizable appearance. The flowers borne in panicles are small
and white and the fruit is a small white drupe with a single seed.2

9.28.12 TOXICODENDRON IN ASIA
9.28.12.1 Clinical
Certain species, particularly T. vernicifluum (Stokes) Barkley, have great economic importance as
sources of lacquer. This species is generally known in English as the Chinese lacquer tree, in
Japanese as urushi, and in Chinese as qi su.100 The lacquer exudate is initially milky but darkens
and thickens on exposure. It can be kept for long periods by storage in closed containers. Lacquer
has been used in China since before the beginning of the Christian era and reached its highest
development there during the Ming dynasty (1368–1644 A.D.). In Japan, the first records go back
to the fourth century. The art there reached its height during the seventeenth century. The process
of lacquering a piece may require several years, and the application of 300–400 coats.101
Although there are indigenous subspecies of poison ivy (T. radicans) in China and Japan,
Toxicodendron dermatitis is recognized as an industrial disease. Usually, it is confined to workmen
who gather the fresh sap or apply it, but there are occasional reports of dermatitis from handling
lacquered articles. One of the more dramatic cases is discussed by Ames102 concerning Japanese
damascene purchased in Kyoto that caused dermatitis in a number of steamship passengers. T.
succedanea (L.) Moldenke is a common source of dermatitis in New Zealand.103 This species also
has been used as a lacquer source in Indochina.78 In Japan, the wax from the fruit mesocarp, is
used much like beeswax. This has also been a component of varnishes, floor waxes, wax varnishes,
ointments, and furniture polish.104 The Bornean species with simple leaves, T. borneese is one of
the rarest toxicodendrons. When Gillis74 wrote his classic treatise on the genus, it had been reported
from only two localities in Sabah, but now is known also from Sarawak and Kalimantan.21 Beaman
tells that while one of their assistants was pressing a collection that had not previously been
recognized as this species, she broke out rather severely on the thighs where she had held the
specimens on her lap. Another member of the party who had been insensitive previously to such
allergy, used the end of a cut stem to mark his arm. The black stain was still present after almost
2 weeks and a distinct erythema resulted.20
9.28.12.2 Chemistry
In 1922, Majima105 isolated the sensitizing component of the Japanese lac tree and found it to be
a pentadecylcatechol, a compound with a benzene ring with hydroxyl substitutions in positions 1
and 2 and a side chain of 15 carbons in length containing varying numbers of double bonds. The
specific structures were extensively investigated by Charles Dawson and co-workers and others
who found that the Anacardiaceae contained plants with resorcinol (meta-dihydroxybenzene) sen-
sitizers as well as catechol (ortho-dihydroxybenzene) sensitizers. In fact, all dihydric benzenes are
potential sensitizers. Because most sensitizers in woods are quinones, it has been theorized that
the alk(en)yl catechols are converted to quinones, but this is not possible in the case of the
resorcinols. Furthermore, hydroquinones have not been found in the Anacardiaceae.106,107
These sensitizers are dihydroxy benzenes with long-chain alk(en)yl groups, and the most potent
sensitizers have unsaturated alkyl side chains. These side chains vary in length: 15 carbons for
poison sumac, poison ivy,70,108,109 poison wood,70 and cashew-nutshell liquid,110,111 17 carbons in
poison oak,108,112,113 Indochina lacquer, and Burmese lacquer.114
Poison ivy, with predominantly pentadec(en)yl catechols also may contain small quantities of
heptadec(en)yl (17-carbon side chains) catechols, and those (such as poison oak) with predomi-
nantly heptadec(en)yl catechols may have small quantities of pentadec(en)yl catechols (15-carbon
side chains).70
The alk(en)yl side chains have varying numbers of double bonds (from 0 to 3)106 and the
quantitative composition may vary somewhat with the geographic area of the collection70 or the
portion of the plant collected.115,116 Several authors have summarized some of the sensitizers found

in members of the Anacardiaceae and other plant families containing the same or closely related
chemical sensitizers.37,117
Several factors influence whether a person is sensitive or immune and just how sensitive and
how immune because each is relative. Persons exposed to the plant oleoresin orally at an early age
become quite tolerant. Nonimmune children, aged 8–16, who were given intramuscular injections
of a total dose of 16 mg of urushiol in olive oil, over a one month period, initially became tolerant
and then became hyposensitized and persisted in that state for 3–6 years.118 It has been hypothesized
that such exposure may explain why persons in South America are less sensitive to toxic Anacar-
diaceae as they ingest mangoes or even are nursed in infancy by mothers who eat mangoes.41
The subject of development of immunity and tolerance to the allergens within the Anacardiaceae
is most complex. Multiple factors include the presence or absence of the atopic state where those
with atopic eczema are less often sensitive and not as easily sensitized.119
Age is also important, as younger experimental animals were more easily sensitized than older
ones,120 and infants were less easily sensitized,121 and older people tend to be more difficult.122-124
There are species differences with Rhesus monkeys that are much more difficult to sensitize,125
while guinea pigs are more easily sensitized. Rats, rabbits, and cats have been traditionally con-
sidered very difficult to sensitize.126
The route of initial administration can determine whether allergy or tolerance occurs. Topical
application in nature and, indeed, even patch testing may sensitize one not previously exposed,
probably because of Langerhans cells in the skin. Parenteral (IM) administration of urushiol before
any topical exposure may result in long-term tolerance.118 Subcutaneous administration may also
result in tolerance,127 but almost all experimental animals are sensitized when an adjuvant is added
to the protocol. Subcutaneous injection with complete Freund’s adjuvant (CFA), an oil-in-water
emulsion containing mycobacteria, produced sensitivity in almost 100 percent of the animals.
Subcutaneous injection with incomplete Freund’s adjuvant or in a vegetable oil solution resulted
immmune tolerance.118,127 When the pentadec(en)yl catechol is applied topically, the subjects tend
to become sensitized.118,124,127
Guinea pigs can be sensitized readily to pentadecyl catechol if they are exposed to the chemical
in acetone or in an oily vehicle,127 and humans are similarly sensitized topically.118,124
Baer106 has done much of the important work in determining the relationship of the chemical
structure of PDC and derivative chemicals to immunologic and irritant function. More water-soluble
compounds tend to induce antibody production rather than cell-mediated immunity. Albumin,
known to induce antibody formation, can cause delayed hypersensitivity if it is methylated to render
it less water soluble.128 This is also true for the dinitrobenzenes. The water-soluble dinitrobenzoyl
chloride induces antibody almost exclusively, while dinitrochlorobenzene (with limited water sol-
ubility) induces mainly delayed contact sensitivity.129,130
The water solubility of alkylcatechols with a chain length greater than eight carbons, is very
limited,131 and they tend to be more effective sensitizers.132 Pentacec(en)yl catechols have very low
water solubility. Following application to the skin, they are very rapidly distributed throughout the
body and are found in all organs and all tissues examined.133
Removal of the site surgically at 1 h following application reduced the percent of animals
sensitized but did not eliminate sensitization.134 Penetration is apparently rapid as prevention by
washing a site after exposure123 must be done early.
A comparison was made of the application, distribution, and disappearance of PDC, a sensitizer,
and a nonsensitizer, pentadecylveratrole (PDV) (which is essentially PDC in which the two hydroxyl
groups are methylated). The rate of disappearance from the site of application for PDC and
disappearance from the draining lymph node was very rapid after approximately five days compared
to PDV. Thus, at the time that sensitization was induced, there appeared to be rapid, immunolog-
ically-related clearance; however, even at 1 month, approximately 0.1 percent of the PDC could
be detected at the site of application.

9.28.13 THE EFFECT OF STRUCTURES ON IRRITANCY AND SENSITIZATION
Phenols interact with proteins and cause alteration of protein structure. As a consequence, they are
used as antiseptics to kill microorganisms and, when placed on the skin, may produce an irritant
effect if the concentration is sufficiently high. The ability to induce visible irritation is also structure
dependent.131 An increase in chain length of 3-alkylcatechols decreased solubility and increased
irritancy and contact sensitivity. Toxicity shows an S-shaped curve of increased irritancy with side
chain length from 3–19 carbons.131 Alkylcatechols with chain length greater than 8 are 10–50 times
more potent sensitizers than methylcatechol and are 10–100 times greater in skin irritant effect.131
Irritancy also depends upon position of the hydroxyl groups on the benzene ring; 3-PDC and 4-
PDC were irritant, while 5-PDR was not.131
Sensitization seems to be increased by certain irritants but not by others. The irritant effect
produced by sensitizers induces a change, presumably in the cellular response in skin, that is
different from that of a nonsensitizing irritant.135 When PDC is used as an irritant, it becomes a
sensitizer, but when the same thing was tried with Croton oil as the irritant, sensitization by PDC
was not so stimulated.136 This sometimes may be seen in human subjects as the extended allergen
syndrome (broadening of the allergic base). The pentadec(en)yl catechols are irritants in some
laboratory animals when sensitization has not yet taken place. However, animals react to smaller
doses after they have had time to become sensitized.106
Poison ivy urushiol varies with the specific clone and other factors, but generally comprises
most pentadec(en)yl catechols with 0, 1, 2, or 3 double bonds and the 3-alk(en)yl substitution.
While one can produce sensitivity to catechol itself, the presence of as few as 11 carbons in a side
chain at the 3 position makes the compound some 2000 times as reactive immunologically as the
basic catechol without a side chain.106 Cross-reactions are also somewhat specific based upon length
of the side chain.132
Much work has been done in animals, mostly in guinea pigs, that shows the aromatic ring and
its alk(en)yl side chain to be critical in many ways. The alkyl dihydroxybenzenes tend to be
sensitizers, but substituting a methyl group at either hydroxyl on the ring changes reactivity.106
Catechols and resorcinols are sensitizers, while 6-pentadecylguiacol, 3-pentadecyl veratrole, and
3-pentadecyl phenol are not sensitizers.132
The aromatic ring structure is important in cross reactivity. Animals sensitized to pentadec(en)yl
catechol reacted to the same molecular structure more efficiently than to the similar but different
pentadecyl resorcinol. The latter compound shows cross reactivity at higher concentration, but one
has difficulty studying the reverse of this (testing animals sensitive to PDR to PDC) because of the
irritancy of PDC at higher concentrations.
Long-chain alkyldihydroxybenzenes seem to be sensitizers. In animal studies, alkylresorcinols
were less potent sensitizers than alkylcatechols.137 Such studies show some cross reactivity between
guinea pigs sensitized to PDC and PDR, but a much greater concentration of PDR was required
for an equivalent in response to animals sensitized to PDC.137 Methylation of only one of the two
OH groups in the catechol prevented sensitization showing the necessity of the dihydroxy benzene
ring for immunologic activity. However, the situation is a bit different in humans who show
somewhat more reactivity to cashew-nutshell oil, a source of PDR’s.4 Baer106 postulated that the
unsaturated side chains in the naturally occurring catechols and resorcinols may have more cross-
reactivity than that shown in guinea pigs with PDC and PDR, neither of which has unsaturated
side chains.
The length of the alk(en)yl groups is also important in cross-reactivity because experimental
animals tend to react more efficiently to a molecular structure with the same length side chain as
those used in sensitization, especially with a difference of more or less than three carbons in length.132
The number of double bonds in the side chain seems to play a more important role in human
sensitivity than in guinea pig sensitivity.138 Poison ivy urushiol becomes much less reactive after

the unsaturated side chains are reduced to completely saturated side chains,139 and the diolefin was
the only component of poison ivy urushiol that produced a response in all who were known to be
allergic to poison ivy. The PDC component, with a fully saturated side chain, produced a response
in only 37 percent of sensitive individuals.140 PDC, the component with a completely saturated side
chain, is often a very minor component of poison ivy urushiol.140 There is also some unpublished
data showing occasional clones with only PDC. In guinea pig studies where PDC is used for
sensitization, elicitation with PDC (where the side chain lacks double bonds) is more likely to
produce a response than in nature, where the dominant sensitizing fractions seem to be the diolefin
and triolefin.140 While naturally occurring catechols have linear side chains, it is possible to
synthesize catechols with side chains that vary in structure. One of these synthetic structures, 3,5-
ditertiarybutylcatechol proved to be a good sensitizer with immunologic specificity because it did
not cross-react with other catechols.141
When synthetic side chains were investigated, the ringed cyclomethylcatechol was an effective
sensitizer and a poor elicitor of catechols with similar, but different, side chains. On the other hand,
octylcatechol that has an aliphatic side chain is as effective an elicitor in guinea pigs sensitized to
cyclohexylcatechol as cyclohexylmethylcatechol itself.141 Apparently, the unbranched side chain of
octylcatechol can assume multiple shapes, including a configuration similar to cyclohexylmethyl-
catechol,106 while the spacial configuration of the compound with an aromatic side chain is less
variable.
According to Baer,106 the alkylcatechols, although very potent sensitizers, have no reactive
groups capable of covalently combining with proteins. This can be explained in two ways: they
could be converted in vivo to compounds that form covalent bonds with proteins or they may be
involved in noncovalent binding to proteins.106 Many authors have postulated that catechols are
converted to compounds that combine covalently with proteins, the most popular choice being
quinones. Catechols can readily be converted to quinones by oxidation, and the quinones produced
react readily with proteins to form covalent bonds. However, when this was actually done, the
conjugate failed to experimentally sensitize guinea pigs but did produce antibody formation.142
Poisonous Anacardiaceae contain enzymes that rapidly oxidize the alkylcatechols to quino-
nes,143 so catechols could be oxidized to quinones and coupled to proteins.144 However, this
mechanism fails when one looks at the alk(en)yl resorcinols that cannot be so converted to
quinones.106 If one assumes oxidation to quinones is the mechanism of protein binding and sensi-
tization for catechols in order to account for the sensitizing ability of catechols, resorcinols, and
hydroquinones, there would have to be at least two different mechanisms.106
A second method might be through the ability of catechols, hydroquinones, and resorcinols to
bind directly to proteins by hydrogen bonds and hydrophobic linkages.145,146 This mechanism would
work for all three dihydroxybenzenes. Oxidation to quinones before binding probably is not the
mechanism, because the internal environment tends to be reducing rather than oxidizing, and the
necessary enzymatic pathways to overcome this are apparently not known to be present in animal
studies.106 In addition, increased hydrophobic linkages leads to delayed hypersensitivity rather than
antibody production.106
There is some evidence that tolerance can be induced, at least temporarily, by administration
of 5-methyl-PDC to both mice and guinea pigs.147
9.29 IMMUNOLOGY OF TOXICODENDRON DERMATITIS

Traditionally the most effective antigens in allergic contact dermatitis have been found to be lipid
soluble and have an affinity for protein, so urushiol has potent antigenic activity. The antigen is a
hapten that can bind to skin macromolecules. Antigen on the surface must penetrate and ultimately
reach an antigen processing cell that can present the processed antigen to a T cell. In most reviews,

this is a CD4+ T cell, but in some cases, including urushiol, it may also be a CD8+ T cell (although
some clones of CD8+ cells have a suppressor function).148
After the Langerhans cell takes up the antigen, it migrates to lymph nodes with specific T cells.
This is discussed briefly by Belsito.149 Langerhans cells present the antigen to TH0 cells that are
naïve (CD45RA+) and manifest L-selectin (to localize them to nodes150). These TH0 cells are
converted to memory cells (CD45RO+) stimulated by the presence of several cytokines. Initially
IL-1, IL-6, and IL-12 and later IL-2 are produced by type-1 T-helper cells (TH1). (For the endogenous
pathway, the expression TC1 is the equivalent used for CD8+ cells.) In the presence of T cells
bearing the universal T-cell antigen CD3+ and T-cell receptor (Ti+) and following149 release of
IL-1b, co-stimulation occurs. Within a few minutes the intercellular adhesion molecule (ICAM-1),
CD86 ligand (also called B7-2) for the (CD28) co-stimulatory molecule, and another co-stimulatory
molecule (CD40) are present on Langerhans cells.151 The (CD40) co-stimulatory molecule binds152
the Langerhans cells to its ligand (CD40-L) on T cells, and this interaction stimulates further
production of CD40 and CD86. CD86 binds to CD28 [co-stimulatory molecule whose ligands are
CD80 (also known as B7-1) and CD86]. The interaction seems to stabilize messenger RNA for T-
cell growth factor (IL-2) and further stimulates T-cell proliferation.153 The presence of the antigen
without (CD28) co-stimulatory activation may result in tolerance rather than allergy.154 An antibody
(CTLA-4Ig) known to block CD28 co-stimulation by linkage to its ligands CD80 and CD86
effectively blocks the (CD8+) delayed immune response to urushiol, ostensibly by preventing co-
stimulation154 and induces anergy rather than allergy.154 The presence of one (CD80) ligand for co-
stimulatory molecule CD28 but not another (CD86) is reported to occur after UVB exposure. This
is said to promote tolerance rather than allergy,155 but this needs confirmation.
The mechanism for allergic contact dermatitis employs T-lymphocytes and, for many years,
this was assumed to be exclusively a function of CD4+ cells, usually considered to be T-helper
cells, while CD8+ cells were considered suppressor/cytotoxic. Now, it appears that either CD4+
or CD8+ cells can induce contact dermatitis by somewhat overlapping mechanisms. However, the
process involving CD8+ cells is the dominant one for allergic contact dermatitis to urushiol,
DNCB, and certain other antigens, especially many that are fat soluble.156 For some endogously
processed antigens (mediated by CD8+ T cells), CD4+ T cells act to suppress TH2 cytokine
production (e.g., IL-4, IL-5, IL-10, and IL-13) that might otherwise reduce the delayed immune
response.157
Presentation (for antigen recognition) by T-helper (CD4+) cells involves class II HLA-D (MHC)
molecules (DR, DP, and DQ in humans), while presentation by CD8+ cells uses class I HLA-D
(MHC I) molecules (HLA-A, -B, and -C).156 In the exogenous (CD4+) pathway, antigens, for
example, bacterial toxins, fungal antigens, and so on, are internalized by endocytosis or
pinocytosis156 (aided by ATPase on the cell surface of Langerhans cells and internalized with the
antigen to help in degradation by driving an acidifying proton pump).158 They then travel to
endosomal vacuoles that fuse with lysosomes and degrade the antigenic material into peptides. The
HLA-D class II molecules, synthesized by the endoplasmic reticulum, are transported to endosomes
bound to a chaperone159 invariant chain160 that prevents their reacting with intracellular proteins.
They are separated in the endosome and free to combine with the processed peptide. These MHC-
peptide complexes are transported to the antigen presenting cell (APC) surface for presentation to
a/b chains of the T-cell receptor on CD4+ T-helper cells.156
Protein antigens that are endogenously produced are processed through a different pathway.161
The CD8+ pathway is considered endogenous because the antigen is derived from cytoplasmic
protein.156 Denatured cytoplasmic proteins are conjugated to ubiquitin, undergo proteolysis, and
are degraded into peptides (with 8–10 amino acids being an ideal length for complexing with class
I molecules162) in the proteasome complex. Then they are complexed with MHC class I antigens.163
This would ordinarily occur with viral, tumor, and transplantation antigens as well as urushiol.156

Urushiol is an oil-soluble material with a lipophilic [alk(en)yl] component that may help
penetration through the cell membrane to reach the site of the endogenous pathway. It forms a
prohapten that is probably bound (as catechols) to protein by hydrogen bonds and hydrophobic
linkages. The route of oxidation of the pentadecy(en)yl catechols to quinones before nucleophilic
attack may be a minor pathway,106 but that mechanism did not sensitize guinea pigs142 and does
not explain sensitization to alk(en)yl resorcinols, as resorcinols cannot form quinones.106 Beta
oxidation has been proposed as part of the processing of the molecule, and this is accelerated by
clofibrate and inhibited by Glutathione because the 2-oxotiazolidin-4-carboxilic acid lowered the
response.164 Sensitivity can be by either CD8+ cells through the endogenous pathway or by the
exogenous route where it is bound to proteins externally, internalized, and processed for presentation
to CD4+ cells.156 However, the former pathway seems to be dominant.156
Following sensitization, the presence of an antigen in the skin should stimulate the immune
system into activity. There are relatively few T-lymphocytes that are specific for urushiol, perhaps
as few as one in 100 to 1 in 3000 at the site of urushiol-induced dermatitis.165 Even then, the
concentration is much higher in the skin than in the peripheral blood.165 This can be from accu-
mulation, retention, or proliferation of the clone.166 The migration does not seem to be antigen
specific, so a local retention or proliferation,166 or both, is likely. The antigen-specific T lymphocytes
recognize the antigen with the help of the antigen presenting (Langerhans) cells.166 Many cytokines
become active or more active, and these come from multiple cell types. Detailed reviews are
presented by Belsito149 and Kalish166 and Kalish and Ashkenase.156
Keratinocytes participate by several mecahnisms including the upregulation of the Langerhans
function. Urushiol is known to directly cause expression of ICAM-1 (intercellular adhesion mol-
ecule-1) on keratinocytes.167 This doubtless contributes to localization in the skin, and it is amplified
by g-IFN (produced by activated T lymphocytes) and by TNF-a.166 Many cytokines are produced
by activated T lymphocytes, which are an important part of this mechanism. In Toxicodendron
dermatitis, elevations of m-RNA for vascular permeability factor (VPF) and other VPF’s in dermal
endothelial cells are overexpressed in keratinocytes. Migration of leukocytes toward the site involves
activation of multiple selectins, as well as b1 and b2 integrins. The b integrins are subunits of another
family of adhesion molecules involved in cell–cell and cell–matrix adhesion. The process, as
currently understood, is a bit complex for this chapter, but it is clearly presented by Belsito.149
9.30 TOXICODENDRON DERMATITIS

Poison ivy sensitivity is said to be present in 61 percent of nonatopic persons tested and another
31 percent as a result of the patch testing.119 It is less common in atopics119 and psoriatics,168 but
in the United States it is so common overall that most primary care physicians suspect the diagnosis
in any severe allergic contact dermatitis seen in the summer months, especially when there are
streaks present. These lines of vesicles are a marker for the pattern of exposure as much as anything
else, and while the eruption often presents with linear lesions it may well lack that pattern.
Toxicodendron dermatitis, for example, poison ivy (oak) dermatitis, is typically produced by
hand transfer of the antigen [pentadec(en)yl or heptadec(en)yl catechols].106,169 The streaks one
observes are from finger transfer. Some of the broad areas of eczema are from rubbing and,
sometimes, handprints can be seen producing a mitten pattern. The height of the eruption varies
from a flat erythema to a vesiculobullous eruption that all too often is accompanied by weeping,
oozing, and crusting in the acute phase. It is characteristically severely pruritic, and one usually
sees localization in exposed sites where the hands can reach. Places that are hard to reach such as
the midline of the back and protected sites such as the scalp are often spared. The palms and soles
are usually not affected even though the antigen is hand transferred. However, when there are breaks
in the skin, when sensitivity is strong and exposure severe, the hands may be affected. On the

hands, poison-ivy dermatitis is perhaps more often seen in finger webs or as streaks on the dorsum
of the hands or fingers.
The tendency to seemingly spread after its initial appearance, and apparently without any
additional exposure, could be from a change in sensitivity, re-exposure, or more often the rate of
absorption. Given equal exposure at the same time one expects the face to be the earliest area
involved,170,171 and, if so, it is usually the first area to clear. This is probably based on percutaneous
absorption of the antigen as much as opportunity for exposure.
Absorption varies with the anatomic area170 with the face involved as early as 5 1/2 h, while the
forearms may take several days to break out, and this takes as long as 15 days in areas where the
skin is very thick such as near the elbow.170 This is sometimes mistakenly blamed on re-exposure
or treatment failure. There are also atypical presentations from erythema multiforme172 to a stocking-
like distribution seen in some cases of poison sumac dermatitis.
Another typical picture is a flare after completing a 6-day course of treatment with a Dose-
Pak. Stopping coverage so early allows the inflammatory response to return while the antigen is
still present. One may also see new areas appear when steroids are withdrawn too early.
In endemic areas,91 poison ivy dermatitis should be suspected in anyone with an acute, severe,
allergic contact dermatitis. For contact dermatitis of unknown cause in the summer months, this
diagnosis is presumptive until it is disproved. This is even more cogent when the eruption is
characterized by streaks, finger marks, and hand prints. However, that pattern, while usually caused
by toxicodendrons, can also be seen with other strong allergens, for example, DNCB, squaric acid
dibutyl ester, as well as some plants, for example, English ivy (Hedera helix),173 Primula obcon-
ica,174 Phacelia,175 and phytophotodermatitis. Phacelia dermatitis seems to occur in naturalists or
botanists, who often suspect the source. Primula dermatitis is seen especially in older housewives
in exposed sites and frequently includes the fingertips. Phytophotodermatitis is often owing to
furocoumarins in the plant, in which case, hyperpigmentation follows the initial eruption which
confirms the earlier presumptive diagnosis.
It is often possible to place the patient’s hand over lesions of Toxicodendron dermatitis to see
how this might have been transferred from the hand. This can help in taking a history of contact
as the patient can usually see the obvious pattern of exposure. Exposure to the face may have taken
place the same day as the eruption, but other parts of the body tend to require 1–2 days or sometimes
much longer.123
In taking a history, one should inquire about outdoor activity, in particular, camping and other
exposure in the woods or when working in the yard, garden, or farm. Other potential sources include
exposure to animals that have been outdoors, clothing worn outdoors by others, exposure to topsoil
or potting soil, and a history of handling firewood. Persons with previous severe episodes of poison
ivy (or poison oak in California) dermatitis are more suspect because the unusually sensitive
probably require less exposure.123
Ordinarily, physicians in the United States will ask patients whether or not they have worked
outdoors or have been in the woods. Sometimes, the common clinical appearance or clinical history
repeated so often and so characteristically in so many patients may blind us to the unusual sources.
Exposure to T. vernicifluum would normally not be expected in Oxford, England, but a severe
dermatitis occurred in the workmen who cut the tree down and sawed it into firewood and in the
person who took logs home for the fireplace.176
9.30.1 BLACK SPOT POISON IVY DERMATITIS

An unusual form of Toxicodendron dermatitis was reported by Mallory et al.177 Within an hour
after severe exposure some individuals have noticed a black stain on the skin often with erythema
around it. Sensitive persons are then likely to develop a prominent allergic contact dermatitis29 after
a suitable reaction time.

The phenomenon has been reported to be useful as a test178 for the toxic nature of these plants
and presence of black spots on sites of injury is useful (when present) in field identification.
Oxidative darkening of the oleoresin was investigated by McNair,179 who found an oxidase in the
plant that caused polymerization and the black coloration.
This substance has been used by primitive societies to mark objects, lacquer furniture and other
uses, and while not infallible, it is perhaps the most simple and reliable way to detect the toxic
members of the family. Interestingly with cold and other injury, leaves may show the darkened
oleoresin outside the resin canals and within the plant parenchyma.180 In the field this can be seen
after the onset of cold weather, provided leaves are still present.
Because Toxicodendron dermatitis is so common, many unusual reactions have been reported
such as urethritis,181 toxic shock syndrome (caused by secondary infection),182 and erythema mul-
tiforme.172,183 One of us (Guin) had a patient with Sweet’s syndrome who developed lesions (of
typical neutrophilic dermatosis) in a handprint pattern (with streaks). She had been exposed to
poison ivy, and the rash caused a precipitation of lesions secondary to the trauma (Koebner
phenomenon).
Systemic problems are rare, but nephritis has been reported from injection,184 ingestion, or
cutaneous exposure to poison ivy or poison oak.185
9.31 SOURCES OF THE ANTIGENS

The antigenic component of poison ivy, poison oak, and poison sumac, called urushiol, is located
in secretory canals in the leaves, the roots, and the plant’s phloem, which is just below the bark.
Antigen is carried in the tiny brown rootlets of T. radicans that attach the vine to the structure on
which it is climbing. However, in most cases exposure occurs when one is exposed to the leaf or
other plant part allowing the oleoresin to be released. Normally, one can touch the unbroken surface
without a problem. Exposure to plants injured by pulling weeds, trimming hedges, or cleaning
grass clippings from a lawnmower bag can be a potent source of the allergenic oleoresin.
The allergen also may be carried on the fur of domestic animals or livestock (who usually are
not affected), on fomites123 such as clothing or garden tools or even between family members
(connubial contact dermatitis or filial contact dermatitis). Incredibly, this genus has been used in
a liniment for sore muscles.186
The antigen in poison ivy seems to be relatively heat tolerant, so it may also be transported in
smoke. However, levels of antigen are low, so risk for this type of exposure is largely limited to
highly sensitive individuals. More direct exposure of forest rangers and firefighters during a forest
fire can be extreme and would not have to be from smoke.
Airborne (pollen) transfer is a concept often voiced, but there is no evidence for it. One can
often sees honey bees gathering nectar from the flowers of poison ivy, but we have never known
anyone to contract poison ivy dermatitis from exposure to honey. Another popular myth is the idea
that the rash can be spread from the blister fluid. This has been shown to be untrue. Blister fluid
contains no antigen, so neither do highly sensitive individuals break out from blister fluid, nor does
the rash spread from scratching the lesions. Poison ivy dermatitis may sometimes break out in new
areas for several days, but this apparently happens because of the irregular absorption of the antigen
through uneven exposure and the differences in the rate of absorption in different anatomical
cutaneous surfaces. Experimentally, transfer from the exposed area of the skin to new sites does
not occur for much longer than three days.123 Where there is natural exposure, the time required to
dissipate the oleoresin from the skin surface is probably much shorter. Antigen exposure is reduced
by washing, and water used as first aid seems to be helpful in reducing severity.187 In addition,
urushiol is rapidly absorbed, so by the time the eruption appears, the site is not likely to contain a
significant amount of antigen. For persons allergic to Japanese lacquer, heat treatment of the product
renders it hypoallergenic.188 Such treatment reduced antigenicity over one order of magnitude.188

Other plant families with putative cross-reacting antigens include Ginkgoaceae, Proteaceae,
and Araceae,189 although the last may not be as common as claimed.190
9.32 PATCH TESTING

Normally one does not test for poison ivy dermatitis, but rather an assessment is made based on
the appearance of the eruption, the history of previous episodes, and the opportunity for exposure.
However, there are some problems with this approach. First, many individuals become less sensitive
with time so that the prevalence is diminished in the older population. Second, one study showed
a lack of correlation with the history of previous dermatitis,191 although those patients were exposed
for only 2 h and were tested to a total of less than 3 mg of penta- and heptadec(en)yl catechols that
is certainly less than the natural exposure to the plant. To adequately evaluate all persons capable
of reacting, it would be necessary to expose every subject to the natural antigen on skin sites with
maximal capability of absorption (such as the face). Jones et al.119 used about 110–140 mg of the
same product for 48 h in persons 21.7 ± 7.3 years old, and 61 percent of the controls reacted with
an additional 31 percent sensitized by the procedure. Even at this concentration, atopics were both
less reactive and less likely to be sensitized by the test procedure.119
Many projects evaluating a group will use doses that are somewhat lower than natural exposure.
Epstein et al.192 used repeated exposure of a diluted urushiol in order to quantitate the antigen and
in that group of reactors, threshold levels ranged from 0.1–10.01 mg. However, they only accepted
persons with sensitivity at the 25 mg level as those who required more would have required higher
levels of exposure and probably would have been less likely to experimentally confirm hyposen-
sitization (the purpose of the project).
Another problem is the variability of the specific molecule to which the patient is most allergic.
Saturated PDC was less effective as a test material than extracted components of a poison ivy
extract containing the unsaturated components.139 This is because the greatest degree of reactivity
to the natural plant is because of the di- and triolefins,140 and about 3 mg of each of the four major
components (PDC and the mono-, di-, and triolefin), left on for 24 h, induces a positive response
to one or more agents in 97 percent of a similar age group.140 To test to each component, one must
do chemical separation of the natural material that is not commercially available as such. Structural
specificity is another problem because persons sensitized to poison ivy require more (PDR) antigen
to elicit a reaction than subjects sensitized to PDR.137 The same phenomenon is probably true for
other plants with potentially cross reacting structure.190
Needless to say, tests for sensitivity to poison oak, poison ivy, and poison sumac that are
published may not be easily reproducible because of problems with methodology, with the age
group,193 and the ability to produce delayed hypersensitivity.119 The chance of sensitizing nonsen-
sitive patients is high, and the dose required to rule out allergy to the plant may be higher than is
safe to administer in clinical practice to potentially negative subjects. Using whole leaf as done
early in this century is probably ill-advised.
9.33 TREATMENT OF TOXICODENDRON DERMATITIS

Perhaps the best prevention is by teaching the patient how to identify the plant. For those who
cannot avoid exposure, wearing disposable vinyl gloves is beneficial and a (barrier) quaternium-
18 bentonite lotion originally developed to benefit forest firefighters194,195 has now been marketed.196
Of seven other barrier creams, six also reduced global severity by up to 59 percent.197
Oral corticosteroid therapy is usually effective, but it must be given in adequate dosage, usually
beginning with 30–60 mg of prednisone per day over 14–21 days.169 Normally, treatment is
maintained until at least 14 days after the initial exposure. The routine use of a 6 day rapid taper
of methylprednisolone is commonly followed after completion by a flare of the condition.198

Injectable (TM) corticosteroids can be used, but they probably have no advantage except that the
prescribing physician can be sure that the medication was administered.
For milder cases, potent topical corticosteroids may be of some benefit.199 Moderately potent
topical corticosteroids can be used with 24 h occlusion in persons unable to take systemic corti-
costeroids. This method can also be used in conjunction with systemic therapy in extreme cases.
Category II–V topical steroids should be applied under occlusion for at least two 24 h applications.
The absorption curve is better for a 1–3 day application than for a period of less than 24 h.200 Use
of more simple topical agents may help reduce broadening of the allergic base (extended allergen
syndrome). Hyposensitization is now an anachronism because oral kits for hyposensitization are
no longer available, and the injectable preparations are too low in concentration to expect effec-
tiveness with the recommended dosage.201
Many home remedies have been reported, and few work. Jewelweed, recommended by many
self-proclaimed naturalists, is ineffective,187,202 but water is worth considering for first aid if nothing
else is available.
NOTE:
The Anacardiaceae were covered in Plant Dermatitis, an issue of Clinics in Dermatology, Vol. 4,
edited by Drs. Guin and Beaman, in which we all contributed. We have updated the material and
cited the appropriate sources including many opinions of the sources. In that publication, the
Anacardiaceae of the Caribbean and Central America were written by Kenneth Lampe, Ph.D. of
South America; Inez Hurtado, Ph.D. of Africa; and David Whiting, M.D.; hyposensitization was
covered by Sue Watson, Ph.D. and several other authors included mention of the Anacardiaceae.
We are also grateful to Dr. Richard Kalish’s helpful suggestions on the clarity and accuracy of one
section in the book.
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203. Stahl, E., Keller, K., and Blinn, C., Cardanol, a skin irritant in pink pepper, Planta Med., 48, 5–9, 1983.

10 Araliaceae
Bjoern M. Hausen
CONTENTS
10.1 Introduction
10.2 Aralia
10.2.1 Aralia spinosa L.
10.3 Brassaia actinophylla ENDL.
10.4 Dendropanax
10.5 Fatsia
10.5.1 Fatshedera lizei (COCHET) GUILLAUMIN
10.6 Hedera
10.6.1 Hedera helix L.
10.7 Oplopanax
10.8 Panax
10.9 Polyscias
10.10 Schefflera
10.10.1 Schefflera arboricola HAYATA
10.10.2 Schefflera heptapleurum
10.11 Tetrapanax
10.12 References
10.1 INTRODUCTION
The plant family of Araliaceae comprises about 1325 species in 47 genera. Many of the species
grow in the Mediterranean area while others are widely cultivated as ornamental pot plants or held
in horticulture. Some Araliaceae species are equipped with secretory canals (oily glands) and
produce an aromatic smell when crushed.1 In their classification a subdivision into Schefflereae,
Aralieae and Mackinlayeae has been proposed. Typical characteristic of this family is the occurrence
of polyacetylenes (polyines).2 One of these polyacetylenes is the sensitizing falcarinol, that has
been found up to this time in the following species:
Falcaria vulgaris BERNH.3

Fatshedera lizei (COCHET) GUILLAUMIN4
Hedera helix L. and subspecies4,5,6
Panax ginseng C. A. MEYER7
Schefflera arboricola (HAYATA) MERRILL6
Tupindanthus calyptrata HOOK. fil & THOM.4

The near related falcarinol derivatives (falcarindiol, falcarinone, and dehydrofalcarinone) do
not play any role either as sensitizing agent or as a cross-reacting allergen.9
10.2 ARALIA
The genus Aralia comprises more than 36 species in North America, East Asia, and Malaysia.
10.2.1 ARALIA SPINOSA

Common names for Aralia spinosa L. are the prickly ash, prickly elder, Hercules club, angelica
tree, and devil’s walking stick.
The shrub is native to North America. The bark and hairs irritate the skin when touched.10,11
Handling of the roots may cause blisters and inflammation.12 The species is suspected of poisoning
livestock. Feeding experiments with the seeds show them being lethal to guinea pigs.13 Another
species not mentioned in modern botanical handbooks—Aralia farinosa—is said to cause coughing
and sneezing.14
10.3 BRASSAIA ACTINOPHYLLA ENDL.

Common names for Brassaia actinophylla ENDL. [syn. Schefflera actinophylla (ENDL.) HARMS]
are Queensland umbrella tree and octopus tree.
The genus Brassaia today belongs to the subdivision Schefflereae. The Queensland umbrella
tree grows in northeast Australia and New Guinea. It is a popular house plant also in Europe.
Brassaia actinophylla has been reported to cause allergic contact dermatitis.15,16 A female working
in a nursery developed eczema of the hands and forearms after two weeks of contact with two
Schefflera species. Schefflera actinophylla was one of the species. Patch tests with a short ether
extract of the leaves and stems were positive.15 In the second case, a female homemaker developed
vesicular dermatitis of the hands, wrist, and forearms after pruning common ivy during the summer.
She suffered from relapses when handling Brassaia actinophylla during the winter in her house.
A patch test with the leaf produced a strong reaction, three controls remained negative.16 The
allergen is still unknown, but might be falcarinol, because this constituent has been found in the
related species Schefflera arboricola.6
10.4 DENDROPANAX
The genus Dendropanax comprises 60 species and is found in East Asia, the Malaysian peninsula,
and Central and South America. The common name for Dendropanax trifidus MAKINO (syn.
Gilibertia trifida MAKINO) is Kakuremino (Japan).
Only one species grows in Japan where it is cultivated in gardens and sometimes used in flower
arrangements.
The plant grows to 5 m in height and contains dendropanaxide, friedelin, epifriedelinol,
b-amyrin, and a glucoside.17 The cis-9,17-octadecadiene-12,14-diyne-1,16-diol was isolated and
identified as an antifungal constituent by Kawazu et al. in 1973.18 Contact dermatitis of the hands,
arms, cheeks, neck, and chin has been observed in Japan in people pruning and arranging the leaves
and branches of the plant.19-23
The main sensitizer was shown to be cis-9,17-octadecadiene-12,14-diyne-1,16-diol, a com-
pound structurally related to falcarinol (only one additional CH2OH-group) (Figure 10.1a). The
safe test concentration is 0.05 percent. The polyacetylene is a strong sensitizer as 4 out of 18
controls were actively sensitized during the investigation. Patch tests with the leaves produced
irritant reactions in 5 out of 18 individuals. Positive responses to ethanol extracts of Fatsia japonica
and cross reactions to urushiol were observed as well.23

FIGURE 10.1 Structures of the sensitizing polyacetylenes.
10.5 FATSIA
The genus comprises three species and is native to Japan and South Korea. The common name for
Fatsia japonica (THUNB. ex MURR., DECNE et PLANCH.) (syn. Aralia japonica THUNB. ex
MURR.) is Japanese Fatsia. Fatsia is a popular indoor pot plant in Europe.
The leaves contain arolein, hederaguin, quercetin, idaeine, and b-profastin.1 Cases of allergic
contact dermatitis have not been described, however Oka obtained positive patch tests with the
leaves.23 A flare-up reaction developed in two controls who had been actively sensitized by a
Dendropanax trifidus extract when they were tested with the leaves of Fatsia japonica. Falcarinol
has not been detected so far, but the occurrence of a near related constituent is suspected.4
10.5.1 FATSHEDERA LIZEI (COCHET) GUILLAUMIN

Fatshedera is a hybrid composed of Fatsia japonica ‘Moderi’ and Hedera helix var. hibernica
(hort. ex KIRCHNER) JÄG by Lizé-Frères in a French plant nursery in 1912. Fatshedera is a
popular pot plant all over the world. A positive patch test was obtained with the leaf by Mitchell16
in a woman sensitized to Hedera helix. Boll and Hansen4 could demonstrate the occurrence of
falcarinol (Figure 10.1b) in the leaves and stems of this hybrid.
10.6 HEDERA
The genus Hedera comprises approximately 4 to 11 species. There are conflicting opinions regarding
its botanical nomenclature. Approximately one to three species are native to the temperate region;

the others grow in East Asia. Some species are cultivated in gardens as a climber, creeper, and
ornamental evergreen wine or wall cover; others grow indoors as a pot plant.
The term ivy is applied to three subspecies of Hedera helix L.:
• Hedera helix L. subsp. helix.

• Hedera helix L. subsp. canariensis (WILLD.) COTINO
• Hedera helix L. subsp. poetarum NYM.
In Great Britain, the second species is known as Canary Island ivy. The Americans named it
Algerian ivy to distinguish it from poison ivy of the Anacardiaceae family. Green Hedera was used
as poet’s crown and wreath of Bacchus, to whom the plant was dedicated.
10.6.1 HEDERA HELIX
The common name for Hedera helix L. subsp. helix is common ivy.
Common ivy contains up to 10 percent of saponins and is, therefore, used for washing. The
cooked leaves are used together with soda for washing clothes, too. French soaps as well as French
creams used for massages and for removing “disadvantageous curves” in females contain ivy
extracts. Occasionally the extract serves as a rubefacient.
The leaves contain the saponins a- and b-hederin, some coumarins, the alkaloid emetin, vitamin
E, and provitamin A as well as some hydrocarbon acids like chlorogenic, fumaric and coumaric
acid.1 Irritant and allergic contact dermatitis have been described since 1899. A list of all cases
with references described between 1899 and 1985 is given by Hausen et al. (135 cases, 31
references).5 More recently, 13 further cases were reported.24-26
The stalks, leaves, and roots contain falcarinol and didehydrofalcarinol (Figure 10.1b and 10.1c)
that have been shown to be the irritants and sensitizers in common ivy.5 Sensitization was achieved
experimentally by three different methods in guinea pigs.5 The safe test concentration of falcarinol
is 0.03 percent. As the leaves are broken during pruning, irritant contact dermatitis often occurs
because the leaves commonly contain more than 1 percent of the sensitizer. Didehydrofalcarinol
is a weaker irritant and sensitizer and, therefore, may be tested at 1 percent in petrolatum.
Falcarinol is chemically very active. It functions as an alkylating agent and can easily react
with amino or other protein groups and, thereby, facilitate covalent binding to the surface markers
of immuno-competent cells.
Falcarinol and didehydrofalcarinol also occur in the Apiaceae (syn. Umbelliferae) family.
10.7 OPLOPANAX
The genus Oplopanax comprises three species native to North America and Japan. The common
name for Oplopanax horridus (SM.) MIQ. (syn. Echinopax horridus SM ex J. G. COOPER) is
devil’s club. Contact with the prickles or a tincture of the leaves produces painful wounds, swelling,
itching, and blisters.27,28
10.8 PANAX
The genus Panax comprises six species. Panax ginseng is native to Korea, North China and parts
of the former Soviet Union.8 The common names for Panax ginseng C. A. MEYER are Chinese
ginseng and Asiatic ginseng.
Because wild ginseng is rare, today most of the material used as a remedy is cultivated in
China, Japan, Korea, Canada, and the United States. Ginseng contains the polyacetylenes

panaxynol, panaxtriol, panaxydol, and heptadeca-1-ene-4,6-diyne-3,9-diol. Panaxynol is identical
with falcarinol.7,29
Allergic contact dermatitis has been described in only one case. Saito and Oka obtained a strong
positive patch test reaction to an ethanolic ginseng root extract in a 24-year-old female who had
developed perioral dermatitis after applying an ointment to her lips containing a ginseng extract.30
Probably panaxynol (syn. falcarinol) was the responsible sensitizer, but it was not available for a
patch test.
Siegel referred to skin eruptions in 13 of 133 ginseng users who suffered also from hypertension,
nervousness, sleeplessness, and morning diarrhea which he called the ginseng abuse syndrome.31
Baranov, of the former Soviet Union, states in his paper that “Eleven patients have been found to
be allergic to ginseng, showing symptoms such as palpitation, insomnia and pruritus.”32
A review of the botany, chemistry, pharmacology, and side effects of ginseng is given in two
recent publications.33,34
10.9 POLYSCIAS
The genus Polyscias (formally Nothopanax) comprises 150 species. Most of them are native to the
Pacific regions, for example, New Zealand, the Pacific islands (Hawaii), and Australia, but many
of them are also cultivated elsewhere in the world. The common name for Polyscias balfouriana
BAILEY (syn. Aralia balfouriana hort. SANDER) is Balfour polyscias and the common name for
Polyscias guilfoylei (BULL) L. H. BAILEY is Guilfoyle polyscias. Skin irritation has been men-
tioned by Morton35 and Arnold36.
10.10 SCHEFFLERA
The genus Schefflera comprises about 650 species in tropical and subtropical areas. Several members
are grown all over the world in nurseries as ornamental pot plants.
10.10.1 SCHEFFLERA ARBORICOLA
The common name for Schefflera arboricola HAYATA is Schefflera. Schefflera arboricola is native
to Taiwan, but grows abundantly in plant nurseries throughout Europe.
A case of eczema of the hands and forearms was described by Hammershøy in 1981.15 The
female nursery worker had handled Schefflera species only for two weeks when she developed the
skin lesions.
Patch tests were positive with the leaves and stems as well as with a short ether extract
(1 percent). All ten controls remained negative. The nursery worker also reacted to Brassaia
actinophylla, but not to Schefflera kyoto and Schefflera heptapleurum. The same patient was tested
again five years later, this time with falcarinol that had been isolated meanwhile by two chemists
from the ether extract of the leaves and stems.6,37 She reacted “strongly positive” to the constituent
but remained “negative” to the tests with the chemically near related polyacetylenes falcarindiol,
falcarinone, and dehydrofalcarinone.9
10.10.2. SCHEFFLERA HEPTAPLEURUM
The common name for Schefflera heptapleurum (syn. Schefflera kwangsiensis) is umbrella tree.
A case of an acute vesico-bullous eruption on the back of the hands, arms, and neck was
observed by Calnan in 1981, in a man working with the umbrella tree in his garden.38 A test with
the leaf was positive at the 96-hour-reading.
Other Schefflera species of Australia are said to cause eruptions of the skin, too.39

10.11 TETRAPANAX
The genus Tetrapanax consists of one single species that is native to Taiwan and South China. The
common name for Tetrapanax papyriferum K. KOCH (syn. Aralia papyrifera HOOK) is the Chinese
rice paper plant.
The small tree is cultivated in Europe, Japan, and North America as an ornamental plant. The
flower stalk and lobed leaves of the unarmed clump-forming shrub are abundantly covered with
hairs, forming a soft white felt. The pulp of the sprouts is used to prepare the Chinese rice paper.
In Chinese folk medicine, it serves also as a drug.
Irritant contact dermatitis owing to the hairs was described by Giannattasio et al. in 1996.40
The papular eruptions and the burning involving the arms, forearms and dorsa of the hands lasted
for more than five days. Of the controls, four out of six responded in the same way by producing
papular eruptions. The trichomes of Tetrapanax papyriferum have a stellate shape with multiple
sharp points containing a structured unknown material. When touched, the hairs will break and
penetrate the skin producing a microtrauma and releasing substances which may make the lesions
worse.
10.12 REFERENCES
1. Karrer, W., Konstitution und Vorkommen der organischen Pflanzenstoffe, Birkhäuser Verlag, Basel,
1976.
2. Bohlmann, F., Burkhardt, and T., Zdero, C., Naturally occurring acetylenes, Academic Press, London,
New York, 1973.
3. Bohlmann, F., Niedballa, U., and Rode, K. M., Über neue Polyine mit C17-Kette, Chem. Ber., 99,
3552, 1966.
4. Boll, P. M. and Hansen, L., On the presence of falcarinol in Araliaceae, Phytochem., 26, 2955, 1987.
5. Hausen, B. M., Bröhan, J., König, W. A., Faasch, H., Hahn, H., and Bruhn, G., Allergic and irritant
contact dermatitis from falcarinol and didehydrofalcarinol in common ivy (Hedera helix L.), Contact
Derm., 17, 1, 1987.
6. Hansen, L. and Boll, P. M., The polyacetylenic falcarinol as the major allergen in Schefflera arboricola,
Phytochem., 25, 529, 1986.
7. Takahashi, M., Isoi, K., Kimura, Y., and Yoshikura, M., Studies on the components of Panax ginseng
II. On the etheral extract of ginseng radix alba, J. Pharm. Soc. Japan, 84, 752, 1964.
8. Shim, S. C. and Koh, H. Y., Polyacetylenes from Panax ginseng roots, Bull. Korean Chem. Soc., 4,
183, 1983.
9. Hansen, L., Hammershøy, O., and Boll, P. M., Allergic contact dermatitis from falcarinol isolated
from Schefflera arboricola, Contact Derm., 14, 91, 1986.
10. Hardin, J. W. and Arena, J. M., Human Poisoning from Native and Cultivated Plants, Duke University
Press, Durham, NC, 1974.
11. White, J. C., Dermatitis Venenata, Cupples & Hurd, Boston, 1887.
12. Muenscher, W. C., Poisonous Plants of the United States, Macmillan, New York, 1951.
13. Reynard, G. B. and Norton, J. B. S., Poisonous plants of Maryland in relation to livestock, Maryland
Agric. Exp. Stat. Tech. Bull., A10, 1942.
14. Kanngiesser, I., Phytonosen, Gartenflora, 59, 395, 1910.
15. Hammershøy, O., Allergic contact dermatitis from Schefflera, Contact Derm., 7, 57, 1981.
16. Mitchell, J. C., Allergic contact dermatitis from Hedera helix and Brassaia actinophylla, Contact
Derm., 7, 158, 1981.
17. Sakakibara, J., Kaiya, T., Taniguchi, K., and Yasue, M., Studies on the constituents of Gilibertia trifida
MAKINO, Nagoya-shiritsu Daigaku Yakugaku Kenkyo Nempo, 24, 27, 1976.
18. Kawazu, K., Noguchi, H., Fujishita, K., and Iwasa, J., Two new antifungal compounds from Dendro-
panax trifidus MAKINO, Tetrahedron Lett., 33, 3131, 1973.
19. Iwashige, T. and Kaneko, O., A case of contact dermatitis due to Dendropanax trifidus, Japan J.
Derm., 85, 489, 1975.

20. Saito, F. and Murao, T., Some cases of allergic contact dermatitis due to Gilibertia trifida MAKINO,
J. Ther. (Japan), 64, 147, 1982.
21. Saito, F., Urushibata, O., and Murao, T., Contact dermatitis from plants for the last 6 years, Hifu, 24,
238, 1982.
22. Ezoe, K., Showo, M., and Hada, S., Contact dermatitis due to Dendropanax trifidus, Rinsho Derm.
(Tokyo), 30, 1602, 1988.
23. Oka, K., Saito, F., Yasuhara, T., and Sugimoto, A., The major allergen of Dendropanax trifidus
MAKINO, Contact Derm., 36, 252, 1997.
24. Gafner, T., Epstein, W., Reynolds, G., and Rodriguez, E., Human maximisation test of falcarinol, the
principal contact allergen of English ivy and Algerian ivy Hedera helix, Hedera canariensis, Contact
Derm., 19, 125, 1988.
25. Massmanian, A., Valcuende Cavero, F., Ramirez Bosca, A., and Castells Rodellas, A., Contact der-
matitis from variegated ivy (Hedera helix subsp. canariensis WILLD), Contact Derm., 18, 247, 1988.
26. Garcia, M., Fernandez, E., Navarro, J. A., del Pozo, M. D., and Fernandez de Corres, L., Allergic
contact dermatitis from Hedera helix L., Contact Derm., 33, 133, 1995.
27. Schwartz, L., Tulipan, L., and Birmingham, D. J., Occupational Diseases of the Skin, 3rd ed., Lea &
Febiger, Philadelphia, 1957, 637.
28. Lopatin, A. I. and Kolesnikova, N. P., Skin diseases caused by the use of extracts of Echinopax elatum
NACAI, Vestn. Derm. Venerol., 48, 83, 1974.
29. Takahashi, M. and Yoshimura, M., Studies on the components of Panax ginseng, J. Pharm. Soc. Japan,
86, 1053, 1966.
30. Saito, F. and Oka, K., Three cases of allergic contact dermatitis due to medical herb, Hifu, 32, Suppl.
8, 155, 1990.
31. Siegel, R. K., Ginseng abuse syndrome, J. Am. Med. Assoc., 241, 1614, 1979.
32. Baranov, A. I., Medical use of ginseng and related plants in the Soviet Union: recent trends in the
Soviet literature, J. Ethnopharm., 6, 339, 1982.
33. Wagner, H., Hikino, H., and Farnsworth, N. R., Eds., Economic and Medicinal Plant Research,
Academic Press, London, 1985, 217.
34. Sonnenborn, U. and Proppert, Y., Ginseng (Panax ginseng C. A. MEYER), Z. Phytother., 11, 35, 1990.
35. Morton, J. F., Plants Poisonous to People in Florida and Other Warm Areas, Hurricane House Publ.
Inc., Miami, FL, 1971.
36. Arnold, H. L., Poisonous Plants of Hawaii, C. E. Tuttle, Ed., Rutland, VM, 1968.
37. Hansen, L. and Boll, P. M., Polyacetylenes in Araliaceae: their chemistry, biosynthesis and biological
significance, Phytochem., 25, 285, 1986.
38. Calnan, C. D., Dermatitis from Schefflera, Contact Derm., 7, 341, 1981.
39. Aplin, T. E. H., Poisonous plants in the garden and other plants harmful to man in Australia, Western
Australia Department of Agriculture Bulletin 396, 1976.
40. Giannattasio, M., Pizzolongo, P., Cristaudo, A., Cannistraci, C., Salvatore, G., and Santucci, B.,
Contact dermatitis from Tetrapanax papyriferum K. KOCH trichomes, Contact Derm., 35, 106, 1996.

11 Asteraceae
Mario Robles, Jan West, Eloy Rodriguez, and Michael

Heinrich
CONTENTS
11.1 Introduction
11.2 Ethnobotany of the Asteraceae
11.3 Asteraceae in Mexico, Historical and Modern Uses
11.4 Toxicity and Pharmacological Properties of the Major Classes of Sesquiterpene
Lactones from Asteraceae
11.4.1 The Sesquiterpene Lactones
11.4.2 Allergic Contact Dermatitis
11.4.3 Neurotoxicity
11.5 Medicinal Activities Reported from the Asteraceae Containing Sesquiterpene Lactones
11.5.1 Antitumor Activity
11.5.2 Anti-Ulcer Activity
11.5.3 Cardiotonic Activity
11.5.4 Antimigraine Activity
11.6 Summaries of Various Genera
11.6.1 Achillea
11.6.1.1 Achillea millefolium L.
11.6.1.2 Achillea nana L. (Achillea ageratifolia)
11.6.1.3 Achillea fragantissima
11.6.1.4 Ambrosia
11.6.2 Artemisia
11.6.2.1 Artemisia ludoviciana Nutt
11.6.2.2 Artemisia abrotanum
11.6.2.3 Artemisia herba-alba
11.6.2.4 Artemisia verlotorum
11.6.2.5 Artemisia monosperma
11.6.2.6 Artemisia tridentata
11.6.3 Cichorium intybusm
11.6.4 Elephantopus
11.6.4.1 Elephantopus spicatus
11.6.4.1.1 Ethnobotany
11.6.4.1.2 Pharmacology/Toxicology
11.6.5 Helenium
11.6.5.1 Ethnobotany
11.6.5.2 Helenium quadridentatum
11.6.5.2.1 Chemistry and Pharmacology

11.6.6 Helianthus annuus (SUNFLOWERS)
11.6.7 Montanoa
11.6.7.1 Montanoa tomentosa
11.6.7.1.2 Pharmacology
11.6.8 Parthenium
11.6.8.1 Parthenium hysterophorus L. (Heliantheae)
Santa Maria Feverfew
11.6.8.1.2 Phytochemistry
11.6.8.1.4 Toxicology
11.6.9 Taraxacum officionale6
11.6.10 Tithonia
11.6.10.1Tithonia diversifolia
11.7 Conclusion
11.8 Acknowledgments
11.9 References
11.1 INTRODUCTION
The Asteraceae family, also known as the sunflower family, includes about 25,000 species. Plants in
this family include weeds (e.g., dandelions), ornamentals (e.g., sunflowers), and vegetables (e.g., lettuce,
chicory, and artichokes).1,2 Many plants of the Asteraceae are used for medicinal purposes throughout
the world. Unfortunately about 180 species are known to cause allergic contact dermatitis worldwide.3
There are about 380 genera with 3000 species currently (1994) recognized in this family in
Mexico. The principal reason for focusing a major review on Mexican Asteraceae (Compositae)
is their enormous importance in the popular medicine of Mexicans and persons with Mexican
ancestry and also to highlight their potential as contact dermatitis causing plants. Allergic contact
dermatitis is defined as inflamation and irritation of the skin owing to contact with an irritating
substance. Members of this botanical family include wormwood (Estafiate, Artemisia ludoviciana
ssp. mexicana), zoapatle (Montanoa tomentosa) and Mexican arnica (Heterotheca inuloides) and
are frequently sought by people who have health problems for which they do not want to consult
a doctor or a health center. For these reasons, it is important to the public health of these peoples
that the medical community have a summary of the pharmacological effects and potential to cause
contact dermatitis.
Although thousands of scientific articles have been published on natural products, each plant
has several hundred different natural products. The great majority of which have not been studied
for their contact dermatitis causing properties. Many of the plants used in folk remedies are
potentially hazardous and have chemical constituents that can elicit allergic contact dermatitis (e.g.,
Parthenium hysterophorus) or liver damage (e.g., pyrrolizidine alkaloids.)4
The review is limited to genera native to Mexico that are known to have contact dermatitis
properties and is divided into two major parts:
1. An initial description of the major types of chemical compounds and their major phar-
macological effects
2. Nine summaries of existing information about plant genera most widely used in popular
medicine of modern and historic Mexico

11.2 ETHNOBOTANY OF THE ASTERACEAE
The Asteraceae have yielded an astounding number of medicines for the native and mestizo
populations of Mexico and the United States, and numerous studies have been conducted on the
uses of these plants in the various regions of Mexico. An important prerequisite for these studies
is a detailed knowledge of which plants are of major ethnobotanical importance and which are
used only by a few people of a community and/or by only a few indigenous or mestizo populations.
While there are numerous reviews of plants traditionally used in North America and Europe, no
modern comprehensive treatment is available for Mexico.5,6 Data used came from both historic and
modern sources to select the most widely used plants for this review.
11.3 ASTERACEAE IN MEXICO, HISTORICAL AND MODERN USES

The most important source of our knowledge about preconquest indigenous plant use in Mexico
is the Florentine Codex compiled by the Franciscan monk Fray Bernardino de Sahagun. Other
important sources are the work of the Spanish physician, Francisco Hernandez, and a herbal guide
written in Nahuatl by the Aztec healer Martin de la Cruz from Tezcoco, who was at the Colegio
de Santa Cruz in Tlatelolco. The work by de la Cruz was translated into Latin by Juan Badiano
and sent to the King of Spain, Philip II in 1552.
In the last 20 years, there have been numerous studies on the traditional plant uses in many
parts of the highlands but also less frequently in the deserts and the tropical parts of Mexico. Such
studies were not only conducted in areas with large indigenous populations but also in the markets
where medicinal plants are sold. These studies are rather diverse in methodology,7,8 some are
botanically oriented with little ethnographic information,9 while others have a strong ethnographic
background.10 Other studies do not focus specifically on medicine and plants but yield relevant
information.11
11.4 TOXICITY AND PHARMACOLOGICAL PROPERTIES OF

MAJOR CLASSES OF SESQUITERPENE LACTONES FROM
ASTERACEAE
11.4.1 THE SESQUITERPENE LACTONES
Sesquiterpene lactones (SQL) are a large and diverse group of biologically active plant constituents
that have been reported from 10 families of flowering plants. However, the greatest number have
been reported from the Asteraceae with over 3000 reported structures. These are the major
sensitizers and are found in the leaves, stems, and flowers. Some of the important medicinal plants
from this family, such as Arnica montana, Artemisia annua, and Tanacetum parthenium contain
sesquiterpene lactones as the active constituents. SQL are commonly present in very large quan-
tities (greater than 2 percent dry wt. of leaves). These sesquiterpene lactones are usually compar-
atively nontoxic but with an intensely bitter taste that presumably deters herbivores. A few SQL
are highly toxic (e.g., repin and helenalin), but many have anti-inflammatory activity and have
been shown to relax smooth muscles in vitro. Previous major reviews by Rodriguez et al.1,2 Fischer
et al.,13 Seaman,14 and Picman15 have discussed the chemistry and taxonomic significance of
sesquiterpene lactones. Stuppner16 and Rodriguez et al. and Picman have reviewed recent aspects
of the biological activity. These studies have suggested that cytotoxicity and contact dermatitis
are mediated by the interaction of the active moiety (exocyclic double bond conjugated with
carbonyl carbon of lactone ring) with enzymes or proteins bearing a sulfhydryl group.12 This
interaction inhibits enzyme activities and metabolism, and interactions with glutathione (GSH).17
Common properties of many of the pharmacologically active SQL are anti-inflammatory effects
mediated by inhibition of prostaglandin synthesis and a stimulation of smooth muscle contractions.

Both of these properties could explain the popularity of SQL containing herbal remedies to treat
gastrointestinal distress.

Sesquiterpene lactones frequently have been shown to cause contact dermatitis. This is presumably
owing to Michael addition reactions between skin proteins and the exocyclic double bond present
in SQLs. The genus Parthenium, one of the most investigated plants, has been reported to cause
allergic contact dermatitis, rhinitis, and hypotension by several investigators.19-22 The contact aller-
gen identified from Parthenium is parthenin.22 Most of these plants contain significant quantities
of sesquiterpene lactones with potent biological activity.
Sesquiterpene lactones that possess an a-methylene-g-lactone moiety undergo thioether conju-
gation in vivo and in vitro. Kupchan18 first proposed this mechanism of action in 1969 when he
reported conjugation with model biological nucleophiles. A reported scheme for this reaction is
given in this section.
Conjugation of sesquiterpene lactones with GSH
SQLs also form adducts with amino acids and proteins containing sulfhydral (SH) groups such
as cysteine.12,16 Previous investigators have reported an in vitro depletion of GSH by SQLs using
several tumor cell lines.23 Some SQLs also have demonstrated the capacity to deplete the levels of
GSH in vivo in different tissues.23 This fact is very important when considering the mechanism of
the action of sesquiterpene lactones.
11.4.3 NEUROTOXICITY
Several plant toxins have been associated with neurodegenerative changes in both the brain and
spinal cord. Until recently, no sesquiterpene lactones have been directly associated with neurolog-
ical disorders. However, in 1954, a specific neurological disease of horses commonly known as
chewing disease, was experimentally linked to the ingestion of large amounts of Centaurea repens,
a member of the Asteraceae with large quantities of SQL.23 Neuropathological examination of the
brain from the intoxicated horse revealed bilateral necrosis of the anterior globus pallidus and zona
reticulata of the substantia nigra. To pursue the hypothesis that SQL might produce neurotoxic
effects, Stevens and Riopelle24 conducted an in vitro neurotoxicity study. The growth of the neurites
was noted in the presence of the different SQL from Centaurea repens and the 50 percent toxic
dose (TD50) was estimated. On a molar basis, repin was 3 to 4 times more toxic than its C-17
isomer subluteolide and 4 to 10 times more toxic than acroptilin and the other SQL tested. In 1991,
Hostettmann and Hamburger25 studied the neurotoxic effects of SQL from yellow star thistle
(Centaurea solstitialis). Hostettmann and Hamburger25 reported that solstitialin cynaropicrin exhib-
ited toxicity to cultured rat fetal brain cells in a concentration-dependent manner and suggested
that these compounds could cause neurodegenerative disorders. In the laboratory, Robles et al.26,27

have demonstrated cytotoxicity to different cell lines and, specifically, to brain cells. They also
demonstrated that repin can deplete levels of intracellular GSH both in vitro and in vivo in mice.
Depletion of GSH reduces the protection from oxidative stress. Therefore, repin neurotoxicity could
be mediated by the depletion of intracellular GSH.
11.5 MEDICINAL ACTIVITIES REPORTED FROM THE ASTERACEA

CONTAININING SESQUITERPENE LACTONES
11.5.1 ANTITUMOR ACTIVITY
Sesquiterpene lactones have been shown to have both cytotoxic and antitumor activity.22 To date,
very little published data have been presented on the in vivo antitumor properties of sesquiterpene
lactones. In 1982, Towers et al.28 reported nonlethal doses of parthenin to have a significant effect
on the percentage survivorship of mice with tumors derived from either L1210 or P815 tumor cells.
Hladon and Chodera29 revealed that eupatoriopicrin can prolong the life expectancy of mice after
transplantation of the tumors Sa180, EAT, and L1210. In 1987, Woerdenbag et al.30 reported that
eupatoriopicrin possesses strong antitumor activity in the Lewis Lung tumor system in mice, an
experimental solid tumor system derived from a very malignant and poorly differentiated epider-
moid human carcinoma. Woerdenbag et al.30 concluded that eupatoriopicrin had a cytostatic effect
against the solid tumor growth when injected i.p. to C57Bl/6j mice. The methanolic flower extract
of Parthenium hysterophorus has been found to have in vivo antitumor effects against P388
lymphocytic leukemic cells carrying mice. Biochemical markers such as reduced glutathione,
cytochrome P450, glutathione transferase, and UDP-glucoronyl transferase in the liver of host cells
showed substantial alterations leading to the slow development of a tumor and an increase in the
survivability of the mice bearing the lymphocytic leukemia. More research on the in vivo antitumor
properties by sesquiterpene lactones is needed.
11.5.2 ANTI-ULCER ACTIVITY

Plants containing sesquiterpene lactones have been used as herbal remedies in different cultures.
In Argentina, leaves of Artemisia douglasiana have been used to prepare an infusion called matico
that is used to treat peptic ulcers and external sores and ulcers. Giordano et al. 31 investigated the
in vivo gastric cytoprotective properties in 1990. In this study, matico demonstrated considerable
protective effects in rats against ulcerogenic agents such as absolute alcohol.
The crude chloroformic extract (SQL containing) of A. douglasiana exhibited significant pro-
tective activity and, upon chromatographic purification a sesquiterpene lactone, dehydroleucodin,
was isolated. Further oral testing demonstrated that this lactone was the anti-ulcer principle in A.
douglasiana, and the protective effect was shown to be dose-dependent. It has been speculated by
Giodarno et al. that the anti-ulcerogenic activity could be related to the induction of endogenous
prostaglandin release. A reduction in the protective effect was observed when rats were pretreated
with indomethacin, a prostaglandin inhibitor.
Giodarno et al. investigated the activity of other sesquiterpene lactones. The lactones ludartin,
8-angeloyloxy-3-hydroxyguai-3, 10-trien-6,12,olide, 11-trien-6,12,olide, hymenin; mexicanin I,
helenalin, and 9-O-desacetylspathulin-2-O-angelate revealed protective activity similar to dehydro-
leucodin, while the lactone desacetoxymatricarin lacked protective effects.15,17,32 Giodarno et al.
reported that the a-methylene-g-lactone moiety is required for the protective effect. In 1992,
Giodarno et al.33 revised the proposed mode of action and speculated that the protective effect was
mediated by more than one mechanism. In a similar fashion, aluminum hydroxyl, a commonly
used ulcer medication, exerts its protective effect by both stimulating prostaglandin release and by
forming adducts with the thiol constituents in the gastric mucosa. These thiol constituents are also
capable of reacting with the lactones. Structure-activity studies with 18 sesquiterpene lactones led

to the conclusion that the presence of a nonsterically hindered Michael addition acceptor, a-
methylene-g-lactone moiety, is a requirement for the cytoprotective activity.33
11.5.3 CARDIOTONIC ACTIVITY

The presence of the azulene skeleton in many SQLs stimulated researchers to investigate the effects
of azulene-containing SQLs on isolated heart muscle. Strips from the left atrium and papillary
muscles from the left ventricle of the guinea pig heart were used to examine the effect of helenalin,
a sesquiterpene lactone isolated from Helenium autumnale, on their contractility. Helenalin was
shown to produce a positive ionotropic effect (PIE) on both. This positive ionotropic effect is dose
dependent, with concentrations effective on the atrial strips in the range between 10-5 and 3 · 10-4M,
and on the papillary muscle in the range between 3 · 10-4 and 10-3M. Furthermore, in this system
the positive ionotropic effect is irreversible because it does not return to control after washing the
preparations. Catecholamine PIE dependency in atrial but not in ventricular muscles was shown in
reserpinized guinea pigs. Studies to investigate the mode of action of helenalin concluded that
helenalin increases cAMP by inhibiting phosphodiesterase.34 This increase of cAMP causes Ca+2
influx and thereby enhances the contractility of the myocardium.
11.5.4 ANTIMIGRAINE ACTIVITY

Tanacetum parthenium, commonly known as feverfew, is widely consumed in England and other
regions of northern Europe as a remedy for arthritis and migraine headaches. Several reviews of
T. parthenium have been published recently, where the botany, phytochemistry and pharmacology
are highlighted.35-38 Heptinstall et al.39 reported that parthenolide (a SQL) was the active constituent
in feverfew. Parthenolide has been shown in vitro to inhibit the prostaglandin synthetase-mediated
pathway, the mediator of inflammation, thereby relieving inflammatory conditions such as arthri-
tis.40 Clinical evidence has demonstrated the efficacy of feverfew to 17 migraine patients.41 Other
clinical studies have demonstrated that parthenolide reduces the incidence and severity of
migraines.41,42 Owing to the curative properties of feverfew in clinical settings, parthenolide’s
biological properties have been extensively investigated in the past 10 years to attempt to understand
its prophylactic activity. Parthenolide can inhibit platelet aggregation and serotonin secretion in
vitro when present at micromolar concentration.42 A decrease in serotonin levels in platelets is the
most consistent of the biological alterations observed in migraine headache.42 This feature is
common to other drugs effective against migraines. Commercial preparations of feverfew are
available through pharmacies and health food stores in England. No serious side effects were
reported in the clinical studies.
11.6 SUMMARIES OF VARIOUS GENERA

11.6.1 ACHILLEA
Achillea is a genus of perennial aromatic herbs native to North America, Europe, and Asia; about
75 species have been reported. Many of them are used in different cultures.
11.6.1.1 Achillea millefolium L.
Achillea millefolium L. is known as Anthemidae, Yarrow (engl.) or Tlaquequetzal. In the

Florentine Codex, it is listed as a remedy for cough and overeating,43 and externally as a remedy
for aches all over the body together with tonalxihuitla (Stevia aliciforlia), atzitzicaztli (Urera
caracasana), atzomiatl (not identified), and lampblack axin (fat from the scale insect Llaveia axin).43
Hernandez44,45 describes the sap as diuretic and emetic. The plant was used to relieve the stomach

FIGURE 11.1 The three new sesquiterpenoids, achimilic acids A, B, and C, isolated from Achillea millefolium L.
and flatulence. It was to be applied locally for scabies and itching of the face mixed with acuahuitl,
ehecapatli (not identified).46 During the twentieth century, it has been used as bitter tonic for nervous
disorders (nerves), hemorrhage, and for colic of the stomach and hypochondria. For an infusion
against hemorrhage, 20 g of the leaves and flowers are used. A decoction of 10 g per l of water
serves to cleanse wounds.47,48 It is a common weed in North America and known to cause strimmer
dermatitis.49
The methanolic extract was found to exhibit activity against mouse P-388 Leukemia cells in
vivo. Bioassay directed fractionation led to the isolation of three new sesquiterpenoids, achimilic
acids A, B, and C.50 Figure 11.1 has the chemical structure of these compounds. BDF1 male
mice at 6 weeks of age were inoculated intraperitoneally (i.p.) with 106 P-388 cells. Test
compounds were also injected i.p. as a single injection on the day following the tumor inoculation.
Antitumor activity was evaluated by the increase in life span (ILS) compared to that of the control
animals. The results showed that at 5 mg/kg dose, all 3 test compounds increased the life span
(ILS percent) The test compound results showed A to be 34 percent, B to be 39 percent and C
to be 35 percent). Doses of 20 mg/kg lost their effectiveness and doses of 50 mg/kg proved toxic
to the treated mice.
11.6.1.2 Achillea nana L.
In vitro inhibition of cycloxygenase and 5-lipoxygenase by alkamides isolated from Achillea

nana L. (Achillea ageratifolia) and Achillea ageratifolia have been reported. These are the key
enzymes of the two major pathways of arachidonic acid metabolism, and are thus anti-inflam-
matory agents. The most potent inhibitor against cycloxygenase enzyme was tetradeca-2E,4E-
10Z-triene-8-ynoic acid pyrrolidide, which was isolated from Achillea nana: 50 mg/ml showed
a 60 percent inhibition. In addition, the most potent inhibitor of the 5-lipoxygenase enzyme was
trideca-2E,4E-diene-8,10,12-triynoic acid piperridide which was isolated from Achillea spinuli-
folia Fenzl exBoiss. Using a dose of 50 mg/ml caused a 64 percent inhibition of arachidonic
acid metabolism.51
tetradeca-2E,4E-0Z-triene-8-ynoic acid pyrrolidide

trideca-2E,4E-diene-8,10,12-triynoic acid piperridide
11.6.1.3 Achillea fragantissima
Cirsiliol, a flavone isolated from Achillea fragantissima, caused a concentration-dependent relax-

ation of rat isolated ileum. The effective concentration (EC50) of cirsiliol for relaxation of ileal
segments was 5.2 ± 0.9 · 10-6M (n=6). It is thought that cirsiliol interferes with calcium channels
and thus inhibits Ca+2 influx from the extracellular compartment.52
11.6.1.4 Ambrosia
Ambrosia is also known as ragweed and can cause contact dermatitis throughout the growing
season.53,54 Warshaw reported in 1996 that American male farmers, 40 to 65 years of age, are more
at risk than their female counterparts.95 They claimed a 20:1 male to female ratio. Different types
of SQLs are thought to ellicit contact dermatitis present in the Ambrosia species.54
11.6.2 ARTEMISIA
The genus Artemisia contains more than 200 species that have been reported from many parts
of the world and has been selected for remedies by cultures throughout the world for medicinal
properties. The reported active constituents of the genus include all the types of common natural
products of the Asteraceae: sesquiterpene lactones, polyacetylenes, flavonoids, essential oils
(monoterpenes), diterpenes, triterpenes, and coumarins. We have included aspects of recent
studies conducted with extracts of the genus to give an indication of the range of biologically
active compounds that could be found in the Mexican species if an exhaustive study were to be
conducted. (One particular compound from A. annua, artemisinin, with antimalarial properties
is not discussed because it appears to be restricted to Chinese species.) The sensitizing SQL are
ludovicins A, B, C.1
11.6.2.1 Artemisia ludoviciana

Artemisia Ludoviciana Nutt. ssp. mexicana Nutt (Anthemidae) Wormweed (engl.)/Estafiate
(span.)/Iztauyatl (Nahuatl) —the Badianus Codex mentions it as a part of a mixture with xoxouh-
capatli and quetzalxoxouhqui (not identified) for weakness in the hands. The treatment also included
putting one’s hands into an anthill.46 Hernandez44 prescribes it to cure pain from cold, flatulence,
colic, or intestinal pain. The Florentine Codex43 prescribes it to clean urine, relieve fever, for coughs,
and for anguish in the heart. Iztauhyatll together with Tagetes lucida (yahuatli) were closely
associated with the Aztec rain god, Tlaloc, and had a number of functions in medicine and ritual
because of it.
Today, it is used for modern internal uses for gastrointestinal complaints in Mexico. Mexicans
generally use the infusion as a bitter stimulant and the powdered flowers as a vermifuge and
stimulant. Because of its spasmolytic properties, the aerial parts are popular for colic. Ruiz Salazar,55
for example, mentions the following uses: lack of appetite, stomachache and parasites, and stomach

and liver infections. On the market of Sonora (Mexico D.F.), the plant is sold for the treatment of
dysentery and vomiting. The flowers are used as tea for colic, dysentery, diarrhea, indigestion, pain,
and stomachaches.56,57 Only a few scattered reports on other modern internal uses are in the literature
in Mexico, such as for colds,56,58 bronchitis,9 chest congestion,58 heart illnesses,48 and menstrual
complaints.55
Modern external uses in Mexico include the following. The leaves are used as a decoction for
washing the ear and as an analgesic by the Zoque (Chiapas). Kept in alcohol, the leaves are used
for external cleansing.59 The Huastec use the leaves against earache, swellings, infections, and
inflammation.11 In Veracruz, it is used for headaches, sudden fright, and earaches.9
The species has been studied in great detail and the samples seem to differ considerably in
chemical composition. Jakupovic et al.60 report on the isolation of several aromatic components
from the essential oil (among them camphor and borneol), of monoterpenes, and sesquiterpenes
(germacranolides, eudesmanolides, guaianolides and seco-guaianolides). Ruiz-Cancino et al.61 iso-
lated further sesquiterpenoids (especially of the eudesmanolide type) and two flavonoids (eupatilin
and jaceosidin).62
11.6.2.2 Artemisia abrotanum
Four flavonols isolated from Artemisia abrotanum have been reported to possess spasmolytic
activity. These flavonols show a dose-dependent relaxing effect on the carbacholine-induced con-
traction of the guinea pig trachea.63
The EC50 values are as follows:
Compound EC50 (mM)

1 30
2 20
3 25
4 Significantly lower and only 22 percent relaxation was
observed at the maximum dose added (48 mM)
11.5.2.3 Artemisia herba-alba
Artemisia herba-alba It is widely used for the treatment of diabetes mellitus. The compound alloxan
is used to produce a hypoglycemic state in experimental animals. Rabbits were fed daily plant
aqueous extract (0.39 g/kg) for 2 to 4 weeks.64 Similar experiments were conducted using male
adult Wistar rats (250 to 300 g).65 The results were similar for both rats and rabbits:
1. Protection against body weight loss

2. Maximum reduction in the blood glucose level
3. A decrease in the elevated serum cholesterol, triglyceride, and phospholipids levels
4. A reduction of the elevated glycosylated hemoglobin level
The extract of the aerial parts of the plant seems to have minimal adverse effect with a high
LD50 value. The LD50 graded doses of the aqueous extract were administered intraperitoneally to
mice (n=6, albino mice, 25 to 30 g). The LD50 value was observed at 4.49 g/kg body weight which
represents 20.54 g of the crude, powdered aerial parts material/l kg body weight.65
11.5.2.4 Artemisia verlotorum
The water–alcoholic extract showed a protective effect against experimental convulsions

elicited by various agents as well as analgesic and hypothermic actions. This plant is used as an

anticonvulsant and analgesic. High doses (2 g/kg) prevented the onset of electroshock (75 mA,
60 Hz) and pentylenetretazole-induced (75 mg/kg, i.p.) convulsions when using male Swiss adult
albino mice (weighing 25 to 30 g).66
Following i.p. acute administration of the plant extract (0.3 to 8.0 g/kg), the animals showed
reduced locomotor activity. Although no deaths or significant changes in gross behavior were
observed following up to 4 g/kg of the plant extract, all animals given doses higher than 4 g/kg
died immediately after treatment.66
11.6.2.5 Artemisia monosperma
The relaxant effects of 7-O-methyleriodictyol, a flavone isolated from the aerial parts of Artemisia
monosperma, on various isolated smooth muscle preparations are shown next.

EC50 (M)
Ileum 5.6 ± 0.8 · 10-5
Trachea 5.0 ± 1.7 · 10-3
Pulmonary artery 7.3 ± 1.7 · 10-5
Urinary bladder 3.5 ± 1.1 · 10-5
Uterus 2.9 ±1.1 · 10-5
Also, the inhibition of contraction induced by known compounds such as acetylcholine and
oxytocin are consistent with the use of this plant in the treatment of certain gastrointestinal disorders.67
7-methoxy-5,3¢,4¢-trihydroxy-flavanone
11.6.2.6 Artemisia tridentata
This plant is frequently used as an anthelmintic, antiseptic, and analgesic. It is also known as
Chamiso hediondo (stinking sagebrush). Many of the compounds identified in this species have
notable pharmacologic activities, particularly the monoterpenes, sesquiterpene lactones, coumarins,
and flavonoids.
Sesquiterpene lactones include santonin, a potent anthelmintic used to treat ascaridiasis and
oxyuriasis. It acts on the ganglion cells of the worm to induce paralysis, so that the parasite can
be eliminated via the feces.71 Another SQL with anthelmintic properties is artemisin.
Several monoterpenes found in Artemisia tridentata have CNS-stimulatory effects (including
camphor, cineole, and thujone). Thujone, even when consumed in small doses, can cause convul-
sions and death owing to its psychomimetic effects.68
11.6.3 CICHORIUM INTYBUSM
Cichorium intybusm is a weed that grows throughout the world that is commonly known as chicory.68
The roots are used to brew a coffee substitute and are also roasted to caramelize sugars that are
used with coffee drinks. The leaves are used in salads and are known as endive. The major allergens
are lactucin and lactopicrin, also found in lettuce (Lactuca sativa).1,69 In addition, lactucin and
lactopicrin have been reported to have neurotoxic properties.70,71
11.6.4 ELEPHANTOPUS
Elephantopus has approximately 12 species of herbaceous perennials in North and South America.
SQL and other biologically active compounds have been reported from this genus.

11.6.4.1 Elephantopus spicatus
Elephantopus spicatus is the synonym for Pseudelephantopus spicatus C.F. Baker, Vernonieae.
The leaves are used for the treatment of cough and headache.11 Applied topically, they are employed
as an antipyretic, for the treatment of erysipelas, skin infections, and measles. A preparation made
from the roots is taken as a remedy for colic. The whole plant helps against diarrhea.9 It is one of
the most popular cough remedies of middle America.49
11.6.4.1.2 Pharmacology/toxicology
Elephantopus scaber has been used as a traditional remedy to cause dieresis, antipyresis, and to
eliminate bladder stones. This genus has been reported to contain the hydroxylated germacranolides,
molephantin and molephantinin, that also possess cytotoxic and antitumor properties.72,73 This plant
also contains phantomin and its cis-epoxide that have been reported to exhibit potent inhibitory
actions on Ehrlich ascites carcinoma and on Walker 256 carcinosarcoma cells.72,73
Pharmacological experiments on the plant extract were conducted by Poli et al.74 Oral admin-
istration (30, 60, 100, 300, and 600 mg/kg) and intraperitoneal injection (3, 10, and 30 mg/kg)
failed to modify the reaction time in the hot-plate test.
Intraperitoneal injection (300 and 600 mg/kg) in adult male Wistar rats significantly reduced
brewer’s yeast induced hyperthermia 1, 2, and 3 h after administration of both extracts. However,
oral administration of both extracts (300 and 600 mg/kg) failed to reduce edema induced by
carrageenan in the rat hind paw at 1, 2, and 4 h following exposure.
In addition, the aqueous (300 and 600 mg/kg, p.o.) extract significantly decreased intestinal
transit in mice. The ethanolic extract, up to 6 g/kg, did not produce significant modifications in the
behavior of mice. Intraperitoneal (i.p.) injection of both aqueous (0.03 to 3 g/kg) and alcoholic
(0.1 to 3 g/kg) extracts induced writhing, loss of muscle tone, ataxia, prostration, and death. The
estimated LD50 in adult male Swiss Webster mice was greater than 2 g/kg i.p. and after oral
administration was greater than 6 g/kg. These acute toxicity experiments reveal a low toxicity for
the plant extract.75
11.6.5 HELENIUM
Helenium is a genus with about 40 species of annual and perennial herbs. A large number of SQL
with pseudoguainolide and germacranolide skeletons have been reported from this genus, many of
the SQL being very toxic.
Helenium mexicanum (synonym for Gomphrena decumbens, fide B. Ortiz de M., Heliantheae)/
Sneezeweed (engl.)/Ueuei itzontecon (nahuatl)—This plant is taken orally if a person is very sick,
the stomach hurts, the heart seems faint, the temples throb, the nerves quiver, or in case of fever
or for pus in the genital organ.44
11.6.5.2 Helenium quadridentatum
Amo9 lists the following uses for fever, catarrh, as a diuretic and an insecticidal and for testicular
inflammations. Martinez47 mentions the plant is used to provoke sneezing, as a diuretic, and against
colic and fever.

11.6.5.2.1 Chemistry and Pharmacology
Sesquiterpene lactones such as helenalin mentioned earlier to possess cardiotonic properties, were
isolated from Helenium autumnale, exhibit anti-inflammatory, hypolipidemic, antibacterial, and
antitumor activity. The likely mechanism of antitumor by helenalin can be explained by a marked
potentiation of the increase in intracellular free [Ca+2] concentration produced by mitogens such
as vasopressin, bradykinin, and platelet-derived growth factor in Swiss mouse 3T3 fibroblasts. The
concentrations used by Powis et al.75 were able to inhibit cell proliferation. However, at higher
concentrations of helenalin, the intracellular [Ca+2] was inhibited. Constitutive activation of intra-
cellular signaling pathway by oncogenes can lead to unregulated cell growth in cancer cells. The
effect appears to be owing to an increase in the uptake of Ca+2 into nonmitochondrial stores by
helenalin and an increase of the extracellular [Ca+2].
Structure of Helenalin
11.6.6 HELIANTHUS ANNUUS (SUNFLOWERS)

Helianthus annuus is thought to have originated in Mexico. These sunflower plants are grown
worldwide for seeds and oil.1,69 People who work in the the harvest or prooduction of its seeds and
oil will develop allergic contact dermatitis. The compound responsible for elliciting this response
is 1-O-methyl 1-4,5-dihydroviveusin A.69
11.6.7 MONTANOA
Montanoa is a small genus of large shrubs in Mexico. Montanoa has a variety of natural products,
the most important being diterpenes.
11.6.7.1 Montanoa tomentosa
Montanoa tomentosa is also know as (Heliantheae)/Cihuapatli.

The Aztec cihuapatli or modern zoapatle is the one species of the Asteraceae that has received the
most attention in recent pharmacological and pharmaceutical research.76 The plant is and was used
as a medicine to speed up labor and also to induce abortion. The literal translation of the two words
of the name cihuatl and patli is woman and remedy/medicine, respectively. This plant was widely
cited as an oxytocic in pre-Columbian times.44,45,77,78,89 De la Cruz46 mentions it as part of a complex
mixture including quauhalahuac (whose botanical identification is still controversial), and the tail
of the tlacuatzin (Didelphis ssp.) which may itself be oxytocic.79 The herb continued to be used
during colonial times and is still used widely, particularly in rural areas.9,80-83

Montanoa tomentosa has been studied and reported to contain diterpenes that are responsible for
its oxytocic property.76
11.6.8 PARTHENIUM
Parthenium is a small genus of approximately 16 species of shrubs, herbaceous perennials, and
annuals. A wide variety of biologically active SQL are found in the genus.
11.6.8.1 Parthenium hysterophorus L. (Heliantheae) Santa Maria Feverfew
It is one of the Asteraceae that is used medicinally by a large number of indigenous and mestizo
groups of Mexico. Villada84 lists the plant as a remedy for malaria, for neuralgia, and as a vermifuge.
It is employed by the Mixe Indians in the form of baths to cure fever and body pain,85 and by the
Huastec to treat sores, muscular aches, epilepsy, and fever11,48 for similar uses from other areas.
The species is rich in sesquiterpene lactones with parthenin as the main compound. Parthenin and
ambrosin are known to be the major allergens for contact dermatitis.87
Parthenin, the main sesquiterpene lactone of P. hysterophorus, was shown to possess in vitro and
in vivo (hepatic amoebiasis in hamsters) amoebicidal activity. The MIC50 in vitro is 10 to 12 mg/ml,
a value that is comparable to that of metronidazole. However, in vivo parthenin (ED50 40 mg/kg)
was less effective than metronidazole. Also, the compound was shown to be quite toxic.86
11.6.8.1.4 Toxicology
In hamsters, a 40 mg/kg dose proved toxic to 2 out of 7 animals. The LD50 and MLD doses in
mice were established as 450 and 600 mg/kg, respectively.86 The plant has now become a pantropical
pest and a strong elicitor of allergic contact dermatitis.88
11.6.9 TARAXACUM OFFICIONALE
Known as the dandelion, Taraxacum officionale derived its name from the French “dent de lion,”
because of its immature seeds and notched leaves resembling lion’s teeth.1,69,87 The allergen is a
sesquiterpene lactone linked to glucose via an ester linkage known as taraxinic acid (1-O-b-
glucopyronoside).
11.6.10 TITHONIA
Tithonia is a small genus of less than 10 species in Mexico and Arizona that has been delimited
variously. Tithonia includes both large herbs and shrubs.
11.6.10.1 Tithonia diversifolia
Tithonia diversifolia is also known as (Hemsl.) A. Gray. (Heliantheae)/Wild Arnica (engl.)/Arnica

de la montana, arnica (span.).
It is one of the most frequently seen plants in gardens of the tropical areas of Mexico and seems
to be an important, but ethnobotanically little known medicinal plant in these regions. With the
Lowland Mixe, it is used orally against malaria and other forms of fever, and used topically to treat

hematomas and muscular cramps.85 Morton48 also cites a use as a liniment from Yucatan. These
uses may be owing to the similarity of the flower heads of this species with the ones of European
arnica (Arnica montana L.) This assumption is corroborated by its popular names Arnica de la
montana and arnica.49,85
The genus is rich in sesquiterpene lactones. From T. diversifolia tirotundin89 and a large number
of other sesquiterpene lactones90 are known. Tirotundin and many of the other sesquiterpene
lactones isolated from this species are interesting phytochemically in that they contain several
epoxides.91
The aerial parts of T. diversifolia, which is also used in the popular medicine of Taiwan, showed
anti-inflammatory effects in the carrageenan induced rat paw edema test. Treatment with the
water extract (1000 mg/kg) decreased the paw edema at a statistically significant level.92 An
ethanolic extract from the aerial part showed no antimalarial effect,85 but did have some
antipyretic action.
11.7 CONCLUSION
In this review, aspects of recent reports of the pharmacology and toxicology and allergic contact
dermatitis of plant extracts and recently identified chemicals from the plant family Asteraceae used
by Mexicans and Mexican Americans/Chicanos are discussed. The number of plant species in this
family in Mexico and the Southwest is numbered in the thousands, and each species undoubtedly
contains hundreds of untested compounds with biological activity. It is impossible at this point to
list all of these activities; instead, the main emphasis has been placed on reviewing the most widely
used herbal remedies to give medical practitioners some idea of the possible physiological effects
of the herbal remedies used by their patients. In turn, this will raise a warning flag whenever
potential hazardous risks of contact dermatitis are present. Contact dermatitis classically involves
men older than 40 years with a history of outdoor activities. Interestingly, women and children are
less frequently sensitized.
Usually, a single small area of the exposed body is involved for some time. Then, a more
widespread eruption takes place that involves unexposed areas of the body. The dermatitis reaction
usually disappears in the winter. Flowers and leaves are usually more potent sensitizers than stems.93
The prevalence of SQL-induced allergic contact dermatitis is not known, but it has been reported
in Europe, Latin America, India, Japan, and Australia. It is a worldwide problem. Avoidance of
SQL containing plants is the best effective treatment but, of course, that is not practical especially
when these same plants are used for medicinal purposes. While no widespread studies of oral
hyposensitization have been reported, several small studies have reported success using patch test
reactions. A protocol developed by Storrs employs the combination of PUVA therapy and oral
prednisone.1
It is important to note that many of the natural products of the Asteraceae have the capacity to
form adducts with glutathione. This reaction will in turn stimulate or inhibit the p-450 mediated
metabolism of xenobiotics, and is relevant particularly to medical practitioners because these effects
may profoundly change the physiological effects of the drugs they are prescribing for their
patients.93,94
11.8 ACKNOWLEDGMENTS
We wish to acknowledge Dr. Ortiz de Monrtellano for his contributions and sharing of the ethno-
botany data presented in this review.

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12 The Pollen Allergens
of the Betulaceae
Heimo Breiteneder, Jun Wen, and Otto Scheiner
CONTENTS
12.0 Abstract
12.1 Introduction
12.2 Betula
12.2.1 Molecular and Immunological Characterization of Bet v 1,
the Major Birch Pollen Allergen
12.2.1.1 Bet v 1-Specific T-Cells: Epitope Mapping and T-Cell
Receptor Characterization
12.2.1.2 Comparison of Immunological Properties of rBet v 1
and nBet v 1
12.2.1.3 Animal Models for the Study of Birch Pollen Allergy
12.2.1.4 Models for Specific Immunotherapy of Birch Pollen Allergy
12.2.2 Bet v 2, Birch Pollen Profilin
12.2.3 Bet v 3, a Novel Calcium-Binding Protein
12.2.4 Bet v 4, a Two EF-Hand Calcium-Binding Protein
12.3 Carpinus
12.3.1 Car b 1, the Major Hornbeam Pollen Allergen
12.4 Corylus
12.4.1 Cor a 1, the Major Hazel Pollen Allergen
12.5 Alnus
12.5.1 Aln g 1, the Major Alder Polen Allergen
12.6 Conclusions
12.8 References
12.0 ABSTRACT
The early flowering trees of the Betulaceae produce large amounts of wind-spread pollen that
represent an important source of inhalant allergens during spring time. These pollen allergens are
capable of inducing IgE-mediated symptoms in susceptible atopic individuals. The major birch
pollen allergen Bet v 1 is by far the best studied allergen at both the molecular and immunological
levels. It was the first pollen allergen whose cDNA sequence was determined. The T-cell epitopes
of Bet v 1 have been mapped, several models for specific immunotherapy have been suggested,
and its crystal structure has been elucidated. Based on sequence similarities Bet v 1 has been placed
among the pathogenesis-related protein family 10 whose members have been described in both
dicots and monocots. A phylogenetic tree has been constructed based on betv1 homologous genes.
The major pollen allergens of alder, hazel and hornbeam, Aln g 1, Cor a 1, and Car b 1, respectively,

FIGURE 12.1 Schematic illustration of the botanical characteristics of Betulaceae. A–B: Corylus avellana,
showing the leaves, fruits, and involucres in (A), and the staminate catkins in (B); C–G: Betula occidentalis,
showing leaves, and male and female catkins in (C), mature bract (scale) in (D), young bract in (E), mature
fruit in (F), and young fruit in (G).
showed similar molecular and immunological characteristics to Bet v 1. The strong interest of
molecular allergology in pollen proteins has also fostered progress in plant molecular biology. Bet
v 2 has been identified as the first plant profilin and two distinct calcium-binding proteins from
birch pollen, Bet v 3 and Bet v 4, were discovered.
12.1 INTRODUCTION
Species of the Betulaceae, or the birch family, are trees and shrubs commonly found throughout
the northern hemisphere. They have numerous small and inconspicuous unisexual flowers, with a
highly reduced perianth (Figure 12.1). The male flowers aggregate into an inflorescence known as
a catkin or an ament. The female flowers form a catkin or a small head. All the betulaceous species
are monoecious and pollinated by wind. They produce copious quantities of pollen that cause hay
fever allergies.1-4 Many betulaceous species bloom in the early spring before the appearance of
leaves that facilitates wind pollination and increases the quantities of their airborne pollen.

The Betulaceae consist of six genera: Alnus, Betula, Carpinus, Corylus, Ostrya, and Ostryopsis,
and approximately 130 species. They are classified in the order of Fagales along with Fagaceae,
the oak family.5 Two subfamilies are commonly recognized within the Betulaceae: the Betuloideae
(Alnus and Betula), and the Coryloideae (Carpinus, Corylus, Ostrya, and Ostryopsis6). The clas-
sification of Betulaceae has been highly controversial. Some workers7,8 recognized two distinct
families: Betulaceae (Alnus and Betula) and Corylaceae (Carpinus, Corylus, Ostrya, and Ostry-
opsis). Kuprianova9 further divided the Corylaceae into two families: Corylaceae (Corylus) and
Carpinaceae (Carpinus, Ostrya, and Ostryopsis), thus recognizing three families. We follow the
concept of the broadly defined Betulaceae.5,10,11
Pollen morphology of the Betulaceae has been examined by various workers.12-14 Pollen grains
of the family are triporate and the exine is slightly rugulate (Figure 12.2). Chen14 recognized three
types of pollen. The Betula type (in Alnus and Betula) is oblate, suboblate, or spheroidal; the
ektexine thickens near the aperture; and the exine is four layered: tectum, columellae, footlayer,
and endexine. The Corylus type (in Corylus) has suboblate pollen grains; the exine has no arci and
there is no thickening near the aperture in the ektexine; the exine is five layered: granular layer,
tectum, columellae, footlayer, and endexine; the columellae is granular; and the endexine thickens.
The Carpinus type (in Carpinus, Ostrya, and Ostryopsis) has suboblate pollen grains; the exine
has no arci; there is no thickening in the ektexine near the aperture; as in the Corylus type, the
exines are five layered; however, the collumellae are columellate (Figure 12.2).
Evolutionary relationships of the six genera in the Betulaceae have been constructed using
morphology, palynology, and molecular markers.15-19 Morphological15 and rbcL phylogenies18 sup-
port the monophyly of both subfamilies, Betuloideae and Coryloideae. Within the Coryloideae,
Carpinus and Ostrya have a sister group relationship. Ostryopsis is between Corylus and the
Carpinus-Ostrya clade.15 The rbcL analysis did not include Ostryopsis. The betv1 phylogeny19
suggested a close relationship between Carpinus and Corylus among the four genera (Alnus, Betula,
Carpinus, and Corylus) with available sequences of betv1 homologues. Chen16 proposed a phylog-
eny based on morphology and palynology. Chen’s phylogeny is largely congruent with the trees
by Crane15 and Bousquet et al.,18 except that Alnus and Betula were suggested to be paraphyletic
and basal with the Betulaceae. Alnus was the most basal group of the family. Additional studies
are needed to test the available phylogenetic hypotheses. The Betulaceae has an excellent fossil
record throughout the northern hemisphere. The family has a high level of diversity in the Tertiary
with almost all the extant genera represented. Asterocarpinus, Corylocarpinus, Cranea, and Pale-
ocarpinus are reported betulaceous genera from the early Tertiary, but are extinct at present.15,20-23
More than 20 percent of the population in the northern hemisphere suffer from IgE-mediated
type I allergic reactions (allergic rhinitis, conjunctivitis, bronchial asthma, and atopic dermatitis).
In this respect, pollen from the early flowering trees of the order Fagales, in particular, birch, hazel
and alder, represent the most important source of pollen allergens. Within this order the birch plays
the leading role, owing to its wide distribution and the large number of trees. The flowering season
of birch is spring; the exact time of pollen flight depends on the geographic situation. The symptoms
of type I allergy are owing to the release of mediators (e.g., histamine) resulting from the cross
linking of allergen specific IgE antibodies that are bound to allergic effector cells (mast cells and
basophils).
12.2 BETULA
Betula (common name: birch) is composed of approximately 40 species. The taxonomy of the
genus is controversial owing to common interspecific hybridization and introgression,24-26 resulting
in a high level of morphological variability. The chromosome numbers vary substantially among
species with 2n = 28, 56, 70, 84, and 112.6
Species of Betula are trees or shrubs with white to dark brown barks. Winter buds are sessile
with several imbricate and smooth scales. Leaves are variously shaped, mostly ovate to deltoid,

FIGURE 12.2 Pollen morphology of Betulaceae. (A) Pollen grain of Corylus avellana under scanning electron
microscopy (SEM), · 3500. (B) Pollen grain of Alnus firma under SEM, · 3500. (C) Exine ultrastructure of
Alnus nepalensis, · 12,000. (D) Exine ultrastructure of Corylus ferox, · 17,000. (C = columellae, En =
endexine, F = footlayer, G = granular layer, In = intine, T = tectum.) (Photographs reprinted from Chen, Z.,
Pollen morphology of the Betulaceae, Acta Phytotax. Sinica, 29, 494, 1991. With permission.)
with serrate to doubly serrate margins and 6–14 lateral veins. Staminate catkins are drooping and
mostly terminal on branches, solitary or two to five in a racemose cluster. Pistillate catkins are
erect, axillary in position, solitary, and cylindric to ovoid in shape. The catkins consist of numerous
flowers, three per scale, and lacking sepals and petals. Staminate flowers have two to three stamens,
and the pistillate flowers have a two to three carpellate pistil, with the stigma one to three lobed.
Scales of the infructescences are three lobed and the shape of the scales differs among species.
Fruits are small samaras with two lateral membranaceous wings. Birches show many morphological
similarities with alders, differing mostly in their infructescences. Birches have three lobed and
deciduous scales (vs. five lobed and persistent in alders), and three (vs. two) fruits per scale.
Furthermore, the winter buds of birches are sessile (vs. stipitate or subsessile).

Birches are common throughout the temperate, boreal, and arctic regions of the Northern
Hemisphere. They occur in cool and moist areas and are frequently the pioneer species on disturbed
habitats. They are also common along stream and river banks and lakeshores. Economically birches
are important for paper-making, plywood, furniture, flooring, wood paneling, doors and door skins,
and firewood. Examples of Betula are B. verrucosa (European birch), B. papyrifera (paper birch
or white birch), B. alleghaniensis (yellow birch), B. lenta (sweet birch), and B. nigra (river birch).
12.2.1 MOLECULAR AND IMMUNOLOGICAL CHARACTERIZATION OF BET V 1, THE

MAJOR BIRCH POLLEN ALLERGEN
Birch pollen is one of the main sources of inhalative allergens in northern Europe. In 1972, Belin
described a major allergen as a thermostable component of aqueous birch pollen extracts.27,28 Early
classification of birch pollen allergens identified a 17 kDa protein, antigen 23, as the major allergen
that was recognized by IgE of 95 percent of birch pollen allergic individuals.29 The antigenicity of
antigen 23 could not be destroyed by boiling the crude aqueous pollen extract for 15 min. This
protein was further characterized by Ipsen and Larsen in immunoblotting experiments as a 16.8
kDa allergen and named Bet v 1 according to WHO guidelines.30 In quiescent pollen grains, labeling
of allergens with human IgE was found in the exine part of the pollen wall and throughout the
highly condensed cytoplasm except for starch grains and lipid droplets.31 In pollen grains soaked
in hypotonic buffer for 15 min, IgE-binding sites were predominantly localized within the intine
and the germination pores.
Jarolim and co-workers showed that more than 95 percent of birch pollen allergic individuals’
sera contained IgE against Bet v 1 that represented the only allergen for around 60 percent of these
patients.32 They also described the heterogeneity of Bet v 1 that separated into 10 spots in the pH
range 4.9–5.9 in two-dimensional electrophoresis indicating the existence of isoallergens. A mon-
oclonal antibodies against Bet v 1 was produced by immunizing BALB/c mice with birch pollen
extract. Two-dimensional immunoblotting revealed that the monoclonal BIP1 reacted with all Bet
v 1 isoallergens that were also identified by human IgE.33
Biologically active messenger RNA was first isolated in 1988 from male inflorescences and
pollen of B. verrucosa and translated in vitro. Several of the resulting proteins were able to bind
patients’ IgE, among them the 17 kDa Bet v 1.34 The gene coding for Bet v 1 was cloned in 1989
from a cDNA library constructed from birch pollen mRNA in the bacteriophage lgt11.35 The library
was screened with the serum of a birch pollen allergic individual for the expression of Bet v 1.
The sequence of the Bet v 1 clone coded for a protein of 159 amino acid residues with a deduced
molecular weight of 17,420 Da. The Bet v 1 sequence showed a high identity to pathogenesis
related (PR) proteins described from pea.36 The purified recombinant Bet v 1 (rBet v 1) became
available in 1993. It was produced as a nonfusion protein in Escherichia coli and proved to be
equivalent to natural Bet v 1 with respect to IgE-binding properties, the ability to induce in vitro
proliferation of allergen-specific T-cell clones, and the ability to release histamine from basophils
derived from birch-pollen allergic patients.37
In an attempt to define the biological function of Bet v 1, the expression of Bet v 1 genes was
studied in birch cell suspension cultures in the presence of fungi and bacteria.38 These culture
conditions led to the rapid induction of a subset of the betv1 gene family of pollen allergens. The
genes were different from those constitutively expressed in pollen. Expression of these betv1-sc
genes was induced in cultured birch cells by Pseudomonas syringae and in leaves infected by the
fungus Taphrina betulina.39
The existence of Bet v 1 isoforms had been known since the first two-dimensional IgE immu-
noblot experiments.32 In 1995, these isoforms were characterized by both cDNA cloning and mass
spectrometry.40 cDNA clones coding for 13 different for Bet v 1 isoforms were obtained by
polymerase chain reaction and the presence of the respective proteins determined by HPLC and
plasma desorption mass spectrometry of proteolytic fragments of purified natural Bet v 1. In addition

to their role as potent allergens, these pollen proteins are closely related to a large number of
proteins belonging to the PR-10 family of pathogenesis-related proteins.41 In fact, betv1 related
genes were identified in a wide range of flowering plants including both dicots and monocots and
could be used for the construction of phylogenetic trees that were congruent with those based on
morphology and other molecules.19
One interesting aspect of tree pollen allergy is the frequent association of this disease with
particular hypersensitivities to fruits and vegetables. The most frequent pollen–fruit syndrome in
patients suffering from tree pollen induced pollinosis is apple allergy. Up to 70 percent of the
patients with birch pollen allergy exhibit oral itching and irritation of the oral mucosa upon ingesting
apples. The cross-reactive allergen to Bet v 1, the major apple allergen Mal d 1, has been cloned
and characterized.42 Genomic sequences of several betv1 homologous genes that were characterized
usually consisted of two exons interrupted by an intervening sequence. Although the intron sizes
varied, their positions were conserved.43
The three-dimensional structure of Bet v 1 has been determined both in the crystalline state
by X-ray diffraction and in solution by nuclear magnetic resonance.44 The main feature of the
structure is a 7 stranded antiparallel b-sheet that wraps around a 25 residue-long C-terminal a-helix.
The b-sheet and the C-terminal part of the long helix are separated by two consecutive helices. A
glycine rich loop connects b-strands 2 and 3. This sequence shows resemblance to the so-called
P-loop motif found in many nucleotide binding proteins such as adenylate kinases and guanine
nucleotide binding proteins. Human monoclonal IgG antibodies were used to localize Bet v 1 in situ
on ultrathin sections of unhydrously prepared birch pollen. Each antibody showed a consistent
association of the gold markers with two pollen compartments, ribosome-rich areas of the cytoplasm
and the pollen nuclei.45 A possible function of Bet v 1 as a nucleotide binding protein would be
in accordance with these immunolocalization data. It has also been described that Bet v 1 exhibited
ribonuclease-like activity in vitro.46,47
12.2.1.1 Bet v 1-Specific T-Cells: Epitope Mapping and T-Cell Receptor

Characterization
The cloning and high level expression in E. coli and purification of Bet v 1 and related tree pollen
isoallergens formed the base for a great variety of immunological studies.48,49 IgE production by
B-cells requires the help of allergen specific T-cells. These T-cells are activated by highly immu-
nogenic peptide fragments of the allergens which are presented by antigen processing cells in the
the context of MHC class II molecules. T-cell clones (TCCs) established from the peripheral blood
of birch pollen allergic donors were used to map the T-cell epitopes of Bet v 1 by the use of
overlapping synthetic peptides. Seven different T-cell epitopes were defined that were distributed
over the whole molecule.50 It was clearly demonstrated that single allergic individuals display
several distinct T-cell specificities and that some of these represent immunodominant epitopes.51
Epitope specificities of TCCs from nonatopics were identical to those found in allergic individuals.
In allergic individuals, however, the activation of allergen-specific TCCs led to a higher ratio of
produced IL-4 vs. IFN-g that is responsible for IgE production.52 T-cell receptor (TCR) a- and
b-chain sequences of Bet v 1-reactive human CD4+ TCCs specific for a C-terminal minimal epitope
showed a striking heterogeneity in length and amino acid composition in their third complemen-
tarity determining regions (CDR3s).53 Nevertheless, all TCCs showed an arginine residue in the
N-terminal region of their TCR b-chain CDR3 loops. TCR a- and b-chain sequences of human
CD4+ TCCs specific for three additional immunodominant Bet v 1 epitopes showed that each
antigenic peptide derived from Bet v 1 was capable of selecting different characteristics in the
responding TCR repertoire.54 Allergen-specific TCCs can persist for years, evidence for which
could be monitored in blood, but also in the target organ of the allergic disorder for up to four
years.55

12.2.1.2 Comparison of Immunological Properties of rBet v 1 and nBet v 1
rBet v 1 has proved to be equivalent to natural Bet v 1 (nBet v 1) in a number of applications. rBet
v 1 produced in E. coli allowed accurate in vivo and in vitro diagnosis of more than 95 percent of
birch pollen allergic patients. No false positive results were obtained in in vitro assay systems such
as ELISA or Western blot, or by skin testing such as skin-prick or intradermal testing.56 In addition,
rBet v 1 also produced postive skin test reactions in patients with allergies to apples, cherries, or
hazelnuts that demonstrated its immunological relationship to food allergens.57 rBet v 1 was equally
potent as nBetv 1 to induce nasal reactions in birch pollen allergic patients with rhinitis and bronchial
reactions in patients with asthma.58
12.2.1.3 Animal Models for the Study of Birch Pollen Allergy

The recombinant allergen and findings from the T-cell research were used to study the effect of
therapeutic approaches on the regulation of specific IgE responses in animal models. rBet v 1a was
injected into rhesus monkeys with aluminium hydroxide as adjuvans and the development of type
I allergy monitored by measuring specific IgE, histamine release tests, cellular proliferation assays,
skin testing, and bronchial provocation tests.59 Systemic application of corticosteroids during
secondary immunizations suppressed specific antibody responses. In a murine model of an allergic
immune response to Bet v 1, it was demonstrated that the subcutaneous injection of high doses of
a dominant T-cell epitope could down-regulate the allergen-specific T-cell response.60 Cholera toxin
mixed with an aerosolized extract of birch pollen induced a Th1-like immune response in mice
with mainly allergen specific IgG2a levels whereas in systemic immunization with rBet v 1 in
aluminium hydroxide, IgE and IgG1 antibodies were dominant.61
12.2.1.4 Models for Specific Immunotherapy of Birch Pollen Allergy

Different vaccines for specific immunotherapy to induce tolerance to an allergen have been sug-
gested based on the application of the molecular characteristics of Bet v 1. The mechanisms
underlying successful immunotherapy are assumed to operate at the level of T-helper cells, leading
to a modulation of the immune response to allergens. T-cell lines and TCCs were established from
peripheral blood of birch pollen allergic patients and induced with either rBet v 1 or rBet v 1
conjugated to cross-linked crystalline surface layers (SL) derived from Gram positive eubacteria.62
Only 21 percent of Bet v 1 specific TCCs isolated from T-cell lines established with Bet v 1/SL
revealed a Th2-like phenotype, the majority belonged to the Th1 phenotype.
Specific immunotherapy is an efficient treatment for patients suffering from type I allergy.
During immunotherapy, increasing doses of allergens are given on a regular basis, and the beneficial
effects for the patient depend on the concentration of the allergen used. On the other hand, the risk
of IgE-mediated anaphylactic side effects also increases with the amount of allergen applied per
injection. A strategy to reduce the anaphylactogenic potential of an allergen made use of the fact
that IgE epitopes on Bet v 1 are conformational. The three-dimensional structure of Bet v 1 was
disrupted by expressing the allergen in two portions which showed almost no allergenicity and
exhibited random coil confirmation as analyzed by circular dichroism.63 Both fragments induced
the proliferation of human TCCs indicating that all important T-cell epitopes had been preserved,
which made them suitable for a T-cell specific immunotherapy.
In a different approach, the T-cell activating potency and IgE-binding properties (allergenicity)
of nine isoforms of Bet v 1 were compared. The results revealed the existence of hypoallergenic
isoforms with very low IgE-binding capacity that were potent activators of allergen-specific T
cells.64 Based on these findings, an immunotherapy treatment with high doses of hypoallergenic
isoforms or recombinant variants of atopic allergens was proposed. In a follow-up study, the
contributions of individual amino acid residues/positions to the IgE-binding of Bet v 1 were

evaluated by site-directed mutagenesis. Immunoblot analyses and inhibition experiments showed
that a multiple point Bet v 1 mutant possessed extremely low reactivity with IgE from birch pollen
allergic individuals.65 Skin prick tests showed that the potency of the multiple point mutant to
induce typical urticarial type I reactions in pollen allergic patients was significantly lower than for
nBet v 1. The mutated isoform kept the capacity to activate T cells that is necessary for immuno-
modulation. This approach may be applied generally to produce allergen variants based on the
combination of information gathered from naturally occurring isoforms to be used in a safe therapy
form of immediate type allergies.
12.2.2 BET V 2, BIRCH POLLEN PROFILIN

The actin cytoskeleton is composed of a network of actin filaments whose precise organization is
regulated by a number of actin-binding proteins. One of them is profilin, a small 12–15 kDa
monomeric actin-binding protein. Profilin was first identified in plants as a ubiquitous allergen from
birch pollen and named Bet v 2.66,67 A clone was isolated from a birch pollen cDNA library with
IgE from a birch-pollen allergic individual. Its sequence revealed high identities to profilins. Most
of the regions of high sequence identity were located at the N- or C-terminus of the molecule that
are presumed to participate in the interaction with actin. Bet v 2 was expressed in E. coli and was
purified by affinity chromatography on poly-(L-proline) sepharose, a method specific for profilins.
Sera with IgE to purified natural and recombinant birch pollen profilin also recognized human
profilin. Therefore, the possibility has been discussed that some of the symptoms caused primarily
by sensitization of mast cells with pollen profilin might be aggravated or prolonged by human profilin.
Bet v 2 is a minor birch pollen allergen. Nevertheless, patients sensitized to plant profilins
(approximately 10 percent of birch pollen allergic individuals) are characteristically allergic to a
broad range of inhalant and nutritive allergens. The ubiquitous occurrence of profilins in only
distantly related plants is one of the reasons for the phenomenon of cross sensitization.68 Bet v 2
was produced in a high level E. coli expression system with yields up to 30 mg/l culture and purified
by its affinity to poly-(L-proline) sepharose.69 rBet v 2 bound IgE, elicited dose dependent histamine
release from patients’ basophils and could be used for skin prick testing without toxic effects.
Profilins not only represent actin-binding proteins but are also linked to the signal transduction
cascade via the phosphoinositide pathways in eukaryotes.70 The inhibition of phospholipase activity
in isolated pea plasma membranes by recombinant birch profilin indicated that plant profilins also
interact with polyphosphoinositides and, hence, may be involved in the signal transduction cascades
in plants.71 Besides binding polyphosphoinositides that can disrupt the profilin-actin complex,
profilins also bind proline-rich ligands that localize profilins to sites requiring extensive actin
filament accumulation.72 A cDNA coding for tobacco profilin was isolated from a tobacco pollen
cDNA library by screening with IgE from a birch pollen profilin allergic pateint.73 A rabbit antiserum
raised against the recombinant tobacco profilin detected a 50–100 fold higher expression in mature
pollen than in other somatic tissues such as leaves. Profilin was homogeneously distributed in the
cytoplasm of in vitro cultered pollen grains and pollen tubes.
The interaction of Bet v 2 with a specifc mouse monoclonal was characterized. The antibody,
whose deduced amino acid sequence was determined selectively, reacted with tree pollen profilins.74
Using synthetic, overlapping peptides, a continuous hexapeptide epitope was identified. The
exchange of a single amino acid (Gln47–Glu47) abolished binding of the monoclonal. Profilin
isoforms have been described in the monocot Zea mays75 and in tobacco.76 The presence of several
profilin isoforms in pollen is interpreted as a mechanism to protect profilin functions in cells which
are rich in actin. No Bet v 2 isoforms from birch have been described so far.
Three variants of birch pollen profilin were produced to study the effect of amino acid exchanges
in a sequential epitope on the binding of Bet v 2-specific IgE. The epitope had been chosen because

it had been identified earlier for a mouse monoclonal that recognized an epitopic area for IgE
antibodies.77 All recombinant profilin variants elicited dose-dependent histamine release from
basophils of a profilin allergic patient and induced immediate type skin reactions indicating the
presence of IgE epitopes that had not been influenced by the mutagenesis.
The X-ray crystal structure of Bet v 2 has been determined at 2.4 Å resolution.78 The Bet v 2
molecule is composed of three a helices and seven b strands. The major IgE-epitopes have been
mapped by the use of a random Bet v 2 peptide fragment library and were found to cluster on the
N- and C-terminal a helices and a segment of the protein containing two strands of the b sheet.
The prevalent epitopes are located in regions with conserved sequence and secondary structure and
overlap the binding sites for natural profilin ligands, indicating that the native ligand-free profilin
acts as the original cross sensitizing agent. In addition, the structure of Bet v 2 in solution was
elucidated by multidimensional NMR and its interaction with poly-(L-proline) confirmed.79 Phy-
logenetic analysis of amino acid sequences of 18 plant profilins indicated that 2 distinct profilin
gene classes are present in higher plants.80 There is one class that is pollen-specific. All genes in
the other class are constitutive and were isolated from vegetative organs. Bet v 2 belongs to the
pollen-specific class.
12.2.3 BET V 3, A NOVEL CALCIUM-BINDING PROTEIN

A lgt11 expression library constructed from birch pollen mRNA was screened with sera from
patients allergic to birch pollen. Allergens were encoded with four IgE-binding clones with high
sequence homology to Ca2+-binding proteins.81 Of the clones with a complete cDNA sequence
coding for a 23.7 kDa protein of 203 amino acid residues one clone was used for further studies.
Approximately 10 percent of the tested patients displayed IgE reactivity with the Ca2+-binding
allergennemed Bet v 3. Bet v 3 contained three Ca2+-binding domains and showed sigificant
homology to the sequence of a potato tuber Ca2+-binding protein. Peptides containing the putative
Ca2+-binding domains of Bet v 3 were synthesized and capable of binding 45Ca. The binding capacity
of Bet v 1 was lost when the protein had been subjected to denaturing SDS-PAGE or Ca2+ had
been depleted from the native rBet v 3. IgE binding could be restored by subsequent incubation
with Ca2+. Bet v 3 mRNA could be exclusively detected in mature pollen where the mature protein
may play an important role in pollen germination and the growth of pollen tubes.
12.2.4 BET V 4, A TWO EF-HAND CALCIUM-BINDING PROTEIN

The cDNA coding for the 9.3 kDa Bet v 4 was isolated from a l ZAP II pollen expression library
by screening with patients’ IgE.82 The deduced amino acid sequence of 84 residues contained 2
typical EF-hand calcium binding domains. Sequence similarities of Bet v 4 to calmodulin are
primarily confined to the calcium binding domains. Significant sequence similarities extending
outside the Ca2+-binding sites were found for a group of pollen-specific allergens of Brassica and
Bermuda grass. Both EF-hand domains were demonstrated to be able to bind Ca2+. Among pollen-
allergic patients, protein-bound Ca2+ was not absolutely required for IgE recognition of Bet v 4.
Approximately 5 percent of birch pollen-allergic patients recognized Bet v 4. Disruption of the C-
terminal Ca2+-binding domain indicated that most IgE antibodies from allergic patients were
directed against this site. rBet v 4 was introduced into growing lily pollen tubes stopping the
cytoplasmic streaming in the vicinity of the electrode indicating a biological role in pollen germi-
nation and tube growth. These effects were not observed with Ca2+-binding deficient mutants of
Bet v 4. A similar study found that serum IgE from approximately 20 percent of pollen allergic
patients reacted with rBet v 4, expressed as a b-galactosidase fusion protein, and that the N-terminus
contributed significantly to the IgE-binding capacity of the molecule.83

12.3 CARPINUS
Carpinus (common name: hornbeam) has approximately 35 species with most species from Asia,
a species from eastern North America (with 2 subspecies), a species from Mexico and Central
America, and 3 species from Europe. The taxonomy of the species from southwestern China is
poorly understood. Two sections are recognized84 and still used6,17: section Carpinus and section
Distegocarpus (four eastern Asian species). Chromosome numbers are 2n = 16, 32, and 64 with
x = 8.6
Species of Carpinus are trees or rarely shrubs with smooth brownish to dark gray bark and
very hard wood. Winter buds are sessile with many smooth and imbricate scales. Leaves are ovate,
narrowly ovate, obovate, or elliptic with doubly serrate to serrulate margins. Staminate catkins are
formed in the previous season, enclosed in buds during the winter, and appear with leaves in the
spring. They are solitary or in a racemose cluster. Pistillate catkins are distal to the staminate ones.
Staminate flowers are three per scale, each with about three short stamens. Pistillate flowers are
two per foliaceous and three lobed involucre. Fruits are small ovoid nuts with longitudinal ribs.
Carpinus betulus is a widespread forest species in Europe; C. caroliniana has an extensive
distribution in the eastern North America; C. tropicalis may be a dominant species in the mountains
of Mexico; and C. cordata, C. fargesii, and C. turczaninowi are common species in China. Horn-
beams are of little economical importance. Wood of hornbeams is very hard and is used as tool
handles and levers in China and Europe.
12.3.1 CAR B 1, THE MAJOR HORNBEAM POLLEN ALLERGEN

Two-dimensional electrophoresis combined with immunoblotting established the presence of more
than a dozen isoforms of the major pollen allergen Car b 1 of hornbeam.85 Car b 1 was extracted
from hornbeam pollen, purified to near homogeneity, and its N-terminal sequence determined.86
Primers, deduced from the N-terminal sequence of the purified protein were used to amplify cDNAs
coding for Car b 1.87 Three clones were characterized in detail. The recombinant allergens were
shown to bind tree pollen allergic patients’ serum IgE or murine monoclonal antibodies raised
against purified Car b 1 from pollen. Car b 1 is encoded by a 159-triplets open reading frame. The
molecular masses of the three Car b 1 isoforms were 17272, 17355, and 17217 Da, respectively.
The deduced amino acid sequences showed pronounced identities (73, 75 and 74 percent, respec-
tively) to Bet v 1.
12.4 CORYLUS
Corylus (common name: hazel) consists of approximately 13 species widely distributed in the
northern hemisphere, with about 7 species in eastern Asia, 1 in western Asia, 1 in the Himalayas,
2 in Europe, and 2 to 3 species in North America. The taxonomy of Corylus, especially those from
eastern Asia, is still controversial. Chromosome numbers are reported to be 2n = 22 and 28.6,88
Furlow88 discussed the possibility of the diploid counts as 28 being erroneous.
Species of Corylus are shrubs or trees with grayish brown bark. Winter buds are sessile with
several smooth and imbricate scales. Leaves are borne on long and short shoots, mostly broadly
ovate to sometimes ovate with often cordate bases and doubly serrate margins. Leaf surfaces are
usually pubescent or bear glandular hairs, especially on the petiole. Staminate inflorescences are
solitary or in a racemose cluster. Pistillate inflorescences are highly reduced and composed of one
to several flowers. Staminate flowers are three per scale with four stamens. Pistillate flowers are
enclosed within a bud at anthesis with only the styles exposed. The fruit is the largest nut of the
birch family and usually enclosed or partially enclosed by an involucre.
Recognized are three sections: section Corylus, section Tuboavellana, and section Acan-
thochlamnys.17,89,90 Section Corylus includes species with a short involucre of two bracts, such as

C. americana, C. avellana, C. colurna, and C. heterophylla. Species of section Tuboavellana have
an involucre with a tubular elongated beak. Examples are C. cornuta and C. sieboldiana. Section
Acanthochlamnys is characterized by an spiny involucre, as in C. ferox. However, intermediates
between the three involucre types exist. The infrageneric classification was criticized recently [e.g.,
References 6 and 88] and no classification of the genus is used by those workers.
Hazels prefer sunny habitats and grow in rich to very rocky and poor soil. They occur commonly
near streamsides, riversides, hill slopes, and edges of woods. Corylus is economically important
as the source of hazelnuts and filberts. The fruits of almost all the species are used by local people
as food. C. colurna and C. maxima are widely cultivated for filberts. In China, hazel bushes are
cut for fuel, firewood, and basket-weaving, and the fruits are used for extracting edible oil.
12.4.1 COR A 1, THE MAJOR HAZEL POLLEN ALLERGEN

Two-dimensional immunoblots revealed the occurrence of isoforms of the major pollen allergen
Cor a 1 of hazel85 and the N-terminal amino acid sequence was determined from the purified
protein.86 Using the reported N-terminal amino acid sequence Cor a 1, cDNAs were amplified by
PCR and cloned. Four clones with cDNA inserts were isolated.91 All four clones contained an open
reading frame coding for 159 amino acids, but differed in the length of their 3’-noncoding regions.
The open reading frames were coded for different isoforms of Cor a 1. The sequence identities
between the Cor a 1 isoforms and Bet v 1 were 71–73 percent. The four Cor a 1 cDNAs were
expressed in E. coli as nonfusion proteins. IgE antibodies from tree pollen allergic patients reacted
with all four recombinant isoforms with marked differences in the IgE-binding patterns of the
distinct isoforms. Cor a 1 isoforms also differed in their ability to stimulate the proliferation of Bet
v 1-specific TCCs which correlated with certain amino acid exchanges affecting the sequences of
T-cell epitopes in comparison to Bet v 1.92
Individuals allergic to pollen of early flowering trees are frequently allergic to various nuts
including hazelnuts. The N-terminus of the major hazelnut allergen was found to be 72 percent
identical to that of the major hazel pollen allergen Cor a 1.93 The nut and the pollen allergen of
hazel belong to the conserved PR-10 class of proteins.41
12.5 ALNUS
Alnus (common name: alder) has about 25 species that occur primarily in the northern hemisphere
and extend into northern Africa in the Old World, and into Central America and the Andes in the
New World. Recognized are three subgenera: subgenus Alnus, subgenus Alnobetula, and subgenus
Clethropsis. Chromosome numbers are 2n = 14, 28, 42, and 56, with x = 7.6,88
Species of Alnus are trees or shrubs with light gray to dark brown barks. Winter buds are
stipitate to subsessile with two to several scales or naked. Leaves are borne on short and long
shoots, ovate, obovate, to elliptic in shape, and irregularly serrate, doubly serrate, or dentate at the
margin. Staminate catkins aggregate into a racemose cluster of three to five. Pistillate catkins are
solitary or in a cluster of two to many. Staminate flowers are three per scale, usually with four
stamens. Pistillate flowers are two per scale. Infructescences are cylindric in shape with five lobed,
thickened, and persistent scales. Fruits are small samaras with two lateral wings.
Species of subgenus Alnus have stipitate winter buds covered by two valvate scales. Their
inflorescences are several in a racemose cluster and developed during the growing season prior to
anthesis. Subgenus Alnobetula has subsessile winter buds with several imbricate scales. The inflo-
rescences are formed the season before anthesis. Subgenus Clethropsis is mostly Asiatic with one
North American species, A. maritima. This subgenus is characterized by its naked buds, blooming
in the fall, and solitary pistillate inflorescences in leaf axils. Copious pollen is produced by the
alder species in the early spring (subgenus Alnus), spring (subgenus Alnobetula), or late in the
summer (subgenus Clethropsis).

Alders like moist soil near streams, rivers, lakes, bogs, and mountain slopes. They may form
pure stands or mixed with other deciduous and/or coniferous species. All the alder species form
root nodules associated symbiotically with species of Frankia to fix nitrogen, and thus, improve
soil condition. Examples of Alnus are A. glutinosa (European or black alder), A. incana ssp. rugosa
(swamp alder), A. rubra (red alder), and A. rhombifolia (white or California alder).
12.5.1 ALN G 1, THE MAJOR ALDER POLLEN ALLERGEN

Aln g 1 the major allergen of alder pollen was the first pollen allergen cloned by amplifying its
cDNA sequence by PCR.94 The deduced amino acid sequence of Aln g 1 showed a high identity
of 81 percent to that of Bet v 1. The recombinant protein expressed in E. coli possessed a weaker
capacity to bind IgE from tree pollen allergic individuals, indicating that Bet v 1 is the predominant
allergen and can replace Aln g 1 in diagnosis and therapy.
12.6 CONCLUSIONS
The detailed study of the major birch pollen allergen Bet v 1, in particular, shows how the interest
in pollen allergens has made progress possible in plant molecular biology. Molecular allergology
has speeded the research of one pollen protein that led to its production as a recombinant protein
and its crystallization.37,44,48,49 Although the function of Bet v 1 is still under discussion, it was
classified as a pathogenesis-related protein belonging to a new class of intracellular PR-proteins.34,41
A subclass of betv1 genes was discovered in birch cell suspension cultures cultivated with bacterial
and fungal pathogens.39 Betv1-homologous sequences, described from a wide variety of species
and genera, were used to construct phylogenetic trees giving another example of how medicine
and botany can interrelate.19 The discovery of several different naturally occurring Bet v 1 isoforms
and their different immunological properties led to a synthetic molecule harboring characteristics
of different isoforms.40,64,65 This designer allergen will form the basis for a clinical study of a new
concept for specific immunotherapy.65 The interest in the second birch pollen allergen, Bet v 2,
fostered the discovery of the first plant profilin that in term, ignited the interest in profilins and
their functions in other plants such as tobacco, corn, and tomato.66,73,75,80 Pure recombinant allergens
are not only excellent tools for diagnosis, study, and immunotherapy of type I allergic diseases,
but they can also be used to study the protein’s function in plants. rBet v 4 introduced into pollen
tubes was able to stop cytoplasmic streaming in its vicinity.82 These studies are examples of how
molecular medicine and plant molecular biology and taxonomy can produce results of mutual
interest and of importance to the advancement of science in both disciplines.
This study was supported by the Austrian Science Foundation (S06707) to Scheiner and the National
Science Foundation (DEB-9726830) to Wen. We thank Dr. Zhi-duan Chen for permission to use
his pollen photographs and Chris Way for making botanical illustrations.
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13 Hydrophyllaceae
Manuel Aregullin and Eloy Rodriguez
CONTENTS
13.1 Introduction
13.2 Phytochemistry, Chemotaxonomy, and Pharmacology of the Hydrophyllaceae
13.3 Allergenic Chemistry of the Hydrophyllaceae
13.3.1 Phacelia
13.3.2 Wigandia
13.3.3 Turricula
13.3.4 Nama
13.5 References
13.1 INTRODUCTION
The family Hydrophyllaceae is comprised of 250 species in 18 genera with cosmopolitan or subcos-
mopolitan distribution except in Australia. The family is especially found in arid zones of southwestern
North America. Hydrophyllacae are normally herbs or shrubs with glandular hairs and trichomes on
the leaves that are usually rough and odoriferous. There are anecdotal accounts of some species of
the Hydrophyllaceae causing blisters, irritations, and, in some cases, severe dermatitis.
Molecular data1 suggests that the Hydrophyllaceae, with the exception of the genus Hydrolea,
form a monophyletic group nested with the woody tropical Boraginaceae. These phylogenetic
considerations also suggest that within the Hydrophyllaceae, there is a division between the woody
clade that includes Wigandia, Eriodictyon, and Turricula and a large herbaceous clade containing
Nemophila, Phacelia, and other smaller genera.
13.2 PHYTOCHEMISTRY, CHEMOTAXONOMY, AND

PHARMACOLOGY OF THE HYDROPHYLLACEAE
In general, very few studies have been conducted on the secondary chemistry of the family
Hydrophyllaceae outside of that relevant to contact dermatitis; these reports are sporadic and broad
in topic, they are summarized at continuation.
There is only one report on the utilization of a member of the Hydrophyllaceae in folk medicine
and its biological properties.2 Wigandia caracasana is used in Guatemala in the treatment of
respiratory diseases, a concoction of the branch tips is used for whooping cough and rheumatism.3
Ethanol and acetone leaf extracts were active against Streptococcus pneumoniae and S. pyogenes.
The chemical ecology of whole leaf hydrocarbons of six Phacelia species (P. distans, P. tan-
acetifolia, P. cicutaria, P. vallis-mortae, and P. rammosissima var. australitorales) were investigated

FIGURE 13.1 Pigment chemistry of Nama hispidum and N. sessilifolium.
for intrapopulation variability and adaptive significance to xerophitic environments in California.4

No taxonomic value was found in the hydrocarbons investigated; however, nonacosane, a hydrocar-
bon suggested to have adaptive value to dry habitats was found to accumulate in relative large
amounts in P. distans collected in the most xerophitic conditions.
There is a report on the pigment chemistry of Nama hispidum and N. johnstonii (Figure 13.1).
The major pigment constituent of the leaf resin of N. hispidum was shown to be 1-(2-hydroxy-4,5-
dimethoxyphenyl)-3-methyl-2-buten-1-one 1 and the corresponding chromanone 2, 2,2-dimethyl-
6,7-dimethoxy-4-chromanone. The dark yellow pigment of N. johnstonii was identified as 1-(2,5-
dihydroxyphenyl)-3-methyl-2-buten-1-one 3.5
The glandular trichome exudates of Eriodictyon sessilifolium, an endemic species of Baja
California in Mexico, was studied and several benzoic acid derivatives (4–6, Figure 13.2), as well
as some known flavonoids, were isolated and characterized.6
There are two reports in the literature where the medicinal potential of the Hydrophyllaceae
has been explored. Using a bioassays guided fractionation of Eriodictyon californicum, 12 fla-
vonoids (7–18, Figure 13.3), with the capacity to inhibit the metabolism of benzo[a]pyrene by
hamster embryo cells in tissue culture, were isolated and identified and proposed as potential cancer
chemopreventive agents.7
FIGURE 13.2 Benzoic acid derivatives from Eriodictyon sessilifolium.

FIGURE 13.3 Bioactive flavonoids from Eriodictyon californicum.
Some aspects of the secondary chemistry of the Hydrophyllaceae have been proposed to be of
utility in delineating some phylogenetic relationships. The distinct flavonoid chemistry (19–26,
Figure 13.4) of Nama rothrockii and N. lobbii suggests that these species are closer allied to
Eriodictyon than either one is to Nama.8
FIGURE 13.4 Flavonoid chemistry useful in the phylogeny of the genus Nama.

FIGURE 13.5 Flavonoid chemistry useful in the phylogeny if the genus Eriodictyon.
The flavonoid chemistry of Eriodictyon californicum, E. angustifolium, and E. tomentosum has

been reported (27–37, Figure 13.5) and is the basis to propose the potential taxonomic utility of
these chemicals in delineating phylogenetic relationships within the Hydrophyllaceae.9
The insecticidal properties of some Nama species has been investigated and it was found that
several of the species contain the well-known antijuvenile hormone principles Precocene I and II
(38, 39, Figure 13.6), as well as an unidentified juvenile hormone mimic.10,11
In addition to several allergenic chemicals found in Wigandia kunthii, the presence of two
flavonoids, 40 and 41, and the sesquiterpene farnesol 42 (Figure 13.7) have been reported.12 These
compounds have been found not to be associated with the allergenic properties of Wigandia.
Chemical arguments, along with morphological data and pollinator specificity, have been used
to address the systematics of Nemophila. The flavonoid chemistry of several taxa of Nemophila
were analyzed and it was determined that Nemophila menziesii is a species aggregate that includes
N. menziesii, N. atomaria, and N. integrifolia. All three species were morphologically and chemi-
cally distinct.13
13.3 ALLERGENIC CHEMISTRY OF THE HYDROPHYLLACEAE

13.3.1 PHACELIA
Phacelia is the more allergenic genus of the Hydrophyllaceae. There are aproximatly 200 species
of Phacelia native to North America and the Andes of South America with some capable of
producing severe linear vesicular dermatitis reminiscent of the delayed contact hypersensitivity
caused by poison oak and poison ivy (Toxicodendron spp; Anacardiaceae).14,15 The following species

FIGURE 13.6 Distribution of the Precocenes I and II in the genus Nama.
FIGURE 13.7 A sesquiterpene and two flavonoids isolated from Wigandia kunthii.
have been noted to produce dermatitis: Phacelia brachyloba, P. campanularia, P. minor, P. pedi-
cellata,14 P. crenulata, P. grandiflora,14,15 P. parryi, P. viscida,15 and P. infundibuliformia.16 However,
some species of Phacelia were found not to elicit the allergic response.14
The chemistry associated with the allergic response caused by Phacelia has been studied
extensively in the species that occur in the North American southwest. Phacelia campanularia,
(Figure 13.8) an annual of the California Mojave Desert, contains the novel farnesylhydroquinone
derivatives, the phacelioids 43, 44, and 45, and 46 in minor amounts.17,18 These compounds were
tested on the shaved skin of guinea pigs sensitized with the crude extract of P. campanularia; of
these compounds, 45 and 46 were recognized as the most active eliciting a response with as little
as 0.002 mmol. Compounds 43 and 44 are active to a smaller extent, probably owing to their facile
polimerization.
The glandular trichomes of P. pedicellata contained two major phenolic compounds 47 and
48. Compound 47 is the principal dermatotoxin18; it acts as an irritant in unsensitized animals at

FIGURE 13.8 Allergenic chemicals isolated from Phacelia campanularia, commonly known as phacelioids.
concentrations of 0.55 mmol and causes an allergic reaction in sensitized animals at a concentration
of 0.061 mmol. Compound 48 is irritating at 1.5 mmol but does not elicit allergic reactions.
Phacelia crenulata, commonly known as desert heliotrope is responsible for most of the
dermatitits caused by Phacelia. It occurrs in the arid southwest of North America (California,
Arizona, Utah, and Nevada), and during spring, people walking among the blooms develop der-
matitis on the ankles and legs. P. crenulata var. funerea J. Voos ex Munz is characterized by a floral
stem of bluish-purple flowers that coil into a fiddleneck. The oily glandular secretions contain a
major constituent, geranylhydroquinone 49.17,19
Geranylhydroquinone (Figure 13.9) is a powerful allergen. It sensitized 19 of 21 human test
subjects at a nonirritating concentration of 0.5 percent. At 4.0 percent concentration, it produced

FIGURE 13.9 Geranylhydroquinone, the major allergen found in Phacelia crenulata.
FIGURE 13.10 Geranylgeranylhydroquinone, the major allergen in the trichome secretions of Phacelia
minor.
bullous reactions. There are some similarities between geranylhydroquinone and the poison oak
and poison ivy pentadecylcatechols and heptadecylcatechols urushiols respectively; but comparative
patch testing in urushiol-sensitive individuals with geranylhydroquinone shows that there is no
cross-reactivity between the two allergens. Dried leaves of P. crenulata do not elicit an allergic
response due to the chemical unstability of geranylhydroquinone, decomposing readily to a dark
nonreactive compound in the presence of air.
Phacelia minor (Harv.) Thell., common to the coastal mountains of southern California, is
similar to P. crenulata but differs in flower morphology being urn-shaped in P. minor with more
round leaves. Similar to P. crenulata, the oily secretions from the glandular trichomes of P. minor
contain a major allergenic principle that has been elucidated to be geranylgeranylhydroquinone 50
(Figure 13.10). A minor constituent in P. minor is 1-oxofarnesylhydroquinone 46.17,19,20 Studies
with guinea pigs show that 50 is a potent sensitizer and is cross reactive with geranylhydroquinone.
A dose of 0.01 mmol of 50 produces an erythema on at least 1/2 of the animals sensitized to 50 or
46. A dose of 0.02 mmol of 46 elicited a reaction in at least 1/2 of the treated animals. In nonsensitized
animals, a dose of 0.08 mmol and 1.5 mmol of 50 and 46, respectively, is needed to cause an irritation.
Another allergenic species of Phacelia is P. parryi that occurs also in the coastal mountains
and foothills of southern California extending south into Baja California, Mexico. The major contact
allergen present in the trichomes is geranylgeranyhydroquinone 50 and a minor constituent is the
hydroquinone 46.17,20
Endemic to the northern part of Baja California, Mexico, Phacelia ixodes Kellog is cited in
the anecdotal literature as a toxic species to the skin. This species is notably densely covered with
glandular trichomes containing a complex mixture of phenolic compounds (Figure 13.11). The
major compound isolated from these glandular trichomes was geranylhydroquinone 49. The second
most abundant constituent is a new phenolic compound, 3-geranyl-2,5-dihydrophenyl acetate 51.
Also, a major constituent was geranylbenzoquinone 52, an oxidation product of geranylhydro-
quinone. In amounts equal to 52 was 2-geranyl-6-hydroxy-4-methoxyphenyl acetate 53. The minor
constituents found were 2-geranyl-4-hydroxyphenyl acetate 54 and 6-hydroxy-2-methyl-(4-methyl-
3-pentenyl)-chromene 55, the latter compound had been isolated previously from the tropical tree
Cordia alliodora (Boraginaceae) and named cordiachromen A.21 One distinct feature of P. ixodes
is that the glandular trichome exudate is not typically transparent and colorless, but yellow and

FIGURE 13.11 Chemistry of the glandular trichome secretions of Phacelia ixodes Kellog. The geranylhyd-
roquinones are responsible for the allergenicity of the plant.
opaque. This is owing to the presence of a flavone that was identified as 6,7-dimethoxyapigenin
56 and found previously in the Labiateae and as a glycoside in the Asteraceae and Scrophulariaceae.
Compound 53, like 49, mentioned earlier, is an irritant and an allergen, but 51 is only an irritant.
Compounds 54 and 55 have not been tested for allergenic properties but at 2 mmol do not cause
an irritation.
Several species of Phacelia have been screened for the presence of hydroquinones and it has
been reported that P. viscida contains geranylhydroquinone 49, while P. distans, P. cicutaria, P.
fremontii, and P. minutiflora do not.18 The former species has been reported to be allergenic and
cross reactive, but P. distans apparently does not cross react with other species of Phacelia.

Other species of Phacelia that have been reported to be allergenic are: P. brachyloba, P.
grandiflora, P. infundibuliformia but have not been investigated for the allergenic principles. Others,
like P. distans, P. tanacetifolia, and P. ramosissima var. subsinuata do not elicit dermatitis in
sensitized individuals.14
13.3.2 WIGANDIA
Another genus that has been associated with dermatitic reactions in the Hydrophyllaceae is the
genus Wigandia. There are five species in tropical America. These are shrubs and trees used in
subtropical garderning. Wigandia caracasana var. macrophylla is used as an ornamental in the
southwest. There are several varieties, some with stinging hairs, painful to the touch; others lack
them. There is only one published report of allergies caused by this plant, but there are several
personal communications with accounts of contact dermatitis.22,23 One case stands out about a group
of students that developed dermatitis on the hands and arms after exposure to a planted stand of
Wigandia in a botany class.24
Wigandia caracasana leaves and stems are covered with stalked glandular trichomes that exude
oil droplets. Several irritants and dermatitis elicitors have been isolated from these glandular
exudates, and some are unusual compounds.24 From the plant, five major chemicals were isolated
and their dermatitic potential evaluated (Figure 13.12). The most potent irritant and contact allergen
in Wigandia is 2,3-dimethoxygeranylbenzoquinone (quinone A) 57. It is one of the most potent
contact allergens in the Hydrophyllaceae and as active as pentadecylcatechol found in poison ivy.
A second quinone was isolated, 2-hydroxy-3-methoxygeranylbenzoquinone (quinone B) 58 and,
surprisingly, the absence of the methoxy group from carbon-2 practically deactivates the compound.
Thus, quinone B is neither an irritant or an allergenic. Another allergenic compound isolated from
W. caracasana, and previously isolated from W. kunthii, is wigandol 59.12 Wigandol is both an
irritant and an allergenic, but it is 10 times less active than quinone A. Methyl wigandol 60, also
isolated from W. caracasana as the major constituent of the trichome exudate, is not an allergenic.
Farnesylhydroquinone 61, also in the exudate and previously reported in W. kunthii, is as potent
as quinone A.
13.3.3 TURRICULA
The genus Turricula is monophyletic with T. parryi being the only species occurring in the North
American southwest and used as a cultivated ornamental, and there is only one report on its
allergenic properties causing severe dermatittis to many persons,25 but there are anecdotal accounts
from field botanists as to the hazards of this plant.26 Stems and leaves are densely covered with
glandular hairs that secrete oils that contain a complex mixture of phenolic compounds,26 the
analysis of these glandular secretions yielded as a major constituent a yellow oil, turriculoic acid-
A, that can be separated into two stereoisomers 62a and 62b. The second most abundant constituent
is a yellow oil, turriculoic acid-B, that is a mixture in a ratio of 2:1 of the E and Z stereoisomers
63a and 63b. The other constituents in decreasing order of relative amount are, turriculoic acid-C
64, turriculoic acid-D 65, the alcohols turriculol-E 66 and turriculol-F 67, and the prenylated benzoic
acid 3-farnesyl-p-hydroxybenzoic acid 68 (Figure 13.13).
Compounds 62-68 were tested on guinea pigs for their potential to elicit allergic contact
dermatitis. None of the compounds tested were irritant to nonsensitized animals at the highest dose
tested of 0.5 mg, and only compound 64, elicited allergic skin erythemas in sensitized animals. A
dose of 0.15 mg (0.5 mmol) is required to give a response in 5 out of 10 animals treated. This
shows that compound 64 is not a particularly strong allergenic hydroquinone when compared with
some of the hydroquinones from the Phacelia species. However, it is clear that the allergenic
properties of Wigandia are related to these compounds.

FIGURE 13.12 Major secondary chemistry of the oily exudates of glandular trichomes in Wigandia cara-
casana. The irritant and allergenic properties are associated with the benzoquinones.
13.3.4 NAMA
Of the remaining 15 genera in the family, only 1 other genus has been reported to contain at least
a species that causes blisters upon contact, the genus Nama,14 of which there are 45 species
distributed in the southwest of North America, and tropical America and 1 species in Hawaii. The
reported species with blistering properties is Nama hispidum var. spathulatum, and occurs in the
North American southwest and northern Mexico. There are no other reports on the allergenic activity
of any Nama species. Several species of Nama have been collected and investigated for the chemistry
and insecticidal properties, including N. hispidum, and their handling has not resulted in injury to
the skin.

FIGURE 13.13 The complex phenolic chemistry of Turricula parryi is mainly comprised of the turriculoic
acids A–F and their respective stereoisomers.
In summary, the chemistry associated with the irritations and contact dermatitis that plants in
the family Hydrophyllaceae cause in humans and animal models is a series of prenylated hydro-
quinones, the phacelioids, with similar structural features to those of the pentadecyl and heptadecyl
catechols in poison ivy and poison oak (Toxicodendron sp., Anacardiaceae). These hydroquinones
appear to be unique to this family and have only been reported in a variety of marine organisms
that include seaweeds, sponges, and urochordates.
The chemical similarities of the phacelioids with the urushiol constituents have led researchers
to propose that both types of compounds possess similar modes of action and act upon the immune
system in an analogous manner. A hypothetical mechanism of action has been proposed, and it
assumes that the phacelioids undergo oxidation to yield the corresponding benzoquinones that act

as haptens. The benzoquinones can then undergo Michael addition reactions with the thiol groups
of proteins to form an antigen that triggers the cascade of events that result in the dermatitic
condition.27,28 This hypothesis is supported by the fact that hydroquinones that cannot undergo
oxidation to the benzoquinone, such as methylwigandol 60, and do not cause dermatitis.
We wish to acknowledge the extensive collaboration with Dr. William Epstein (UCSF) in all aspects
of the clinical testing of natural allergens, and the contributors of Dr. Gary Reynolds (UCI) to the
knowledge of the chemical nature of irritants and allergens in plants. We also thank the National
Institutes of Health (NIAID) for Financial Support.
13.5 REFERENCES
1. Ferguson, D. M., Phylogenetic analysis of Hydrophyllaceae and a preliminary study of biogeographic
patterns and life history evolution, Am. J. Bot., 83, Suppl. 6, 155, 1996.
2. Caceres, A., Figueroa, L., Taracena, A. M., and Samayoa, B., Plants used in Guatemala for the
treatment of respiratory diseases 2. Evaluation of activity of 16 plants against Gram-positive bacteria.
J. Ethnopharmacol. 29(1), 77, 1993.
3. INN (Instituto Indigenista Nacional), Aspectos de la medicina popular en el area rural de Guatemala,
Guatemala Indíg. 6, 1, 1971.
4. Horner, P. and Scora, R., Leaf hydrocarbons of Phacelia species (Hydrophyllaceae), Phytochemistry,
22(11), 2489, 1983.
5. Roitman, J. and Wollenweber, E., b,b-dimethacrylophenones and a chromanone from Nama hispidum
and Nama johnstonii, Phytochemistry, 33(4), 936, 1993.
6. Arriaga-Giner, F. J., Wollenweber, E., Schober, I., and Yatskievych, G., Three new benzoic acid
derivatives from the glandular excretion of Eriodyction sessilifolium Hydrophyllaceae. J. Biosci., 43(5-
6), 337, 1988.
7. Liu, Y. L., Ho, D. K., Cassady, J. M., Cook, V. M., and Baird, W. M., Isolation of a potential cancer
chemopreventive agents from Eriodictyon californicum, J.Nat. Prod., 55(3), 357, 1992.
8. Bacon, J. D., Fang, N., and Mabry, T. J., Systematics of Nama (Hydrophyllaceae): flavonoids and
phyletic position of sect. Arachnoidea and sect. Cinerascentia, Plant Syst. Evol., 151, 223, 1986.
9. Bacon, J. D., Hannan, G. L., Fang, N., and Mabry, T. J., Chemosystematics of the Hydrophyllaceae
flavonoids of three species of Eriodyction, Biochem. Syst. Ecol., 14(6), 591, 1986b.
10. Binder, B. F., Bowers, W. S., and Evans, P. H., Insect anti-juvenile hormone and juvenile hormone
activity from plants in the genus Nama, Experientia, 47(2), 199, 1991.
11. Binder, B. F., Trichomes of Nama (Hydrophyllaceae) that produce insect-active compounds, Alosi,
14(1), 35, 1995.
12. Gomez, F., Quijano, L., Calderon, J. S., and Rios, T., Terpenoids isolated from Wigandia kunthii,
Phytochemistry, 19(10), 2202, 1980.
13. Cruden, R. W., Information on chemistry and pollination biology relevant to the systematics of
Nemophila menziesii (Hydrophyllaceae), Madroño, 21(8), 505, 1972.
14. Munz, P. A., Dermatitis produced by Phacelia (Hydrophyllaceae). Science, 76, 194, 1932.
15. Berry, C. Z., Shapiro, S. I., and Dahlen R. F., Dermatitis venenata from Phacelia crenulata, Archs.
Derm. (Chicago), 85, 737, 1962.
16. Mitchell, J. and Rook A., Botanical Dermatology, Greengras Ltd., Vancouver, BC, 1979, 352.
17. Reynolds, G. W. and Rodriguez, E., Geranylhydroquinone: a contact allergen from trichomes of
Phacelia crenulata, Phytochemistry, 18(9), 1567, 1979.
18. Reynolds, G. W. and Rodriguez, E., Dermatotoxic phenolics from glandular trichomes of Phacelia
campanularia and P. pedicellata, Phytochemistry, 25(7), 1617, 1986.
19. Reynolds, G., Epstein, W., Terry, D., and Rodriguez, E., A potent contact allergen of Phacelia

20. Reynolds, G. W. and Rodriguez, E., Prenylated hydroquinones: contact allergens from trichomes of
Phacelia minor and P. parryi, Phytochemistry, 20(6), 1365, 1981.
21. Reynolds, G. W. and Rodriguez E., Prenylated phenols that cause contact dermatitis from trichomes
of Phacelia ixodes, Plant. Med., 43, 187, 1981.
22. Allen, P. H., Poisonous and injurious plants of Panama, Am. J. Trop. Med.. 23 (Suppl.), 23, 1, 1943.
23. Anderson, N. P. and Ayres, S., Jr., Dermatitis venata due to Wigandia caracasana, Calif. West. Med.,
34, 278, 1931.
24. Reynolds, G. W. and Rodriguez, E., Contact allergens of an urban shrub Wigandia caracasana, Contact
Derm., 21, 65, 1989.
25. Munz, P. A. and Keck, D. D., A California Flora, University of California Press, Berkeley, 1965.
26. Reynolds, G. W. and Rodriguez, E., Prenylated phenolics that cause contact dermatitis from glandular
trichomes of Turricula parryi, Plant. Med., 6, 473, 1985.
27. Polak, L., Contact Derm., 4, 249, 1978.
28. Liberato, D. J., Byers, V. S., Dennick, R. G., and Castagnoli, N., Jr., J. Med. Chem., 24, 28, 1981.

14 Primulaceae
Lars P. Christensen
CONTENTS
14.1 Introduction
14.1.1 Botany and Classification
14.1.2 Primula
14.1.2.1 Primula obconica Hance
14.2 Chemistry
14.2.1 Flavonoids and Free Flavonoid Aglycones
14.2.2 Quinones and Phenols
14.2.3 Saponins and Other Triterpenes.
14.3 Clinical Effects
14.3.1 Allergenic Principles
14.3.2 Contact Dermatitis to Primulaceae Plants
14.3.2.1 Primula Dermatitis (Primula obconica Hance)
14.3.2.2 Dermatitis from Other Primulaceae Species
14.3.3 Patch Testing
14.4 References
14.1 INTRODUCTION
The Primulaceae (Primrose family) is a family of perennial or annual herbs, including a number
of popular garden ornamentals, such as primulas and cyclamens. Approximately 1000 species,
distributed among 23 genera, constitute this family of dicotyledons. The family is cosmopolitan in
distribution but with most members found in the north temperate zone.1-5
Many species in this family have medicinal properties and have been used frequently in
herbal medicine. Anagallis arvensis (scarlet pimpernel), a weed of worldwide distribution known
to be poisonous if taken internally, is, for example, used as a direutic or pyretic in Europe, as a
remedy for bites by snakes and mad dogs, and has been shown to possess antiviral properties.6-8
Lysimachia vulgaris, also known as yellow loosestripe, is used in herbal medicine as an astringent
and stypic but has also reputed uses as a febrifuge or fever reducing agent.4,9 Some species of
the Primulaceae are also known for their allergenic properties and especially, Primula obconica
(poison primrose) and a few other primulas are frequent producers of allergic contact dermatitis
(see Section 14.3.2).
Economically, the Primulaceae is mainly of ornamental importance and many species from
different genera are in cultivation; however, Primula and Cyclamen species constitute the major
part of cultivated ornamentals.4,5,10 Many Primula species are cultivated for their attractive flowers
either as house pot plants (e.g., P. · kewensis, P. malacoides, and P. obconica), in rock gardens

(e.g., P. auricula and P. allionii), or as garden borders (e.g., P. denticulata and P. bulleyana). A
number of Cyclamen species including C. hederifolium are grown in gardens, whereas C. persicum
is the progenitor of the popular winter flowering pot cyclamens.
14.1.1 BOTANY AND CLASSIFICATION

The Primulaceae occupies a relatively isolated position in most taxonomic treatments, usually
placed on grounds of flower morphology near to the Plumbaginaceae, Theophrataceae, or Myrsi-
naceae in the order Primulales.1-4 Once the Primulaceae was considered to be related to the
Caryophyllaceae.1-4
Most species perennate by means of sympodial rhizomes (as in Primula) or tubers (as in
Cyclamen). The leaves are simple (usually entire) without stipules (except in Coris), arranged
opposite or alternate or in a rosette. Often the leaves and stems bear simple or compound glandulair
hairs.1-5
The flowers are often borne on a leafless scape, and are solitary or in umbells, racemose or
paniculate inflorescences. The flowers have bracts and are usually regular (irregular in Coris),
bisexual, and often have heterostylous. There are normally five sepals fused into a persistent calyx
tube with four or five pointed segments. Most often five petals are fused into a tube, but with the
lobes reflexed in some genera (e.g., Cyclamen). The exception is the genus Glaux, which has no
petals. There are five stamens fused to the corolla tube opposite the petals. In a few cases there are
also five staminodes (e.g., in Samolus and Soldanella). The ovary is unilocular with free central
placentation and few to numerous ovules. There is a single style with a head-like stigma. The fruit
is normally a five-valved capsule, usually containing numerous small seeds with a small straight
embryo surrounded by a fleshy or hard endosperm.
Taxonomically, the Primulaceae are described as a natural family which is usually divided into
subfamilies. Thus, on the basis of morphological characteristics only, such as floral symmetry,
position of the ovary, and aestivation of the corolla, the Primulaceae is divided into five subfamilies
or tribes according to Engler’s Syllabus.3 The five tribes are Primuleae, Cyclamineae, Lysimachieae,
Samoleae, and Corideae of which, Primuleae and Lysimachieae are further subdivided. Primuleae
is divided into Primulinae and Soldanellineae, whereas Lysimachieae is divided into the subtribes
Lysimachiinae and Anagallidinae.
Primuleae (syn. Androsaceae): The tribe includes the following genera: Androsace (about 120
species), Ardisiandra (3 species), Cortusa (7 species), Dionysia (about 40 species), Dodecatheon
(about 50 species), Douglasia (8 species), Hottonia (3 species), Omphalogramma (13 species),
Primula (primroses, about 425 species), and the monotypic genera Bryocarpum and Vitaliana
(former Gregoria) all belonging to the subtribe Primulinae, and Soldanella (6 species) being the
only genus in the subtribe Soldanellineae. Species belonging to the Primuleae are mainly distributed
in the Northern Hemisphere. For example, there are species belonging to Douglasia and Dodeca-
theon mainly found in North America, whereas the genus Androsace is widely distributed in Europe.
The genera Primula, Dionysia, and Omphalogramma are mainly found in Asia. Most taxonomic
problems occur in the largest genus Primula that is divided into subgenera and sections (see Section
14.1.2). Identification of species in such a large genus may be difficult as is the separation of
Primula from similar genera such as Cortusa, Dionysia, and Omphalogramma. Characteristic
features for the whole tribe are ovary superior, corolla lobes imbricate in the bud, and capsule with
valvate dehiscence.
Cyclamineae: This tribe includes only Cyclamen (about 20 species) and the characteristic
features are tubers, ovary superior, flowers with reflexed petals, and capsule with valvate dehiscence.
Species are distributed in the Northern Hemisphere, mainly in the Alps and from the Mediterranean
to western Asia.
Lysimachieae: This tribe includes the genera Asterolinum (2 species), Glaux (1 species),
Lysimachia (about 200 species), Pelletiera (1 species), Steironema (4 species sometimes included

in Lysimachia), and Trientalis (4 species), all belonging to the subtribe Lysimachiinae, and Ana-
gallis (about 28 species), and the monotypic genus Centunculus belonging to the subtribe Anagal-
lidinae, with the latter genus sometimes included in Anagallis. Species are mainly distributed in
the Northern Hemisphere, although some species of Anagallis and Lysimachia are found in southern
Africa and the monotypic genus Pelletiera in South America. Characteristic features for the whole
tribe are ovary superior, corolla lobes contorted in the bud, and capsule with valvate dehiscence
or a pyxis.
Samoleae: This tribe includes only the genus Samolus (between 10 and 15 species) that is
mainly found in the Southern Hemisphere. It is characterized by a semi-inferior ovary.
Corideae: This tribe includes only Coris with two species, mainly distributed in the Mediter-
ranean area. This is a curious genus of small thyme-like shrubs, sometimes referred to its own
monotypic family, the Coridaceae. Characteristic features are the spiny calyx and irregular flowers.
14.1.2 PRIMULA
Primula is an important garden genus in terms of the number of varieties grown and the income
generated by the horticultural industry.5,10 Primula is also among the largest and most widespread
of all plant genera.5 According to Richards,5 the genus Primula consists of approximately 425
species that are primarily distributed in the north temperate regions. By far, the greatest concen-
tration of species is found in the great mountain chain of the Himalaya and western China. According
to Richards,5 the genus is systematically divided into 37 sections, of which, 24 sections are endemic
to the Sinohimalaya. In the eastern Sinohimalaya, between 90 and 100°E and 25 to 30°N, encom-
passing Sichuan, Yunnan, Upper Burma, Assam, and southeast Tibet, about half of all Primula
species (225 species) are to be found. In the adjacent central Himalaya, an additional 63 species
are recorded and in the western Himalaya about 29 species are found. All together, temperate Asia
accounts for approximately 80 percent of all Primula species. In contrast, Europe only has 33
species, classified into 4 sections, and North America has 20 species classified into 5 sections.
Primula is not present in Australia and in southern and central Africa and only one species has
been found in South America.
Primulas are herbaceous perennials or, in a few cases, biennials or annuals. Many species
produce farinose (meal) on leaves, stems, and/or inflorescences. Typically they have a basal rosette
of leaves, with or without petioles. The lamina may be simple or lobed and the margins entire or
toothed. Flowers are solitary, in umbells, or in superimposed whorls. Flower colors range from
white through cream to yellow and orange, from pale pink to deep red, and from purple, violet-
purple, to blue. The flowers have a tubular, funnel-, or bell-shaped, five-parted, persistent calyx
and a corolla with a slender cylindrical- or funnel-shaped tube and five spreading or, less often,
more or less erect lobes (petals) often emarginated at the apex. There are five stamens with short
filaments and one style. The relative lengths of stamens and style differ in individual plants
(heterostylous). The fruits are capsules.
Many species and horticultural varieties of Primula are today grown in gardens worldwide and
some are very popular as pot plants. Primulas were already popular in Europe in the eighteenth
and nineteenth centuries. The cultivated primulas at that time were complex hybrids of European
species such as P. vulgaris Hudson (common primrose), P. veris L. (cowslip), and P. elatior (L.)
Hill (oxlip), today known as P. · polyanthus or hybrids of the common primrose and the bear’s
ear (P. auricula L.) known as the garden Auriculas.5,10 At the same time, the Chinese and Japanese
cultivated their own horticultural varieties of P. sinensis Sabine ex Lindley (syn. P. praenitens Ker-
Gawl.) and P. sieboldii Morren. However, it was the European who introduced and started to breed
the Asian species P. obconica Hance and P. malacoides Franchet (fairy primrose) that turned out
to be very popular twentieth century house plants. Unfortunately, these are also among the most
allergenic ones and, especially, P. obconica has been and still is responsible for numbers of severe
cases of allergic contact dermatitis (see Section 14.3.2.1).

FIGURE 14.1 Picture of an allergenic Primula obconica variety.
14.1.2.1 Primula obconica Hance
Primula obconica Hance was introduced by Charles Maries from Ichang, west Hubei in 1879 to
Messrs. Veitch (London) and, in 1880, the first description of the plant was published by Hance
who gave it the present name.11,12
Primula obconica is a very popular plant for heated glasshouses, and is by far the most
successful primula as a house plant, primarily because it is remarkably tolerant to modern central
heating; that is not the case for most primulas.5,10 P. obconica is relatively short-lived, needing
replacement from seeds. However, if the plants are repotted after flowering they may last for several
years, although they rarely flower well in subsequent years. In tropical and Mediterranean climates,
P. obconica is sometimes used for decorative bedding schemes, but it is less popular than P.
malacoides or P. sinensis because the latter species are faster regarding the development of flowers,
for example. P. obconica is also very successful in window boxes and hanging baskets.5,10
There exist several horticultural varieties of P. obconica. The varieties identified as P. obconica
Grandiflora-Group and P. obconica Gigantea-Group (Figure 14.1) have larger flowers in clearer
and more diverse colors than the naturally occurring species. P. obconica Grandiflora is a direct
desendant of the species P. obconica, whereas P. obconica Gigantea is a hybrid between P. obconica
and the nonallergenic P. megaseifolia Boiss. & Bal.10,12 The first horticultural varieties of P. obconica
Grandiflora and P. obconica Gigantea that were bred in the beginning of the twentieth century were
very allergenic. Since then there have been many attempts to breed new nonallergenic P. obconica
varieties12-15 (see also Section 14.3.2.1). In 1990, new strains were introduced with the names
Freedom and Beauty, and claimed to lack the allergen primin5 and, more recently, a new P. obconica
strain named Libre was introduced to the market and should also be nonallergenic.15
Primula obconica is widespread in the Chinese provinces of Yunnan and Sichuan, and occa-
sionally found in the provinces of Hubei, Kweichow, Kwangtung, and southeast Tibet. The species
occurs on limestone, sandstone, and clay-slate up to 3200 m. P. obconica is very variable in size,
leaf-shape, hairiness, flower color, and form. Furthermore, it is difficult to delimit the species
because P. obconica tends to form a morphological continuum with several other species, for
example, P. barbicalyx Wright, P. sinolisteri Balf.f., and P. parva Balf.f.5 Owing to the variability
of P. obconica, at least three varieties within P. obconica have been recognized with, perhaps, more
species being included in P. obconica.5 However, the cultivars of P. obconica are invariable and
according to Richards5 many of the existing horticultural variants were perhaps among the seedlings
of Charles Maries’ initial introduction of the plant.

The species P. obconica is a perennial rhizomatous evergreen that lacks meal but has long and
sticky hairs on leaves, stems, and inflorescences (characterize all species in the section obconica).
Leaves are rounded (up to 17 · 11 cm), entire, slightly toothed, undulated, or shallow lobed. Usually
the leaves are heart-shaped at the base with a long petiole with a revolute vernation. The petiole
is succulent and up to 10 cm long and white or tawny-hairy. Stems can measure up to 25 cm,
usually exceeding the leaves (Figure 14.1), and are stout and hairy, carrying not more than 13
flowers, usually in a single umbel on hairy pedicels that can measure up to 25 mm. The calyx is
bell-shaped (up to 10 mm) with hairs and is scarcely cut in most plants. Corolla (petals) occurs in
rose, lavender, pink, or white colors, are hetero- or homostylous, exannulate to weakly annulate,
and flat-faced up to 2.5 cm in the wild, but up to 5 cm in cultivation. The corolla tube is about two
times as long as the calyx and petal lobes are broad, rounded, and emarginated. Capsule are globose
and top shaped. The chromosome numbers are 2n = 24, 48. The plants naturally flower from winter
to early spring.
14.2 CHEMISTRY
From the many phytochemical investigations carried out so far on species belonging to Primulaceae,
it appears that triterpenoids, flavonoids, and other phenolics are widely distributed in the family.
Mono-, di-, and oligosaccharides that primarily function as storage products, are accumulated both
in roots and aerial parts of most species in the Primulaceae.16-20 For example, the sugars are
hamamelose, hamamelitol, and clusianose and are widely distributed in the genera Primula, And-
rosace, and Soldanella.17-20 Alkaloids so far have not been isolated from Primulaceae. This is not
surprising, considering the fact that alkaloids only seem to be sporadically present in related families
such as Plumbaginaceae and Myrsinaceae.21
14.2.1 FLAVONOIDS AND FREE FLAVONOID AGLYCONES

At present over 150 species, representing 18 of the 23 genera, of the Primulaceae have been
investigated for flavonoids and free flavonoid aglycones (Table 14.1). The largest variation in
flavonoid structures occurs in the tribe Primuleae, especially in the genus Primula. Many Primula
species have on inflorescences and leaves a farinose coating that primarily consists of free flavonoid
aglycones with a remarkably low degree of oxygenation.16,17,22-37 For example, the dominating
component of the Primula farina is flavone (1) that completely lacks O-substitution. Flavone have
been detected so far in about 52 Primula species but also seem to be widely distributed in the
closely related Dionysia (Table 14.1). Also mono- and disubstituted flavones (2–5, 8, 10, 12, 14,
15), that lack substitution in either the A or B ring, are widely distributed in Primula together with
the disubstituted flavones 6 and 9 (Table 14.1 and Figure 14.2). A few chalcones, the biosynthetic
precursors to the flavones and other flavonoids,38 also have been isolated from the farinose exudate
of Primula species although they seem to be rare. So far the chalcone 18 has been found as a
constituent of the farinose exudate of P. bulleyana Forrest, P. denticulata Smith, and a few other
Primula species, whereas the chalcone 19 has only been isolated from P. macrophylla D. Don.
(Table 14.1). An interesting compound is 2´,b-dihydroxychalcone (20a), a novel representative of
the rare group of b-diketones or dibenzoylmethanes that have been shown to be converted easily
into flavone by dehydration.36 2´,b-Dihydroxychalcone is present in the farina of P. japonica Gray
and P. pulverulenta Duthie (Table 14.1), and is most likely the precursor of flavone and related
compounds.
The flavonoid aglycones found in Primulaceae, with the exception of the flavones 1, 3, and 4
that occur regularly in Pimelea species (Thymelaceae),39,40 only have been isolated from this family,
although flavonoid aglycones with a low degree of oxygenation are common in, for example,
Asteraceae, Rutaceae, and Lamiaceae.31,40 As the lipohilic nature of the flavonoid aglycones
excludes their accumulation in the aqueous environment of the cell sap, this leads to external

TABLE 14.1
Distribution of Flavonoids and Free Flavonoid Aglycones in the Primulaceae
Tribe/Genus/Species Flavonoids/Flavonoid Aglyconesa References
Corideae
Coris hispanica Lange 25(G), 27(G) 47
C. monspeliensis L. 24, 25(G), 27(G) 47, 158
Cyclamineae
Cyclamen africanum Boiss. & Reut.b 25(G), 27(G), 38 46
C. balearicum Willk. 27(G) 46
C. cilicium Boiss. & Heldr. 38 46
C. coum Mill. 27(G), 38 46
C. cyprium Ky. 38 46
C. graecum Link 25(G), 27(G), 29(G), 38 46, 47
C. libanoticum Hildebr. 27(G), 38 46
C. neapolitanum Ten. (= C. hederifolium Aiton)c 25(G), 27(G), 38 46
C. persicum Mill. 25(G), 27(G), 29(G), 37, 38 46, 159
C. pseudibericum Hildebr. 27(G), 38 46
C. purpurascens Mill. (syn. C. europaeum L.)c 25(G), 27(G), 38 46
C. repandum Sibth. & Smith 27(G), 38 46
C. rohlfsianum Asch. 38 46
Lysimachieae
Anagallis arvensis L. 25(A,G), 27(A,G), 33, 38 47, 159, 160
A. arvensis L. f. coerulea 23(A,G), 27(G), 38 161
A. linifolia L. (syn. A. monelli (L.))c 25(G), 27(G) 47
A. rubricaulis Bojer ex Duby 27(G) 162
Asterolinum stellatum Hoffm. & Link (syn. A. linum- 25(G), 27(G) 47
stellatum (L.) Duby)c
Centunculus minimus L. (syn. Anagallis minima (L.) 25(G), 27(G) 47
Krause)c
Glaux maritima L. 27(G) 47
Lysimachia atropurpurea L.b 25(G), 27(G) 47
L. christinae Hance var. typica Knuth 24, 25(G), 28(G) 163
L. cuspidata Blume 27(G) 47
L. ephemera L. 25(G), 27(G), 29(G), 35, 37 159
L. fortunei Maxim. 25(G)–27(G) 164
L. japonica Thunb. 25(A,G), 27(A,G) 63, 64
L. clethroides Duby 25(G), 27(G) 63
L. nummularia L. 25(G), 27(G)–29(G), 34, 35, 37 47, 165, 166
L. mauritiana Lam. 25(G), 27(G) 167
L. punctata L. 27(G), 29(G), 35, 37 159, 168
L. stricta Soland. 25(G), 27(G) 47
L. thyrsiflora L. (syn. Naumburgia thyrsiflora (L.) 25(G), 27(G) 47
Reichenb.)c
L. vulgaris L. 25(G), 27(G), 29(G), 35, 37 47, 159, 169-
171
L. vulgaris L. var. davurica (Ledeb.) R. Knuth 25(G)–28(G) 171
Steironema ciliatum L. (Rafin.) 25(G), 27(G), 29(G), 35, 37d 47, 159
S. heterophyllum Rafin. 27(G)d 47
S. radicans A. Gray 25(G), 27(G) 47
Trientalis americana Pursl. 25(G), 27(G) 47
T. europaea L. 25(G), 27(G) 47

Primuleae
Androsace lactea L. 25(G), 27(G) 47
A. lanuginosa Wall. 27(G), 35 47
A. obtusifolia All. 25(G), 27(G) 47
A. sarmentosa Wall. 25(G), 27(G), 35 47
A. sempervivoides Jacquem. 27(G), 35 47
A. villosa L. 25(G), 27(G) 47
Cortusa matthioli L. 1, 15(G), 25(G), 27(G), 38 16, 23, 47
Dionysia archibaldii Wendelbob 40 27
D. aretioides (Lehm.) Boiss. 1, 15(G), 25(G), 27(G), 32(G) 27, 47
D. bornmuelleri (Pax) Clay 1, 15(G), 25(G), 27(G), 32(G) 27
D. bryoides BoisS. 15(G), 40 27, 47
D. curviflora Bunge 40 27
D. diapensiifolia Boiss. 1, 15(G), 25(G), 27(G) 16, 23, 47
D. microphylla Wendelbo 1, 15(G), 25(G), 27(G), 40 27
D. paradoxa Wendelbo 15(G), 25(G), 27(G), 32(G) 27
D. revoluta Boiss. 1, 15(G), 25(G), 27(G) 16, 23, 47
D. tapetodes Bunge 1 16, 23
D. teucrioides Davis & Wendelbo 1, 15(G), 27(G) 27
Dodecatheon meadia L. 15(G), 25(G), 27(G), 38 47
D. cusickii Greene 15(G), 25(G), 27(G) 47
D. clevelandi Greene 15(G), 27(G) 47
Douglasia vitaliana B. & H. 27(G), 32(G) 47
Hottonia palustris L. 25(G), 27(G), 35 47, 159
Primula algida Adamsb 1 16, 23
P. alpicola (Smith) Stapf 1, 2, 5, 6, 10, 11, 15(A,G), 25(G), 30, 47
27(G), 30(G), 32(G), 40
P. americana Rydb. (= P. incana M. E. Jones)c 1 16, 23
P. anisodora Balf.f. & Forrest (= P. wilsonii Dunn)c 25(G), 27(G), 40 47
P. aurantiaca Smith & Forrest 15(G), 27(G), 35 47
P. aureata Fletcher 1, 15(G), 27(G) 27
P. auricula L. 1, 2, 5, 6, 10, 15(A,G), 25(G), 29(G), 16, 23–25,
38 30, 47
P. beesiana Forreste 1, 2, 5, 6, 9, 12, 14, 15(A,G), 25(G), 16, 24, 25, 30,
27(G), 38, 40 34, 35, 47
P. boothii Craib 15(G), 25(G), 40 47
P. boveana Decne. ex Duby (syn. P. involucrata Sweet)c 1, 15(G), 25(G), 27(G) 27
P. bulleyana Forreste 1–3, 5, 6, 9, 12, 14, 15(A,G), 18, 16, 24, 25, 30,
27(G), 38, 40 33–35, 47
P. burmanica Balf.f. & Ward 1, 15(G), 25(G), 27(G), 38, 40 16, 24, 25, 47
P. capitata Hook.f. (syn. P. mooreana Balf.f. & Smith)c 1–3, 5, 6, 15(A,G), 25(G), 27(G), 29, 16, 23–25,
40 30, 33, 47
P. capitellata Boiss. 1 16, 23
P. cawdoriana Ward 15(G), 25(G), 27(G), 40 47
P. chungensis Balf.f. & Ward 1, 15(G), 27(G), 35 16, 24, 25, 47
P. chionantha Balf.f. & Forrestf 10, 15(G), 25(G), 27(G) 27, 47
P. clarkei Watt 15(G), 25(G), 39 47
P. cockburniana Hemsl. (syn. P. operculata R. Knuth)c 15(G), 27(G), 35 47

P. cortusoides L. (syn. P. saxatilis Komarov)c 1, 15(G), 25(G), 38 16, 23, 47

P. denticulata J. E. Smith 1, 2, 5, 10, 15(G), 17, 18, 25(G), 16, 23–25,
27(G), 35, 37, 40 30, 33, 37,
47, 159
P. elatior (L.) Hill 15(G), 25(G), 27(G), 32(G) 47, 172
P. farinosa L. (syn. P. nivalis Turcz.)c 1, 2, 5, 6, 10, 15(A,G), 25(G), 27(G), 16, 23, 30, 47
40
P. floribunda Wall. 25(G), 27(G), 35, 37 159
P. florindae Ward 1–3, 5, 6, 10, 11, 15(A,G), 27(G), 16, 24, 25,
32(G) 28–30, 33,
47
P. forrestii Balf.f. 1 16, 23
P. frondosa Janka 1, 2, 5, 15(G), 25(G), 27(G), 40 16, 23-25, 30,
47
P. gaubeana Bornm. 1, 15(G), 25(G), 27(G) 27
P. glaucescens Moretti 25(G), 40 47
P. gracilepes Craib 15(G), 25(G), 40 47
P. halleri Gmel. (syn. P. longiflora All.)c 1–3, 5, 10, 15(G), 25(G), 40 16, 23, 30, 33,
47
P. hirsutag 40 173, 174
P. helodoxa Balf.f. 1, 27(G) 16, 24, 25, 47
P. heydei Watt (= P. minutissima Jacq.)c 1 16, 23
P. hookeri Watt (syn. P. vernicosa Ward)c 1 16, 23
P. imperialis Jungh var. gracilis Usteri 1, 5 16, 175
P. involucrata Wall. 25(G), 27(G), 40 47
P. integrifoliag 38 173, 174
P. ioessa Smith 15(G), 25(G), 27(G), 37 47
P. jaffreyana King (syn. P. lhasaensis Balf.f. & Smith)c 1 16, 24, 25
P. japonica A. Gray 1–3, 5, 12, 14, 15(A,G), 20a, 27(G), 16, 22, 24, 25,
38 30, 33, 34,
36, 47
P. · kewensis Hort. 15(G), 25(G), 27(G) 47
P. · kewensis Wats. 1–3, 5, 6, 10, 15 30, 33
P. longipes Freyn & Sint. 1 16, 23
P. luteola Ruprecht 15(G), 25(G), 27(G) 47
P. malacoides Franchet 1, 2, 5, 6, 10, 11, 15(A,G), 25(G), 38 16, 23–25,
30, 47
P. macrocarpa Maxim. (syn. P. hayaschinei Petitm.)c 1, 15(G), 25(G), 27(G) 27
P. macrophylla D. Don. (syn. P. stuartii Wall. var. purpurea 4, 19, 21(G) 176, 177
Watt)c
P. marginata Curtis (syn. P. microcalyx Lehm.)c 1, 2, 5, 10, 15(G), 40 16, 23–25,
30, 47
P. megaseifolia Boiss. & Bal. 27(G), 40 47
P. minima L. 25(G), 40 47
P. microdonta Franchet & Petitm. 1 16, 24, 25
P. mistassinica Michaux 10 61
P. modesta Bisset & Moore 1, 10 16, 178, 179
P. modesta Bisset & Moore var. fauriei (Franch.) Takeda 1 16, 23

P. nivalis Pallas (syn. P. speciosa Gmel.)c 1 16, 23

P. nutans Franchet 15(G), 18, 25(G), 27(G), 40 33, 47
P. obconica Hance (syn. P. poculiformis Hook.f.)c 15(G), 25(G), 27(G), 35–38 47, 159, 174,
180
P. palinuri Petagna 1, 3, 9, 12, 14, 18 16, 23, 33–35
P. petiolaris Wall. (syn. P. tridentata Don)c 1 16, 23
P. polyantha Mill. 25(G), 27(G), 35, 37 159, 181
P. polyanthusg 38 174, 182
P. polyneura Franchet 15(G), 18, 25(G), 27(G), 38 33, 47
P. praenitens Ker-Gawl. (= P. sinensis Sabine ex Lindley)c 1, 2, 5, 15, 16, 25(G), 27(G), 29(G), 16, 23, 30, 41,
33–38h 47, 174, 183
P. prolifera Wall. 27(G) 47
P. · pubescens Jacq. 1 16, 23
P. pulchelloides Ward (= P. pulchella Franchet)c 1 16, 24, 25
P. pulverulenta Duthie (syn. P. shihmienensis Fang)c 1, 2, 5, 6, 9, 12–14, 15(A,G), 16, 18, 16, 22, 24, 25,
20a, 27(G), 38, 40 30, 33–36,
47
P. reidii Duthie 15(G), 25(G), 27(G) 47
P. rosea Royle (syn. P. elegans Duby)c 25(G), 27(G), 39 47
P. rotundifolia Pallas (syn. P. nutans Georgi)c 1, 15(G), 25(G), 27(G) 27
P. rubra Gmel. (= P. hirsuta All.)c 25(G), 40 47
P. rusbyi Greene (syn. P. serra Small)c 15(G), 25(G), 40 47
P. scotica Hook. 1, 15(G), 25(G), 27(G), 40 16, 23, 47
P. secundiflora Franchet 27(G), 29(G), 38 47
P. sherriffae Smith (syn. P. ludlowii Smith)c 1 16, 24, 25
P. sikkimensis Hook.f. (syn. P. microdonta Franchet ex 1, 15(G), 32(G) 16, 24, 25, 47
Petitm.)c
P. sinopurpurea Balf.f.f 15(G), 25(G), 27(G), 40 47
P. smithiana Craib 27(G), 29(G) 47
P. stricta Hornem. 1 16, 23
P. stuartii Wall. 1 16, 23
P. veris L. (syns. P. officinalis (L.) Hill, P. suaveolens 1, 15(G), 22, 23, 25(A,G)–27(A,G), 47, 159, 184,
Bertol.)c 29(G), 31(G), 32(G), 35, 37 185
P. verticillata Forsk. 1, 5, 15(G), 25(G), 27(G) 16, 23–25, 27
P. viscosag 38 173, 174
P. vialii Delavay ex Franchet 1, 2, 5, 6, 10, 15(A,G), 25(G), 34, 40 30, 47
P. vulgaris Hudson (syn. P. acaulis (L.) Hill)c 1, 3, 8, 15(G), 16, 25(G), 27(G), 47, 159, 174,
32(G), 37 185
P. waltonii Watt ex Balf.f. 1, 2, 5, 6, 10, 11, 15(A,G), 27(G), 30, 47
32(G), 38, 40
P. warshenewskiana Fedtsch. 25(G), 35 47
P. whitei Smith 15(G), 25(G), 38, 40 47
P. yargongensis Petitm. 25(G), 27(G), 40 47
P. yuparensis Takedo 1, 15(G), 25(G), 27(G) 27
Soldanella alpina L. 25(G), 27(G), 37 47, 159
S. carpatica Vierh. 22(G), 23(G) 47
S. hungarica Simk. 22(G), 23(G) 47
S. montana Mikan. 22(G), 23(G), 25(G), 27(G), 37 47

S. reticulatag 25(G), 27(G), 37 47

S. pusilla Baumg. 22(G), 23(G) 47
Samoleae
Samolus valerandi L. 25(G), 27(G), 35, 37 47, 159
a The letters G and A in parentheses signify occurrence as a glycoside and the aglycone, respectively. No letter in
parentheses implies that the compound will occur only as the aglycone, with exception of the anthocyanidins 33–40 that
all occur as glycosides (anthocyanins). All compounds have been isolated from aerial parts (leaves, stems, and/or flowers).
b Leucoanthocyanins, such as leucocyanidin and leucodelphinidin, are present in nearly all species investigated of this
genus.47
c Synonyms are given in parentheses and are in accordance with those recorded by Richards 5 and/or in Flora Europaea.212
d Contains glycoflavones of unknown structures.47
e Primula beesiana and P. bulleyana are similar in structure and are sometimes treated as one species. Richards 5 classify
them as subspecies.
f Richards5 treats Primula chionantha and P. sinopurpurea more or less as one species.
g The authority for the species investigated is not given in the reference(s).
h Contains also dihydroflavonols, such as dihydrokaempferol. 47
accumulation as a consequence of glandulotropic or epidermal excretion. Flavonoid aglycones are,

therefore, often encountered in and on glandular trichomes as in, for example, Primula, in bud
excretions, in thin epicuticular layers on leaves, in leaf wax, or in leaf resins in contrast to the
tissue flavonoids that are in Primulaceae water soluble flavonol glycosides and more rarely flavone
glycosides (Table 14.1). In the Primulaceae, the glycoside part of the flavonoids, consists normally
of one to three sugars and is often linked in the 3-position and more rarely in the 7-position of the
flavonol aglycones (Table 14.1 and Figure 14.2). The most common sugars detected are glucose,
galactose, rhamnose, and arabinose. In the present survey of the tissue, flavonoids in the Primulaceae
will only be focused on the distribution of the aglycone because it may have sensitizing properties
(see Section 14.3.1) and because the glycoside part and position on the aglycone in many chemical
investigations have not been determined.
It is striking that none of the exudate flavones of the Primula species, except for one, exhibit
7-O-substitution and nine do not exhibit 5-O-substitution either which are substitution patterns that
characterize the tissue flavonoids in the genus (Table 14.1 and Figure 14.2). The flavonoids found
in Primula are mostly glycosides based on the flavone 15 and flavonol glycosides based on
kaempferol (25) and quercetin (27). Sometimes, the flavonoids also are based on herbacetin (30)
and gossypetin (32) and, more rarely, isorhamnetin (26), myricetin (29), and limocitrin (31). The
plant tissue flavonoids found in Primula, thus are primarily well-known polyoxygenated flavonols
widely distributed in many other plant families,41,42 whereas the exudate flavones normally have a
remarkably low degree of oxygenation with an unusual substitution pattern. The glandular cells,
therefore, seem to have their own particular biosynthetic pathway and one might suggest that the
biosynthesis of exudate flavones, in general, follow another biosynthetic route than the tissue
flavonoids. The leaf flavonoids found in Dionysia are flavonol glycosides based on kaempferol
(25), quercetin (27), and gossypetin (32), and flavone glycosides based on 15. Glycosides of
kaempferol and quercetin also seem to be common constituents of other Primuleae genera, for
example, Androsace, Coris, Dodecatheon, and Soldanella, whereas glycosides of 15 seem to be
less common although they have been found in the genera Cortusa, Dodecatheon, Dionysia, and
Primula (Table 14.1). The genus Soldanella differs to some extent from the other genera of
Primuleae owing to the regular occurrence of tissue flavone glycosides based on apigenin (22) and

FIGURE 14.2 Chemical structures of flavonoid aglycones (1–9) from the Primulaceae occurring as glycosides
or free aglycones.
luteolin (23). These compounds have so far not been isolated from other species within Primulaceae,
although the aglycones have been isolated from Primula veris L. (Table 14.1).
The tissue flavonoids in the tribe Cyclamineae are based on the well-known flavonols
kaempferol (25) and quercetin (27) that also seem to be the case for the tribes Samoleae and
Corideae, although a di-C-glucoflavone (24, vicenin-2) has been isolated from the latter tribe. C-
Glycosylflavonoids are widely distributed in the plant kingdom43 but have only been detected in
Coris monspeliensis L., Lysimachia christinae Hance var. typica Knuth (24), and two Steironema
species (structures of C-glucoflavones not determined) within Primulaceae (Table 14.1). The fla-
vonol glycosides in the tribe Lysimachieae, in addition to kaempferol and quercetin, also are based
on myricetin (29) and sometimes also on isorhamnetin (26) and syringetin (28) (Table 14.1).
Members of Cyclamineae, Corideae, Lysimachieae, and Samoleae are, in general, not characterized
by farinose coating and they seem not to produce low oxygenated flavones (Table 14.1).
The genus Primula also shows a rich variation in anthocyanins (flower pigments). The antho-
cyanin hirsutin (hirsutidin (40) 3,5-diglucoside) is the most common anthocyanin found in Primula
and it also occur regularly in Dionysia (Table 14.1). Anthocyanins based on the anthocyanidins
cyanidin (35), delphinidin (37), and malvidin (38) are also common pigments in Primula and
especially cyanidin and delphinidin appear to be widely distributed in the subtribe Primuleae. More
rare in Primuleae are the anthocyanins based on pelargonidin (33), peonidin (34), petunidin (36),
and rosinidin (39) (Table 14.1 and Figure 14.2). The tribe Cyclamineae is characterized by antho-
cyanins exclusively based on malvidin, whereas in the tribe Lysimachieae, pigments based on
malvidin, cyanidin, and delphinidin are regularly found (Table 14.1). From the tribe Samoleae,
anthocyanins based on cyanidin and delphinidin have been isolated, whereas the small tribe
Corideae so far has not been investigated for anthocyanins. The anthocyanins found in Primulaceae
are widely distributed in the plant kingdom except for those based on rosinidin.44,45
Leucoanthocyanins, which are widely distributed in nature, also are shown to be present
throughout the Primulaceae, although the genus Soldanella do not seem to contain these compounds

FIGURE 14.2 (continued) Chemical structures of flavonoid aglycones (10–18) from the Primulaceae occur-
ring as glycosides or free aglycones.
(Table 14.1). Nearly all leucoanthocyanins present in Primulaceae yield cyanidin or delphinidin
upon acid treatment, indicating that the majority of leucoanthocyanins are based on the flavan-3,4-
diols leucocyanidin and leucodelphinidin.46,47
14.2.2 QUINONES AND PHENOLS

Many species within the genus Primula especially, have roots that give a characteristic odor when
they are dried or injured.16,17 Primula species may be divided into four groups according to the
odor of the roots. In the first group, the odors resemble that of anise, in the second, that of methyl
salicylate, and in the third group, the disagreeable odor of bed bugs is observed. Finally, in the
fourth group, the roots have no odor.16,17 The odors are due to volatile phenolic compounds that
are produced from simple phenolic glycosides by hydrolysis when the roots are injured. In spite
of these characteristic features of Primula roots, only a few species have been investigated chem-
ically for phenolic glycosides. From the roots of Primula vulgaris Hudson, Goris et al.48 isolated
several phenol aglycones, including methylsalicylate (53), 5-methoxymethylsalicylate (54), 4-meth-
oxymethylsalicylate (55), 2-hydroxy-5-methoxyacetophenone (56), 2-hydroxy-4-methoxyace-
tophenone (equal to paeonol, 57) and the yellow 3-nitro-5-methoxymethylsalicylate (58), but they

did not identify the glycoside part. However, previous investigations of the roots of P. vulgaris have
shown that 54 and 55 are present as the glycosides primulaverin and primverin, respectively, both
having the disaccharide primeverose (6-O-b-D-xylopyranosyl-D-glucose) linked in the 2-position.49
Primulaverin and primverin have also been isolated from P. elatior (L.) Hill, P. X kewensis Hort.,
and P. veris L. (Table 14.2). A further glycoside has been isolated from the roots of P. auricula L.
that has been shown to consist of paeonol (57) and primeverose.50 The phenolic glycosides found
in the roots of Primula species have so far only been found in this genus, with the exception of
the aglycone paeonol, that has, for example, also been isolated from Bathya meridionalis (Rubi-
aceae)51 and Cyanchum paniculatum (Asclepiadaceae).52
Many Primula species produce farinose coating on leaves and stems and in the majority of
cases this coating constitutes low oxygenated flavones, as mentioned in Section 14.2.1. However,
P. obconica Hance lacks meal. Instead, its glandular hairs produce simple phenols (43–49) and
quinones (41, 42) of which primin (41) and miconidin (43) are the major constituents (Figure
14.3).53-55 Primin, the major allergen in P. obconica, has also been isolated from the aerial parts of
P. elatior (L.) Hill subsp. elatior and preliminary investigations of several species of the Primulaceae
family by TLC and Craven’s test have indicated the presence of primin in 15 Primula species and
in Androsace hirtella Dufour, Dionysia aretiodes (Lehm.) Boiss., and Glaux maritima L. (Table
14.2).56 Primin has also been isolated from the black rock seaurchin, Paracentrotus lividus Lam.,57


TABLE 14.2
Distribution of Quinones and Phenols in the Primulaceae
Genus/Species Quinones/Phenolsa Reference
Androsace hirtella Dufour 41b 56

Dionysia aretioides (Lehm.) Boiss. 41b 56
Glaux maritima L. 41b 56
Lysimachia japonica Thunb. 50–52 62–64
Primula apennina Widmer 41b 56
P. alpicola (Smith) Stapf var. alba Smith 41b 56
P. auricula L. 57(G)c 50
P. denticulata J. E. Smith 41b 56
P. elatior (L.) Hill 54(G)c 49
P. elatior subsp. elatior 41 56
P. hirsuta All. (syn. P. rubra Gmel.)d 41b 56
P. · kewensis Hort. 55(G)c 49
P. kitaibeliana Schott (syn. P. integrifolia Vis.)d 41b 56
P. latifolia Lapeyr. var. cynoglossifolia Widmer 41b,c 56
P. malacoides Franchet 41b 56
P. minima L. 41b 56
P. muscarioides Hemsley (syn. P. tsarongensis Balf.f. & Forrest)d 41b 56
P. obconica Hancee 41–49 53–56, 85, 86, 186, 187
P. praenitens Ker-Gawl.e 41b 56
P. · pruhoniciana Hort. 41b 56
P. rosea Roylee 41b 56
P. spectabilis Tratt. 41b 56
P. veris L.e 41, 54(G),c 55(G)c 49, 185
P. veris subsp. veris 41b 56
P. vulgaris Hudsone 53(G)c–58(G)c 17, 48, 49
P. vulgaris subsp. vulgaris 41b 56
a Compounds detected or isolated from aerial parts (leaves, stems, and/or flowers) unless otherwise noted. The letter G
in parentheses signifies occurrence as a glycoside.
b The presence of primin (41) was only verified by TLC and Craven’s test.
c Compound(s) isolated from roots.
d Synonyms are given in parentheses and are given according to Richards. 5
e For the synonym, see Table 14.1.
and from Miconia species (Melastomaceae) that also contain miconidin.58-60 Other quinoid com-
pounds of unknown structures have been detected, furthermore, in 48 other species of the Primu-
laceae by using TLC and Craven’s test.56 The majority of these compounds are most likely flavonoid
hydroquinones such as primetin (10) because they occur regularly in Primulaceae (see Section
14.2.1 and Table 14.1) and are positive in Craven’s test.61 From Lysimachia japonica Thunb.,
salicylic acid (52) has been isolated together with two cytotoxic resorcinol derivatives (50, 51).62-64
Cytotoxic activity also has been demonstrated for primin and miconidin.58-60
14.2.3 SAPONINS AND OTHER TRITERPENES

Triterpenes appear to be common constituents of the Primulaceae, although only a few members
of this family have been investigated for these compounds (Table 14.3). The majority of triterpenes
found in Primulaceae are saponins. The term saponin is applied to a group of natural products that
have in common the property of foaming when shaken with water. Chemically, the saponins are

FIGURE 14.3 Chemical structures of quinones (41, 42) and phenols (43–58) isolated from Primulaceae.
glycosides that yield on hydrolysis, one or more sugar units and sugarfree aglycones commonly
referred to as sapogenins. Triterpenoid saponins as, for example, those found in Primulaceae are
widely distributed in the plant kingdom and constitute the majority of the naturally occurring
saponins.65-67 Most of these triterpenoid saponins differ only in the numbers and the type of the
carbohydrate moiety linked to the particular sapogenin. In the majority of chemical investigations
of the saponins from the Primulaceae they have been hydrolysed to sugars and the respective
aglycones and identified separately. The hydrolysis of saponins is normally achieved with 2–6 N
HCl, although other methods have been used such as enzymatic hydrolysis.65-67 However, as the
acid hydrolysis of saponins often initiate rearrangements or chemical breakdown of the sapogenins,

owing to the rather drastic reaction conditions, some sapogenins isolated from, for example, the
Primulaceae species are artifacts,65,67 and thus are not described in the present survey. Furthermore,
we will be focused primarily on the distribution of different sapogenins in the Primulaceae and not
saponins, although the total structure of several saponins from this family have been elucidated
more recently, particularly owing to improved spectroscopic methods. The triterpenoid sapogenins
most frequently detected in the Primulaceae are pentacyclic triterpenes of the b-amyrin group and
the most common sugars in the glycosid part of the saponins are the hexoses glucose, galactose,
glucoronic acid, rhamnose, and the pentoses arabinose and xylose.65-67 The sugars are often linked
in the 3-position of the sapogenin as an oligosaccharide consisting of three or more sugars
(Figure 14.4).
Saponins containing the sapogenins protoprimulagenin A (59) and cyclamiretin A (72) are
widely distributed in the genus Cyclamen. Other sapogenins isolated from this genus are 66, 74,
78, and 81 (Table 14.3 and Figure 14.4). In the tribe Lysimachieae, saponins have been isolated
from the genera Anagallis and Lysimachia. The sapogenins isolated from Lysimachia are protoprim-
ulagenin A (59), priverogenin B (61), aegicerin (65), and dihydropriverogenin A (79), the former
being present in all species investigated (Table 14.3). From Anagallis, comprising only one inves-
tigated species, A. arvensis L., different types of triterpenes have been isolated including the
sapogenins 60–63, 67–69, and 71,6,8,68-71 and closely related nonglycosylated oleanane triterpenes
64, 68, and 70 (Figure 14.4).72,73 A special type of triterpenes isolated from A. arvensis are the
nonglycosylated cucurbitacins 86, 88, 90, and 93–95 and the related glucosides 87, 89, 91, and 92
(Figure 14.4).74-76 Cucurbitacin triterpenoids are well-known as bitter principles in plants of the
Cucurbitaceae and Cruciferae, and have also received attention owing to their antitumor activity
and other biological activities.77-80 The presence of these compounds in A. arvensis could be of
chemotaxonomic as well as pharmacological interest.
The tribe Primuleae is characterized by the regular occurrence of protoprimulagenin A and
related sapogenins (e.g., 60, 61, 65, 68, 72, and 73) (Table 14.3). Primula rosea Royle differs from
the other investigated species of this tribe due to the presence of pentacyclic triterpenes of the
epoxy serratane type (83–85) including one saponin yielding 82 and the sugars glucose, galactose,
and rhamnose upon acid hydrolysis.81,82
14.3 CLINICAL EFFECTS

14.3.1 ALLERGENIC PRINCIPLES
Primin (41) is a very strong contact sensitizer and is considered to be responsible for most cases
of primula dermatitis. The allergen was first isolated by Nestler83 in 1904 from Primula obconica
Hance and 23 years later Bloch and Karrer named it primin.84 The chemical structure of primin
was, however, first elucidated by Schildknecht and co-workers in 1967 who characterized it as
2-methoxy-6-pentyl-1,4-benzoquinone by different spectroscopic methods and synthesis.85,86
The presence of a second allergen in P. obconica has been described by Cairns,87 who found
two components in the plant that caused positive patch reactions. Hausen56,88 has suggested that
the second allergen of Cairns is a quinhydrone (Figure 14.5), formed during extraction and isolation
procedures that might cross-react with primin. However, in a recent investigation of P. obconica
the presence of a quinhydrone could not be verified, instead equal amounts of primin and its
biosynthetic precursor miconidin (43) were isolated from unchopped plant material (aerial parts).53
Horper and Marner,54,55 confirmed these results and found in addition, several minor phenolic
constituents (42, 44–49). The sensitizing properties of miconidin, however, are not known. Primin
and miconidin are to some extent structurally related to the allergenic geranylbenzoquinone and
geranylhydroquinone that occur regularly in Phacelia species (Hydrophyllaceae).89-93 Geranylben-
zoquinone, like many other quinones, is a very potent allergen. It is about 30 times stronger than
the corresponding geranylhydroquinone that is also a powerful allergen.89,90,92 This is consistent

TABLE 14.3
Distribution of Sapogenins (Saponins) and Other Triterpenes in the Primulaceae
Tribe/Genus/Species Triterpenes Isolateda References
Cyclamineae
Cyclamen africanum Boiss. & Reut. 59(G),b 72(G) 188
C. balearicum Willk. 59(G),b 72(G) 188
C. cilicicum Boiss. & Held. 59(G),b 72(G) 188
C. coum Mill. 72(G), 74(G), 81(G) 189
C. coum subsp. coum 59(G)b, 72(G) 188
C. creticum Hildebr. 59(G),b 72(G) 188
C. cyprium Schott & Kotschy 59(G),b 72(G) 188
C. graecum Link 59(G),b 72(G) 188, 190
C. mirabile Hildebr. 59(G), 72(G), 74(G), 78(G) 188, 191
C. neapolitanum Ten.c 59(G),b 72(G) 188, 190
C. persicum Mill. 59(G),b 72(G) 188
C. pseudibericum Hildebr. 59(G),b 72(G) 188
C. purpurascens Mill.c 59(G),b 66(G),d 72(G) 188, 190, 192–194
C. repandum Sibth. & Smith 59(G),b 72(G) 188
C. repandum var. rhodense Meikle 59(G),b 72(G) 188
Lysimachieae
Anagallis arvensis L. 60(G)e 63(G),e 64,e 67(G),e 68(A, G),e 6, 8, 68-76, 160
69(G),e 70,e 71(G),e 86e 95,e
Lysimachia clethroides Duby 59(G),b 65(G),d 79(G)d 195, 196
L. japonica Thunb. 59(G),f 64, 196
L. mauritiana Lam. 61(G), 79(G)d 195, 196
L. sikokiana (L.) Miquel 59(G)e 197
Primuleae
Androsace rotundifolia var. hazaricag 59(G)b,e 198
Androsace saxifragifoliag 72(G), 73(G),e,f 199-201
Primula denticulata J. E. Smith 72(G)e 202, 203
P. elatior (L.) Hill 59(G), 77(G)d 204-206
P. elatior subsp. meyeri (Rupr.) Valentine & Lamond 59(G) 207
P. japonica A. Gray 59(G),b 79(G) 195, 196
P. rosea Roylec 82(G),e 83e 85e 81, 82
P. sieboldii Morren 59(G), 65(G)d 195, 196, 208
P. macrophylla D. Don. 75(G)e 209
P. veris L.c 59(G),b 60(G), 61(G),d 80(G) 16, 195, 210, 211
P. veris subsp. macrocalyx (Bunge) Ludi 60(G), 61(G), 68(G) 207
P. vulgaris Hudsonc 59(G)b 16, 210
a Compounds have been isolated from roots unless otherwise noted and the letter G in parentheses signifies occurrence
as a glycoside (saponin). Sapogenins obtained after acid hydrolysis of saponins and that are known to be artifacts are
not included in Table 14.3, unless it is uncertain whether they are artifacts or not.
b Primulagenin A (76) was isolated after acid hydrolysis of saponins and is likely to be an artifact. The original sapogenin
is more likely to be protoprimulagenin A (59).

c For synonym(s), see Table 14.1.
d Sapogenin obtained after acid hydrolysis and/or periodate oxidation of saponins and could be an artifact.
e Compound(s) isolated from aerial parts and/or whole plants.
f Common phytosterols (e.g., b-sitosterol) have also been isolated.
g No authority for the species investigated has been given in the reference(s).

FIGURE 14.4 Chemical structures of sapogenins and other triterpenes (59–80) isolated from members of
Primulaceae.

FIGURE 14.4 (continued) Chemical structures of sapogenins and other triterpenes (81–95) isolated from
members of Primulaceae.
FIGURE 14.5 Chemical structure of a quinhydrone postulated to be present in Primula obconica.
with the theory that phenolic contact allergens require oxidation to a quinone that can then bind
covalently to a protein nucleophile generating an antigenic complex (Figure 14.6).94,95 It is, therefore,
very likely that miconidin that easily can be oxidized to primin in vivo is allergenic, and, if so,
cross-reactivity between miconidin and primin will be expected. Furthermore, if miconidin has
sensitizing properties, it may be the second allergen of Cairns.

FIGURE 14.6 Possible mechanism for a nucleophilic addition (Michael addition) of a skin protein on primin
(hapten) forming a protein-hapten complex (antigen). Arrow (fi ) indicates a further active site on primin
suitable for nucleophilic attack.
The reactivity of primin towards proteins lies in the electrophilic properties of the quinoid
structure (Figure 14.6). Besides primin, many other naturally occurring benzo- and naphthoquinones
have shown to be strong sensitizers, in accordance with their reactivity toward skin proteins.95
Structure-activity relationships in allergic contact dermatitis with different derivatives of primin
have shown that the sensitizing capacity of naturally occurring quinones depends not only on the
quinoid structure but also on the position, configuration, and the length of their side chains.96-100
For example, increases in the sensitizing potency of primin analogues with increasing length of
the alkyl side chain from C1 to C10 reaches a maximum at 11 and 12 C-atoms. On further elongation,
the sensitizing potency decreases beyond C13, reaching sensitizing values that finally are comparable
with those obtained from primin analogues with 1 to 3 C-atoms.99,100 Similar structure-activity
relationships have been found with ortho-hydroquinones (catechols) chemically related to urushiol,
the active principle of, for example, poison ivy (Toxicodendron radicans, Anacadiaceae)101-104 and
prenylated phenols from the Phacelia species,89-93 although hydroquinones first have to be oxidized
to the corresponding quinones in order to gain sensitizing activity. Other studies with primin and
related quinones have shown that optimal sensitizing reactivity occur when the alkyl chain in the
6-position is opposite to the methoxy group in the 2-position (Figure 14.3).96,97 Substitution in the
5-position clearly diminishes the reactivity that indicates that the position of the side chains in the
quinones are of importance for sensitizing activity.96,97 Also, the number of substituents in the ring
has a great influence on the sensitizing activity of quinones owing to steric hindrance and because
the number of active sites are reduced with increasing numbers of substituents.105 Finally, it has
been shown that quinones with a cyclic configurated side chain have a lower sensitizing activity
than quinones having an alkyl side chain. For example, primin has a much stronger sensitizing
effect in guinea pigs than the allergenic dalbergiones [e.g., R-5,6-dimethoxy-2-(1¢-phenylallyl)-1,4-
benzoquinone (equal to R-3,4-dimethoxydalbergione)] that are quinones with almost the same
quinoid structure as primin but with side chains of 9 to 10 carbon atoms in cyclic configuration.98
The dihydroxyflavone primetin (10), found in several Primula species (Table 14.1) has been
shown to possess strong contact sensitizing properties as demonstrated in some experiments with

guinea pigs.61 Primetin is, therefore, most likely the contact sensitizer in Primula mistassinica
Michaux, a plant that have been responsible for some cases of allergic contact dermatitis.106 The
sensitizing properties of primetin probably are owing to its uncommon 5,8-arrangement of hydroxy
groups that easily can be oxidized in vitro or on the skin to the corresponding quinone (primet-
inquinone). Primetinquinone also has been shown to possess strong sensitizing properties and cross-
reaction between primetin and primetinquinone have been demonstrated.61 Flavonoids thus appear
to be another class of metabolites that in some cases are contact sensitizers. This has been confirmed
in a study performed by Schmalle et al.,107 who showed that flavonoids that can be transformed
either chemically, photochemically, or enzymatically in the skin to reactive para-quinones, ortho-
quinones, or quinone methides are likely to be strong sensitizers. However, flavonoids which cannot
bind covalently to the receptor protein also may have sensitizing properties owing to hydrogen
bonds and/or nonpolar hydrophobic interactions with the receptor.107 For example, in flavone (1)
the phenyl ring may interact with ring systems of amino acids like tyrosine and phenylalanine of
the receptor protein explaining the weak sensitizing properties of this compound.107 Thus, flavones
such as 2, 3, 5, 8, and 16, and the chalcone 20a (Figure 14.2) also may have sensitizing properties
owing to the presence of an unsubstituted phenyl ring, hydroxy hydrogens, and/or methoxy groups
that may interact with the receptor. Similarly to primetin, many other flavonoids in Primulaceae
can be oxidized to their corresponding para-quinones (e.g., 11–13, 30, and 32, Figure 14.2) and
thus are potentially strong contact sensitizers. However, flavonoids that could plausibly be oxidized
to ortho-quinones such as, for example, luteolin (23) and quercetin (27) seem only to have weak
or no sensitizing activity.107 Because many of the low oxygenated flavones that are mainly present
in the genus Primula, are situated on the outside of the plant, people can easily come into contact
with these compounds and it is, therefore, not unreasonable to assume that some of them may be
responsible for cases of contact dermatitis.
The active principles in medical plants from the Primulaceae are often associated with biological
active saponins and triterpene aglycones that are also known to have irritant effects.9,97 The irritant
properties of species from Primulaceae could, therefore, be owing to the presence of saponins that
are found in both roots and aerial parts of the plants (Table 14.3).
14.3.2 CONTACT DERMATITIS TO PRIMULACEAE PLANTS

14.3.2.1 Primula dermatitis (Primula obconica Hance)
Primula dermatitis is caused nearly always by Primula obconica, although case reports of dermatitis
or skin irritating effects from other Primula have been reported (Table 14.4 and Section 14.3.2.2).
After the introduction of P. obconica into England from China in 1880, the plant rapidly became
established as a popular ornamental plant throughout Europe and the United States. Very soon after
case reports of dermatitis appeared and it became clear that P. obconica was a highly sensitizing
plant.9,108-119 The sensitizing properties of P. obconica are probably due to the accessibility of the
allergen primin on the surface of the plant.56,83,88,97,120,121 The allergen is formed in minute glandular
hairs consisting of three to five cells. The allergen accumulates between the cuticula and the cell
membrane of the outmost cell. When the cuticula burst, the concentrated allergen accumulates as
irregular resinous drops on the top and sides of the hair. Primula obconica has, similar to many
other Primula species, visible long hairs (1–3 mm) (see also Sections 14.1.2 and 14.1.2.1). However,
these hairs do not contain primin, and an impression of hairiness does not give any indication of
the site of the allergen.56,83,88,97,121 For example, the petiole appears (leaf stem) very hairy but contains
less primin than the other organs. The highest concentrations of primin is normally found on the
calyx and decreases in the following order: pedicel (flower stalk), carpel, leaves, petiole, and
inflorescent stem.56,83,88,97,121
The amount of allergen formed in P. obconica varies considerably, depending on the season,
photoperiod, cultivation practice, and the horticultural variety.9,97,121,122 The primin content is, for

TABLE 14.4
Species within Primulaceae Known or Reported to Cause a Clinical Effect (See Also
Section 14.3.2)
Species Common Name(s) Clinical Effects References
Anagallis arvensis L. Scarlet pimpernel Irritant properties; leaves and 9, 56, 88, 148
flowers can cause dermatitis
Cortusa matthioli L. Alpine bells Frequently produces irritant 9, 56, 149, 150
patch test reactions and can
cause allergic contact
dermatitis
Cyclamen persicum Miller Sowbread Dermatitis described 9, 56, 88
Lysimachia nummularia L. Creeping Jenny or Dermatitis described 56, 88
Moneywort
Primula auricula L. Bear’s-ear Contact dermatitis described 88
P. cortusoides L. Mild skin irritant effect and can 9, 83, 123
produce irritant patch test
reactions
P. denticulata J. E. Smith Drumstick primula Dermatitis observed 56
P. elatior (L.) Hill Oxlip Can cause allergic contact 56, 145
subsp. elatior dermatitis
P. farinosa L. Bird’s-eye primrose Dermatitis described 9, 56, 106
P. japonica A. Gray Japanese primrose May cause dermatitis 56, 88
P. malacoides Franchet Fairy primrose Can produce irritant patch test 9, 83, 123, 126, 137
reactions and cause allergic
contact dermatitis
P. mistassinica Michaux Causes allergic contact 56, 61, 106
dermatitis; allergen identified
as primitin (10)
P. obconica Hance Poison primrose Causes frequently allergic e.g. 9, 56, 108–121,
(syn. P. poculiformis Hook.f) contact dermatitis; allergen 123–130, 137–148,
identified as primin (41) and 151–154
probably more are present
P. praenitens Ker-Gawl. Chinese primrose Potential irritant by patch test 9, 56, 123, 142–144
(= P. sinensis Sabine ex Lindley) and can cause allergic contact
dermatitis
P. sieboldii Morren Skin irritant properties 9, 83
P. veris L. Cowslip Allergic contact dermatitis 9, 146
(syn. P. officinalis (L.) Hill) described
P. veris subsp. columnae (Ten.) Dermatitis described 9, 88
Ludi (syn. P. suaveolens Bertol.)
P. veris subsp. veris Dermatitis described 56, 147
example, highest during a warm summer and lowest during the winter when a plant may give
negative patch test reactions in a primin sensitive person. Because of the commercial importance,
many new varieties has been produced by selection, hybridization, and mutations.5,10,13-15 Most of
the new varieties of P. obconica have the same density of glandular hairs where the allergen is
formed. However, some varieties produces less allergen than others and there have also been reports
of some P. obconica varieties that do not produces primin (see Section 14.1.2.1).13-15 However,
Fregert and Hjorth120 have been able to detect primin in P. obconica Reizfrei that should be free
of primin. It is, therefore, advisable to test so-called primin-free cultivars carefully before intro-
duction to the market because they still may produce small amounts of primin. This may be the

case, particularly, under growing conditions different from those where the plants were tested to
be negative.
Contact with a P. obconica always bears the risk of sensitization. For example, the removal of
dead flowers from the plant involves immediate contact with the most allergenic parts of the plant,
the calyx and the pedicel. This is probably how most people (housewiwes, nurserymen, and florists)
become sensitized.9,97,123,124 Due to the normally low allergen content in the winter or early spring,
only weak signs of sensitization may occur and when the allergen content increases during summer
a widespread dermatitis may develop by a mere touch of the leaves. Indirect contact with P. obconica
via, for example, door handles or handshakes can elicit an allergic reaction in very sensitized
patients as well. Finally, small plant parts or dust particles containing primin can be released from
P. obconica plants resulting in airborne contact dermatitis,125 whereas direct emission of primin is
not likely to elicit an allergic reaction.9,97 Although primin sublimes at 110°C, the vapor concen-
tration in the air would be insufficient to provoke an allergic reaction even in an extremely sensitized
person.97
Primula dermatitis has a variable clinical picture that is often misdiagnosed because patients
normally do not present a typical picture of plant dermatitis with blotches and linear strikes on the
skin.122,123,126-131 The degree of sensitivity and the intensity of exposure determine the pattern of
dermatitis. The main pattern of primula dermatitis is facial dermatitis, alone or in combination with
limb or hand dermatitis.9,97,122-124,126-131 Also, arm and forearm dermatitis may occur in combination
with facial dermatitis. Hand, arm, and forearm dermatitis may also occur alone.9,97,123,124,128,129,131 A
disseminated dermatitis is sometimes observed in highly sensitive patients.9,97,123,131 A characteristic
feature of hand dermatitis is dermatitis of the fingertips sometimes with vesicular eruptions (blisters)
on the sides of the fingers that occurs as a consequence of patients picking off the dead flower
petals.9,97,123,128 Hand dermatitis may also have a patchy nondescriptive appearance sometimes with
vescular eruption of the hand. More rarely a typical clinical appearance of a plant contact dermatitis
with streaks is observed.9,97,123,128 The clinical appearance of primula dermatitis observed on the
arms and forearms are almost the same as with hand dermatitis with blotches, linear strikes, and
vescular eruption (Figure 14.7).9,97,123,128 Hand, arms and/or forearms dermatitis is sometimes spread
to the face. The sites affected with facial dermatitis are often the cheeks and the chin, the eyelids,
the area around the mouth, and, more rarely, the ears and tongue.9,97,123,128 In mild cases, the affected
areas of the face often itch, burn, and appear red and swollen (often the eyelids and lips) whereas
in more severe cases when, for example, the diagnosis is overlooked, and the patients continue to
handle the plants, the eruption may become very extensive and the face strongly edematous.9,97,123,130
Strongly edematous reactions may also occur on the hands, arms, and forearms and are not
infrequent.124,126,129 Patients with primula dermatitis recover completely within a period of time if
they avoid contact with P. obconica and treatment should, therefore, be based on the avoidance of
the plant.124,127,128
Primula obconica and other primulas may also cause Type I allergy, with conjunctivitis, keratitis
and iritis as the most common reactions.132,133 Based on the few reports on immediate allergic
reactions to Primula, it must be considered rare and of minor importance compared to the wide-
spread Type IV allergy.
Owing to the clinical variability of primula dermatitis in terms of site, morphology and severity,
contact dermatitis to P. obconica is easily overlooked. If primula dermatitis is suspected, the
identification of P. obconica as the offending plant is important and color pictures of P. obconica
should be available to help patients with the identification. Finally patch tests with synthetic primin
(0.01 percent in petrolatum) will often reveal the dermatitis and, consequently, synthetic primin
has now been included in the European standard series of patch tests.127 In the United States, primin
is, in general, not included in routine patch tests and that may also explain the lack of knowledge
on the prevalence of primula dermatitis in the United States.128 The use of synthetic primin for
patch testing instead of primula extracts or leaves of the plant is preferable for several reasons. For
example, the amount of allergen is standardized, and the risk for sensitizing patients is reduced as

FIGURE 14.7 An example of primula dermatitis on the forearm caused by Primula obconica. (Kindly
provided by Professor Klaus E. Andersen, Department of Dermatology, Odense University Hospital, Denmark.)
are both false negative and false positive irritant reactions (see Section 14.3.3). However, there
might be more than one allergen in P. obconica and, therefore, there is also a minimal risk for a
false negative reaction when using synthetic primin for patch testing.53,56,87,134 Dooms-Goossens et
al.134 have, for example, described two cases in which primula dermatitis would have been missed
if they only had relied on patch testing with synthetic primin instead of plant material or extracts.
Several investigations have shown that the frequency of positive patch tests with primula leaf or
primula extract in consecutively patch tested patients are higher (3.4 to 8.8 percent positive patch
tests)122,124 than those patch tested with 0.01 percent synthetic primin (0.3 to 1.8 percent positive
patch tests).127,129,134 These differences may be owing to a larger number of false positive irritant
reactions in the patch tests performed with extracts or plant material when compared to those
performed with primin (see Section 14.3.3). Furthermore, patch testing with synthetic primin in a
low concentration perhaps only gives positive results if the patient has developed an allergy to a
certain high level. So far, only one case of photoallergic contact dermatitis to P. obconica has been
described where only patch tests with synthetic primin in the presence of UV-A light gave a positive
reaction in a person with severe primula dermatitis.135 Although P. obconica is very popular in
Spain and Portugal, for example, positive patch tests to primin are rare.135 It is, therefore, possible
that many cases of primula dermatitis are overlooked, simply because they present with primula
photosensitivity. Therefore, one might suggest photopatch tests in patients with suspected primula
dermatitis who are negative in standard patch tests.
Primula dermatitis is seldom found among males. This is in accord with several major patch tests
studies with primin or P. obconica extracts showing that among patch test positive patients between
85–95 percent were females.9,97,122,124,126,129 Florists and nursery persons are commonly sensitized, but
the majority of cases of primula dermatitis are found among housewives. This also explains the few
number of males with primula allergy because it is still uncommon in most countries that males have
household duties. Primula dermatitis is not very common under the age of 30 but occur regularly
among middle age persons.9,97,124,127,129,131 However, in more recent investigations on the prevalence
of primula sensitivity in Northern Europe, there seems to have been an increase in the number of
sensitized persons in the group between 55–80 years and a decline in the number of sensitized persons
in the groups under the age of 40 when compared to previous investigations.127,129 This tendency could
be due to the fact that more women are working outside the home than before and, pressumably, they
have much less time for household duties such as taking care of flowers compared to older women.

Another explanation could be that older women have developed an allergy to a certain high level, a
process that may take several years. Thus, older women are more likely to give a positive reaction
with synthetic primin in a low concentration (0.01 percent).129 Younger patients may first show a
positive reaction if patch tested with a higher primin concentration (e.g., leaves and/or extracts) used
in some of the previous investigations.9,97,122,126
Primula obconica has long been known as a significant source of allergic contact dermatitis in
Europe, especially in England, Germany, and the Scandinavian countries, and, consequently, there
have been and still is some reluctance by breeding companies and nurseries, especially in Denmark,
to breed P. obconica. However, according to data from the Aasmeer flower market in Holland, the
production of P. obconica and other primulas, has not declained.124 So despite the sensitizing
capacity of P. obconica, it is still very popular in Europe and, therefore, a likely source for contact
dermatitis. In the United States, P. obconica is not considered a major source of contact dermatitis,
probably because the plant is less popular when compared with Europe and because cases of primula
dermatitis are not being correctly recognized, as mentioned earlier. In Japan, primula dermatitis
has increased in recent years but is still not very common, except in occupational cultivators.9,136–138
From Australia, a few cases of primula dermatitis have been described and it has been indicated
that many more cases are to be expected in the future owing to an increase in the production of P.
obconica.139,140
A few unrelated studies have shown that P. obconica may cross-react with rosewood (Dalbergia
species), teak, and other tropical woods that also contain quinones, the so-called dalbergiones.98,105
The structural relationship between these quinones and primin explains the possible cross-reactivity.
However, in a more recent study by de Corres et al.,141 the quinones R-3,4-dimethoxydalbergione
(from Machaerium scleroxylum Tul.—Pao ferro), deoxylapachol (from Tectona grandis L.—teak-
wood), and 9,10-phenanthene quinone (from the orchid species) were not able to elicit any positive
reaction when patch tested in 12 patients with contact dermatitis from P. obconica, results which
have been confirmed by Hausen’s own observations in more than 30 patients.141 Cross-reactivity
among quinones are regularly seen in guinea pigs, but the results of de Corres et al.141 indicate that
this may not be the case with humans. A possible explanation for the co-existence of positive
reactions to P. obconica and tropical woods may be due to simultaneous sensitization than to true
cross-reactivity.141 Further investigations is needed on this matter and it is, therefore, not advisable
for patients allergic to teak or rosewood, for example, to come in contact with Primula and vice
versa. Other quinone containing plant species should also be avoided. This includes certain members
of Bignoniaceae, Gesneriaceae, Hydrophyllaceae, and Orchidaceae owing to the risk of sensitization
and/or true cross-reactions.105
14.3.2.2 Dermatitis from Other Primulaceae Species
The presence of primin in other primulas than P. obconica may explain the few reports of dermatitis
and skin irritant properties of species such as P. praenitens Ker-Gawl. (equal to P. sinensis Sabine
ex Lindley), P. denticulata Smith, P. elatior (L.) Hill subsp. elatior, P. malacoides Franchet, P.
veris L., and P. veris subsp. veris (see Tables 14.2 and 14.4). The first reports on the skin irritating
properties of P. praenitens appeared around 1900.142,143 Later, Fregert and Hjorth144 showed that
the plant can produce irritant patch test reactions and is a potential irritant by patch test.144 P.
praenitens9,123 has also been shown to cause allergic contact dermatitis but only very rarely, and
the same goes for P. elatior subsp. elatior,56,145 P. veris,146 and P. veris subsp. veris.56,147 Primula
malacoides9,123 can produce irritant patch test reactions, but it has never been proven that the plant
can cause allergic contact dermatitis, although Richards5 claims that P. malacoides and P. praenitens
are more allergenic than P. obconica.
Contact dermatitis from Primula mistassinica Michaux where reported by Sharpe,106 who
described four cases of contact dermatitis on the hands in farm workers (milkers). The dermatitis
was attributed to handling the udders of cows that had grassed among the plants and, thereby, took

up the allergen on their udders later to be transmitted to the hands of the milkers. Sharpe identified
the inciminated primrose as Primula farinosa L. but Hausen et al.61 have shown that the P. farinosa
discussed by Sharpe was actually P. mistassinica. Furthermore, primetin (10) has been shown to
be the contact sensitizer of P. mistassinica and, therefore, the probable source of allergic contact
dermatitis in the four milkers.61 Primetin also has been shown to be present in the farinas of many
other Primula species (Table 14.1) and these species may, therefore, be considered as a potential
allergenic. Primetin could be responsible for the skin irritating properties of P. farinosa, P. dentic-
ulata, and P. malacoides (Table 14.4), although the two latter species most likely also contain
primin (Table 14.2).
Furthermore, it has been reported that Primula cortusoides L.83,123 and P. sieboldii Morren83
have skin irritant properties and that the former can produce irritant patch test reactions. So far
flavone (1) (Table 14.1) and triterpenes (59, 65) (Table 14.3) have been isolated from P. cortusoides
and P. sieboldii, respectively. Whether or not these compounds are responsible for the observed
reactions is not known.
Reports of contact dermatitis or skin irritant properties from other Primulaceae species than
Primula are few. Anagallis arvensis L., also better known as scarlet pimpernel, has long been used
in herbal medicine. The plant has irritant properties and often causes dermatitis in persons working
in fields and forests.9,148 About 6 percent of individuals are sensitive and develop dermatitis when
handling the leaves or flowers.9,148 Triterpenoids are present in relatively large amounts in A. arvensis
and could be responsible for the irritant and allergenic properties of this plant (see Section 14.2.3).
Cortusa matthioli L. frequently produces irritant patch test reactions and the plant can cause allergic
contact dermatitis.9,56,149,150 The sensitizing compounds are not known but could be flavonoids (Table
14.1) or unknown quinones.56 Finally, Cyclamen persicum Miller has been reported to produce
positive patch test reactions, but whether or not the plant may cause allergic contact dermatitis has
not been proven.9
14.3.3 PATCH TESTING

Several methods of standard patch testing for primula dermatitis have been used. They include
direct testing with leaves or extracts of P. obconica, 122-124,128,134,151-153 and synthetic
primin.127,129-131,154,155 Most substances included in standard patch tests are used in concentrations
adapted to minimize the risk of active sensitization or false negative and false positive reactions.
By using the leaves of P. obconica, the strength of the allergen varies beyond control, resulting
in false negative and false positive reactions if the concentrations of primin are too low or too high,
respectively. If the concentrations are too high, active sensitization may occur. This can be detected
either by flare-up reactions developed a week or later after the patch test or by conversion from a
negative to a positive reaction demonstrated by repeated testing.9,97,122 In view of the previously
mentioned reactions, the use of leaves for patch testing, for example, cannot be recommended.
The allergen content in extracts obviously also varies depending on the plant and the time of
season for preparing the extracts. Extracts may be prepared according to the method described by
Agrup et al.,152 implying extraction of unchopped plant material with ether, an extraction method
that has been shown to be useful for routine patch testing for primula dermatitis. The strength of
an extract may be determined by various chemical methods such as Craven’s156 or Brachtendorf’s157
tests that, however, only give a crude measure of the allergen concentration. In order to aviod false
negative, false positive, or sensitization by using extracts for patch testing, the exact allergen
concentration in the extracts should be known. It can easily be determined by gas chromatography
(GC) and/or gas chromatography–mass spectrometry (GC-MS).53,152 Investigation of the extract by
GC–MS may also reveal the presence of potential allergens other than primin (41), such as
miconidin (43).
Synthetic primin (Hermal-Trolab) is easily available and is included today in the European
standard patch test series.127 The use of synthetic primin for patch testing is preferable in most

cases because of the known and well-defined concentration. However, in rare cases patch testing
with synthetic primin may lead to false negative reactions probably because there is more than one
allergen present in P. obconica (Section 14.3.2.1). Fregert et al.154 have shown that primin sensitized
patients will show positive reactions in a concentration of 0.005 percent. A concentration of 1
percent causes primary irritant reactions that are also common at concentrations of 0.1 percent. A
concentration of 0.01 percent that is used in most standard patch test series, including the European,
can give rise to patch test sensitization but not to primary irritant reactions.
Patch tests (closed or open), are normally performed on the back of the patients. The reading
time for patch test reactions are usually performed after 48 h or 96 h, in which most primin sensitive
patients will show a reaction,129 although reading times beyond 4 days or more in some cases
increases the number of positive reactions when compared with 48 h or 96 h.131 If 0.01 percent
synthetic primin is used for patch testing, false negative reactions could probably be eliminated by
increasing the patch test concentration, but this is not advisable primarily owing to the risk of active
sensitization.
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210. Tschesche, R., Tjoa, B. T., and Wulff, G., Über Triterpene, XXI. Über die Sapogenine aus den Wurzeln
von Primula veris L., Liebigs Ann. Chem., 696, 160, 1966.
211. Tschesche, R., Tjoa, B. T., and Wulff, G., Über Triterpene XXIII. Über Struktur und Chemie der
Priverogenine, Tetrahedron Lett., 2, 183, 1968.
212. Tutin, T. G., Heywood, V. H., Burges, N. A., More, D. M., Valentine, D. H., Walters, S. M. and Webb,
D. A., Flora Europaea, Cambridge University Press, Cambridge, 1976.

15 Urticaceae
Javier Avalos
CONTENTS
15.1 Introduction
15.2 Botany and Classification
15.3 Genera of the Urticaceae of Biological Concern
15.3.1 Parietaria
15.3.1.1 Pollen of Parietaria
15.3.2 Urtica
15.3.2.1 Stinging Hairs
15.4 Chemistry of Urticaceae
15.4.1 Active Agents of the Parietaria
15.4.2 Active Compounds of Stinging Hairs
15.5.1 Allergenicity Due to Parietaria
15.5.2 Contact Urticaria to Urtica
15.5.2.1 Other Evaluations of Urtica Extracts
15.6 References
15.1 INTRODUCTION
The Urticaceae, a family of shrubs, lianas, herbs, or trees, has been responsible for many derma-
tologic reactions. The family is composed of approximately 550 species with 49 genera.1,2 Members
of this plant family can be found in temperate to tropical climates. The family is cosmopolitan in
distribution except for the frigid zones.1,2
Components of two of the species from this family have or are being considered for medicinal
purposes. In earlier times, urtication was practiced for the treatment of certain diseases and
consisted of beating the skin with Urtica nettles.1,3,4 Erythema and whealing are the usual response
in skin following contact with Urtica nettles. However, the skin would cease to react under fresh
contact after the third or fourth successive application of nettles. More recently, the roots or
extracts of the roots, that contain the superantigen Urtica dioica agglutinin (UDA), have been
reported to exert a number of pharmacologic activities such as the treatment of benign prostatic
hyperplasia or systemic lupus.5-8 Currently, the superantigen UDA is being used to explore the
mechanism by which T-cell activation occurs in its presence.5,9-11 In addition, allergens from
Parietaria pollen are being considered for specific immunotherapy for the purpose of therapeu-
tically controlling allergic diseases.12-15 However, the majority of the medical reports involve
either the urticaria reactions observed after exposure to Urtica species or allergic reactions to
Parietaria species.
Although the majority of the plants in Urticaceae are weeds, some members of this family are
still used for economic purposes. For example, the stinging nettles (Urtica species) constitute edible

and quite palable greens.2 Other economic uses of the Urticaceae are the generation of commercial
cordage fiber (ramie) obtained from Boehmeria nivea or Girardinia zeylanica.1,2 In addition, a few
Pilea species are grown as novelties and some Parietaria are used as ornamentals.2
15.2 BOTANY AND CLASSIFICATION

Plants in the Urticaceae family can be shrubs, lianas, herbs, or trees. The botany and classification
are fully described by Watson and Dallwitz,2 Shaw,16 and Allen.17 In general, plants are without
laticifers (usually) whereas in Urtica, the plants are with laticifers (non-articulated and unbranched).
These plants are mesophytic and self-supporting or climbing. Plants do not have basal or terminal
aggregations of leaves. Most of the plants in the Urticaceae are not heterophyllous, with the
exception of Urtica pilea which is obviously heterophyllous. The leaves can vary from small to
large and are alternate or opposite. When they alternate, the leaves spiral. Leaves are usually
petiolate or sessile and are nonsheathing. Lamina is usually on the entire leaf, but in rare occasions
is dissected. When dissected, it is palmatified and cross-venulated, either pinnately veined or
palmately veined. Leaves stipule in most cases. However, Parietaria exstipulate. Stipules are
interpetiolar or intrapetiolar and free of one another.
Anatomically, the stomata of the leaves are anomocytic or anisocytic. In addition, the leaves and
stems of the Urtica contain stinging hairs. Lamina is dorsiventral and cystoliths are usually present.
In general, the mesophyll contains mucilage cells. Minor leaf veins without phloem transfer cells
(four genera) can also be found. Young stems are often tetragonal. Secretory cavities, when present,
contain latex or mucilage. Cork cambium can be present either initially deep-seated and then
superficial. Nodes are tri-lacunar. An internal phloem is present and anomalous thickening also
develops from a single cambial ring in Myriocarpa. Secondary thickening developing from a con-
ventional cambial ring is usually present in this family. Xylem contains vessels, that are end-walls
simple. The wood can be storied or partially storied. Sieve-tube plastids are S-type without starch.
Plants are monoecious, or dioecious, or polygamomonoecious. The Urtica species are usually
dioecious that is to say, that plants have only male flowers or only female flowers. Female flowers
can have either staminodes (scalelike) or not. Gynoecium of male flowers is usually vestigial or
absent. Flowers are rarely solitary and can aggregated as inflorescences. The terminal inflorescence
unit is cymose. Inflorescence axillary is loose, glomerate, spiked, racemed, panicled, or capitate
cymes. The flowers often condense into heads or sometimes crowd on a common receptacle that
may be concave or convex. Flowers can also bracteate into small, regular (3-)4-5(-6) merous.
The fruit of this family can be fleshy in some members while in other members it is not. The
fruiting carpel (treated as monomeric) is indehiscent or drupaceous. Fruit, if recognized as syncar-
pous and indehiscent, is achene-like, a nut, or a drupe (rarely). When the fruit drupes, it will drupe
with one stone. Fruit contain one seed and the seeds are sometimes scantily endospermic. The
endosperm can be oily.
As to the physiology or biochemistry of members of this family, the family is not cyanogenic
and iridoids are not present. Alkaloids can also be found to be present. Within the Boehmeria,
anthroquinones have been detected.2 In general, several classes of compounds have been found in
members of this plant family. These are the proanthocyanidins and flavonols. When the proantho-
cyanidins are present, cyanidin is the compound identified. When the flavonols are present, quercetin
is commonly found. Sometimes, both kempferol and quercetin can be found. Ellagic acid has been
reported to be absent in eight species and five genera.2 In addition, arbutin was absent and aluminium
accumulation was not found.
Taxonomically, the Urticaceae are described as a family divided into subfamilies. The tribes
or subclasses identified are the Dicotyledonae, Malviflorae, and Hamanelidae. In all, 550 species
have been characterized in approximately 49 genera. The genera are Aboriella, Achudemia, Archi-
boehmeria, Astrothalamus, Australina, Boehmeria, Chamabainia, Cecropia, Cypholophus, Debre-
geasia, Dendrocnide, Didymodoxa, Discocnide, Droguetia, Elatostema, Fleurya, Forsskaolea,

Gesnouinia, Gibbsia, Girardinia, Gyrotaenia, Hesperocnide, Laportea, Lecanthus, Leucosyke,
Maoutia, Meniscogyne, Myriocarpa, Nanocnide, Neodistemon, Neraudia, Nothocnide, Obetia, Ore-
ocnide, Parietaria, Pellionia, Petelotiella, Phenax, Pilea, Pipturus, Poulzolzia, Procris, Rousselia,
Sarcochlamys, Sarcopilea, Soleirolia, Touchardia, Urera, and Urtica.
15.3 GENERA OF THE URTICACEAE OF BIOLOGICAL CONCERN

Within the family of Urticaceae, there are approximately 49 genera. Several of the genera have been
reported to cause urticarial or allergic reactions. The genera responsible for these biological reactions
are the Boehmeria, Cecropia, Dendrocnide, Fleurya (syn. Laportea), Girardinia, Gyrotaenia, Hes-
perocnide, Laportea, Nanocnide, Obetia, Parietaria, Scepocarpus (syn. Urera), Screptocnide (syn.
Laportea), Urera, and Urtica.1 The Boehmeria is a genus found in the tropical and northern subtropical
regions of the world. There are approximately 100 species in this genus. Like the Boehmeria, the
genus Cecropia also has 100 species within this genus. These species are native to the tropical region
of the Americas. Approximately 70 species of the Dendrocnide are found in the tropical and subtropical
regions of the world. In the Girardinia, eight species are native to tropical Africa, Madagascar, eastern
Asia and Indo Malaysia. The genus Gyrotaenia is found in the West Indies with only six species.
California and Hawaii have two native species of the Hesperocnide. The Laportea are distributed in
the tropical and subtropical regions and in temperate eastern Asia, northeastern America, southern
Africa, and Madagascar. This genus has about 23 species comprised of bushes and trees. Within
eastern Asia, four species of the Nanocnide are found while five species of the Obetia can be found
in tropical Africa and Madagascar. Another genus of wide distribution is Parietaria. There are 30
species located in temperate and tropical regions of the world. The genus Urera, composed of 35
species, is distributed in warm America, Hawaii, tropical and southern Africa, and Madagascar. Finally,
there are about 50 species of Urtica, that are found primarily in the north temperate regions, but a
few are found in the tropical and south temperate regions of the world.
15.3.1 PARIETARIA
Parietaria is a wind pollinated perennial weed. Members of this genus commonly grow in Italy,
Greece, Portugal, Spain, France, United Kingdom, and throughout southeastern and eastern
Europe.18-26 Species of the Parietaria have also been found in the United States27-29 and Australia.21,31
Parietaria has been reported in the United States for 180 years and in northern California in the
last century.26,27,32,33 Parietaria officinalis and P. judaica are the most common species in the
Mediterranean and Europe within the genus Parietaria. Other species are P. lusitanica, P. mauri-
tanica, and P. cretica.34 P. judaica along with P. floridana, and P. pensylvanica are distributed
widely in the United States.26,32,33 These plants are highly productive and anemophilous. The species
are characterized by numerous, grouped, individually small and drab, scentless florets. Typically,
Parietaria will grow wild and abundantly on walls, ruins, roadsides, and ditches. P. judaica is
thermophilic and heliophilic.25 In Europe, P. judaica will grow commonly in coastal Mediterranean
countries such as Spain, Italy, southern France, the former Yugoslavia, Albania, and Greece.18-25
The habitat for P. officinalis is distributed further in Spain, France, northern Italy, Austria, Bulgaria,
the Czech Republic, Romania, and southwestern regions of the former Soviet Union and in more
hilly or mountainous areas (under 1000 m in altitude) than P. judaica.18-25
15.3.1.1 Pollen of Parietaria
The pollen of P. judaica, P. officinalis, and P. lusitanica are very similar in size and appearance.26,27
When examined under a microscope, the pollen grains take an expanded spherical appearance
and are about 15 m in diameter (mean diameter 12–16 m).24,26 Factors that influence pollen output
have been described by D’Amato et al.24 These include temperature, humidity, and light intensity.
Size and shape of the pollen also favor wind pollination. Pollen output begins with the propulsion

(spring release) of the triporate pollen grains from the anther’s flexible filaments. Warm and dry
weather will open the anthers of Parietaria. The opening of anthers usually occurs during daylight
hours and can also be initiated by rapid changes in cloud coverage. Water withdrawal from the
anther endothelium will favor anther dehiscence that causes splitting of the anther and release of
pollen in clouds.
Aerobiological pollen surveys have delineated the pollen season for various plant families in
various geographical regions. The pollen season for Parietaria varies with climate and is associated
with the geographical location. In the United Kingdom, Parietaria flowers from June to September.35
Pollination occurs from April to September in northern Italy, southern France, and on the Medi-
terranean coast of Spain.18,19,21-25,36,37 In southern Italy, the pollination period is longer than northern
Italy. Pollination of Parietaria in southern Italy occurs from February through December.21,24,38,39
Peak pollination is between May and June in southern Italy.21 In the United States, pollination also
varies with climate. In northern California, pollination has been noted from late February through
December.27,32,40 Peak pollination occurs in May and June.27 Urticaceae pollen have been found in
July through October in the Tampa Bay, FL area.29 However, Parietaria (commonly known as
“pellitory”) has been found to flower from January to June.29 Because the pollination period of
Parietaria overlaps with the Urtica period and the pollen grains of Parietaria and Urtica cannot
be distinguished easily microscopically, the pollination period for these two species are often
referred to as Urticaceae pollen period.24,26-28,41
15.3.2 URTICA
The Urtica species is a cosmopolitan weed and is highly variable in size. These dark green plants
can grow from 30 to 150 cm high. As described in Section 15.2, most of the 50 species are found
in north temperate regions with a few in tropical and south temperate regions.1 The species most
noted for their stinging capabilities are the Urtica chamaedryoides, U. crenulata, U. dioica, U.
echinata, U. ferox, U. gracilis, U. holosericea, U. hyperborea, U. incisa, U. lobulata, U. lyallii, U.
parviflora, U. pilulifera, U. purpurascens, U. stimulans, U. urens, and U. urentissima.1,42-49 The
majority of these species have been reported in the United States. Besides being found in the United
States, the common nettle (U. dioica) and small nettle (U. urens) were introduced into Europe and
can be found in Australia and South Africa.1 There are two other species that can also be found in
Australia: U. holosericea and U. incisa.1 The U. ferox is native to New Zealand and can be found
throughout the North Island and west of the main divide in the South Island.49-51 U. ferox can grow
up to 3 m in height from sea level to 600 m in altitude.49 In India, three species of the Urtica have
been reported to cause stinging: the common nettle (U. dioica), U. hyperborea, and U. parviflora.1,45
The Urtica are usually dioecious and are with nonarticulated and unbranched laticifers. The
leaves are opposite, ovate, more or less cordate at the base, toothed, petioled, and about 3 to 12
cm long.2,52 The inflorescence is spike-like, axillary, up to 10 cm in length, and the perianth of
flowers is greenish in 4 out of 5 segments.2,52 Male flowers have four or five stamens. The Urtica
received their name from the Latin word, “urere,” which means “to sting.” This species contains
stinging hairs on all stems and leaves.2,52 Shaw,16 classified the Urticaceae by the presence or lack
of stinging hairs, and also identified the Urera and Laportea species with stinging hairs. In addition,
several other species of the Urticaceae are also know to contain stinging hairs.1,4,17,46 These are
Cecropia, Dendrocnide, Fleurya, Girardinia, Gyrotaenia, Hesperocnide, Laportea, Nanocnide,
Obetia, Scepocarpus, and Sceptronide.
15.3.2.1 Stinging Hairs
The structure of the stinging hair has been described by Thurston.53 The syringe-like hairs have
elongated epidermal and subepidermal layer cells. The apical walls are composed of silica bodies.
The silica bodies are more pronounced at the tip of the hair and decrease in concentration toward

FIGURE 15.1 Cryptopleurine, a biologically active com pound found in Boehmeria platyphylla and members
of the Lauraceae family.
the base of the hair. At the base of the stinging hair, the cell wall lacks silica bodies. The tip of
the hair is very hard and brittle. Once the hair touches the skin, the top of the hair breaks and the
liquid contained within the hair is injected into the skin (see Section 15.4.2 for the contents of
the fluid).
15.4 CHEMISTRY OF URTICACEAE

Hegnauer first recorded the chemistry of the Urticaceae in 1966.54 As noted in Section 15.2, several
classes of compounds have been found in members of this plant family. The classes of compounds
reported are the alkaloids, proanthocyanidins, and flavonols. Cyanogens and iridoids were not
observed.2 Cyanidin is the representative compound of the proanthocyanidins identified while
quercetin and, sometimes in combination with kempferol, is (are) the representative compound(s)
for the flavonols. Ellagic acid has been reported to be absent in eight species and five genera.2
Within the Boehmeria, anthroquinones have been detected.2 One of the alkaloids of biological
significance found in Urticaceae is cryptopleurine (Figure 15.1). Cryptopleurine was isolated in
Cryptocarya pleurosperma (Lauraceae) and also found in Boehmeria platyphylla.55 This compound
has vesicant properties that could lead to dermatological changes if placed on the skin.1 Other
agents of biological significance are those compounds found in Parietaria sp. and members of the
Urticaceae with stinging hairs.
15.4.1 ACTIVE AGENTS OF PARIETARIA

The allergens found in the pollen of Parietaria have significant biological activity around the world.
For this reason, the pollen of several species of Parietaria have been extracted and fractionated by
several chromatographic techniques in order to identify the active agents.25,31,56-85 From Parietaria
judaica, Geraci et al.65 found nine arcs of IgE-binding components with the method of crossed-
radio immunoelectrophoresis (CRIE). The same group of researchers found nine bands of IgE-
binding components with sodium dodecyl sulfate polyacrylamide gel electrophoresis
(SDS–PAGE).31 For P. officinalis, four arcs were identified with CRIE and eight bands were detected
with SDS–PAGE.70 In all, the extract of P. judaica was composed of 26 distinct allergens. Using
size exclusion chromatography and immunochemical analysis, Geraci et al.65 determined the appar-
ent molecular weights for 17 antigens found in P. judaica. The molecular weight of 10 of the
antigens ranged from 10 to 40 kD while one had a molecular weight of less the 10 kD and 6 had
a molecular weight of more than 40 kD.65 Geraci et al.65 also classified nine of the antigens as
major allergens (four of the nine antigens), intermediate allergens (three of the nine antigens), and
minor allergens (two of the nine antigens).
One of the bands (band 9) identified by Geraci et al. that bound IgE from 26 different Parietaria
pollen-allergic subjects also was found to react with 50 of 52 sera in the studies by Ford et al.31

and Geraci et al.65 This allergen, the main Parietaria judaica allergen, has been further purified by
biochemical techniques,31,62,66,75 immunochemical methods,62,64,65 size-exclusion high performance
liquid chromatography (SEC-HPLC),60,66,67 ion-exchange–high performance liquid chromatography
(IEC–HPLC),56,57,59 high performance ion-exchange chromatography (HPIEC), or combinations of
these techniques.58,59 The allergen, Par j I (current designation is Par j 1.0101) is a glycoprotein
and was found to be very unstable in solution. 1,2,367 The molecular weight of this allergen has
varied from 10 kD to 26 kD, depending on the method used to isolate and characterize the
allergen.59,67,73,74 Under reducing conditions such as SDS–PAGE analysis, the corresponding mono-
mers would yield fragments of 10 to 14 kD.31,60,62,65 Cocchiara et al.67 found a molecular weight
of 12.6 kD for each monomer. Also, the same group found that Par j I was composed of 118 amino
acid residues.67 The number of hydrophobic residues is similar to the hydrophilic residues. The
more abundant amino acid residues were glutamic acid (14), aspartic acid (12), alanine (12), glycine
(11), leucine (10), serine (8), valine (8), lysine (7), proline (7), threonine (7), and arginine (6). Only
tryptophan was not detected while asparagine and glutamine were included as part of the aspartic
acid and glutamic acid values, respectively.67 More recently, Costa et al.76 isolated, cloned, and
sequenced Par j I. The investigators found that Par j I was a protein of 139 amino acids with a
deduced molecular weight of 14.5 kD.
The pollen from P. officinalis also has been extracted and the major allergen has been purified
and characterized.68-72,77,78 The major allergen in P. officinalis is Par o I. Similar to Par j I, the
counterpart in P. officinalis is also a glycoprotein with a protein-to-carbohydrate ratio of 100 :
21.68,78 The molecular mass of Par o I, as determined by SDS–PAGE, Sephadex G-50 gel filtration,
and size exclusion HPLC, varied from 13.5 to 14.5 kD according to the method employed to
calculate molecular weight.68 Giuliani et al.79 also isolated and purified the major allergen from P.
officinalis pollen. They identified a glycoprotein with a mass of 15 kD. The amino acid analysis
yielded the following as the most representative residues: glutamic acid or glutamine (12), glycine
(12), arginine (8), aspartic acid or asparagine (8), alanine (8), leucine (7), and lysine (8).67 The
investigators also identified the sequence of the N-terminus. They determined that there were amino
acids. However, the investigators had difficulties assigning a single amino acid residue at 3 of the
12 positions. The observation was explained by a limited heterogeneity of Par o I or the occurrence
of isoforms of the protein.
The microheterogeneity observed in the earlier studies has resulted in the search for various
isoforms of each of the two major allergens. Ayuso et al.83 found that Par j I migrated as a doublet
under the SDS–PAGE conditions used. The investigators demonstrated that the faster component
on the gel (Par j Ib) and the slower migrating component (Par j Ia) were cross-reactive by ELISA
inhibition. Par j Ia had a deduced molecular weight of 13,000 Da and Par j Ib had a deduced
molecular weight of 10,500 Da. Amino acid analysis and partial N-terminal sequencing demon-
strated an extensive homology and also determined the existence of some structural differences
between the two isoallergens. The isoallergens were reconfirmed by Duro et al.85 Ayuso et al.83
also found that 28 P. judaica-sensitive individuals recognized both isoforms when a skin prick test
was performed. In addition, the allergenic epitopes present in both of these isoforms are responsible
for most of the allergenic activity of the whole extract.
Isoallergens found in P. officinalis also migrated as a doublet in SDS–PAGE under reducing
conditions.69,78 Coscia et al.78 found the molecular masses of the two bands to be 14.5 and 14.0 kD
for the faster band (Par o Ia) and slower band (Par o Ib), respectively. Further analysis of each
isoallergen revealed that Par o Ib had at least three cathodic arcs under CIE examination78 whereas
Par o Ia only gave one anodic arc.68 In addition, Par o Ib consisted of a complex of molecules
differing in the isoelectric point.69,78 At least 5 peaks were obtained with polyacrylamide gel
isoelectrofocusing (PAG–IEF) and their pI values were 7.9, 8.2, 8.4, 8.8, and 9.6.78 As with the
isoallergens of P. judaica, Par o Ia and Par o Ib shared most of the IgE-binding epitopes of the
whole extract even though they only account for 15 to 30 percent of the total protein in the extract.69
The amino acid sequence of 2 P. officinalis isoallergens, Par o Ia and Par o Ib (pI 8.8), had 13

residues out of 24 residues in common. Kahlert et al.70 also found an extensive degree of homology
between the isoallergens of P. officinalis. The N-terminus of 6 proteins found in P. officinalis by
Kahlert et al. had identical amino acids at positions 4, 5, 6, and 7, and at positions 11, 13, and
15.70 Furthermore, the amino acids found at positions 11 through 15, in six proteins, had the same
3 amino acids but in different ratios.
The purified major allergens (as well as the isoallergens) of P. officinalis and P. judaica (Par
o I and Par j I, respectively) have been demonstrated to have similar physicochemical and allergenic
features.62,69,78,80 Preparations of both allergens contain similar molecular species that differ by
charge, molecular weight, presence of carbohydrate, and electrophoretic mobility.68,69,78,81 The
cDNA of both allergens, Par o I and Par j I, has also been described to have a sequence encoding
for an epitope common in both.82 The amino acid composition and the sequence of 12 N-terminal
residues for the isoallergens identified also show much similarity between the isoallergens.59,67-
69,74,78 A comparison between the amino acid sequence at the N-terminus for Par o Ia and Par j Ia
found a high degree of homology (94 percent).69,78 Similarly, a comparison between Par o Ib and
Par j Ib found that only 3 of 19 residues were different: 84 percent homology.78 Kahlert et al.70
found a greater concordance between the N-terminus amino acid sequence for one of the isoallergens
of P. officinalis and the sequenced cDNA for Par j I (83 percent) compared with the 50 percent
homology identified by Ayuso et al. The discordance in molecular weight, amino acid homology,
and other parameters have been attributed to differences in plant species, extent of heterogeneity
of the major allergens in Parietaria extracts, and/or the degree of purity of the isoallergen.
The cross-reactivity between the major allergens found in P. judaica and P. officinalis also
extend into other species of Parietaria. Ayuso et al.84 also found that a strong cross-reactivity existed
between the major allergens of P. judaica and P. officinalis with the major allergen of P. mauritanica.
Using a monoclonal antibody-based ELISA for the quantification of Par j I, proteins homologous
to Par j I were identified (Par o I and Par m I) in P. officinalis and P. mauritanica extracts,
respectively. The proteins then were purified by affinity chromatography and crossed-inhibition
experiments demonstrated that Par j I, Par o I, and Par m I competed for the binding of specific
IgE from a P. judaica-sensitive patient serum pool.85
15.4.2 ACTIVE COMPOUNDS OF STINGING HAIRS

A total of three small molecular weight compounds (Figure 15.2) were implicated as the agents
responsible for the itching and urticaria observed following contact with the stinging hairs of the
Urtica, Cecropia, Dendrocnide, Fleurya, Girardinia, Gyrotaenia, Hesperocnide, Laportea, Nanoc-
nide, Obetia, Scepocarpus, and Sceptronide. Of the active agents, two found in the Urtica genera
were first described by Emmelin and Feldburg in 1947.42 The compounds were acetylcholine and
histamine. Collier and Chesher87 described a third active compound, 5-hydroxytryptamine (seroto-
nin), in 1966. Later, the three compounds were confirmed by several investigators.43-45,88,89 These
compounds are responsible for the immediate reaction observed following the exposure to the nettle
hairs: histamine is responsible for the itching sensation, acetylcholine is responsible for producing
a burning feeling, and serotonin is a vasoconstrictor and platelet aggregrator. In addition, the
presence of a fourth agent, a histamine liberator, was suggested to occur in one species, Urtica
parviflora (Roxb.).45 Oliver et al.89 have also suggested that the presence of substances in the nettle
fluid are directly toxic to nerves or capable of secondary release of other mediators because the
stinging sensation persists for over 12 h.89
The concentration of the three active agents in the stinging hairs has been reported. Emmelin
and Feldburg42 found the content of histamine to range from 8.5 to 22 ng (or a concentration of
1/1000 to 1/500) in each hair. Oliver et al.89 found a lower content of histamine (6.1 ng). The
concentration of acetylcholine reported by Emmelin and Feldburg42 was 1/100 (approximately 0.8
ng). The content of the third active agent, serotonin, in each hair was found to be 33.25 ng by
Oliver et al.89

FIGURE 15.2 Active agents found in the stinging hairs of the Urticaceae.

In the Urticaceae, two distinct types of clinical effects have been reported in humans following
contact or inhalation of the active agents in members of this family. The two most common types
of clinical manifestations are contact urticaria to the genus Urtica and sensitization to the pollen
of the genus Parietaria. No antigenic cross-reactivity has been observed between the two genera
even though both genera are very similar in taxonomy.9,63,80 However, these investigators have found
a common 10-kD allergenic polypeptide in the pollen of 4 different Parietaria species that weakly
cross-reacted with Urtica dioica pollen.24
15.5.1 ALLERGENICITY DUE TO PARIETARIA

The extent of sensitization to Parietaria pollen will vary with geographic location. Overall, Pari-
etaria pollinosis is most prevalent in the Mediterranean.18,21-24,90 Parietaria pollinosis has also been
reported in the United Kingdom, United States, Austria, Bulgaria, the Czech Republic, Romania,
and southwestern regions of the former Soviet Union.18-27,40 Within the Mediterrean region, sensi-
tization to Parietaria occurs more commonly in the coastal towns than among urban regions.24
Clinically, sensitization to members of the Parietaria genus cannot be delineated from one
another owing to the cross-reactivity between these species. Extensive homology between the major
allergens has been observed in two of the main Parietaria species, P. judaica and P. officinalis.24,63,80
The major allergens responsible for the sensitization are Par j !a, Par j !b, Par o 1a, Par o 1b, and
Par m 1. These allergens have been extracted from the pollen of these plants. However, the leaves
and stems of P. judaica also contained antigenic activity.86
Parietaria pollinosis is very prevalent in many regions of the world. In southern Italy and the
Ligurian coast, the prevalence of Parietaria pollinosis has ranged up to 80 percent among pollinosis
patients.21,38 In other parts of the Mediterranean (Spain and France), the incidence is up to 60
percent and 25 percent, respectively.36,93 A lower incidence (13 percent) of Parietaria-reactive
patients with respiratory allergy have reported in the United Kingdom (Southampton area).35 The
incidence of Parietaria pollinosis for the United States remains unclear. Kaufman27 found that 8
percent of 100 sequentially tested patients with seasonal respiratory allergy gave a positive reaction
following a prick test with P. judaica and P. officinalis.
Overall, Parietaria pollinosis can persist from 4 to 10 months of the year, depending on the
location. The small size of the pollen, the reactivity of the allergenic proteins, and the high quantities

of pollen result in a large number of individuals sensitized to Parietaria. Parietaria pollinosis tends
to occur less frequently before the age 10 and more frequently in females when compared with
males. The gender differences have been observed in Europe and the United States.24,26,27,91,92
15.5.2 CONTACT URTICARIA TO URTICA

Similar to the genus Parietaria, members of the Urtica genus are distributed worldwide. As a result,
nonimmunologic contact urticaria reactions occur worldwide. The nonimmunologic contact urti-
caria reaction is initiated by the introduction of the active agents found in the liquid of the stinging
hairs. The urticarial reaction that is observed within minutes of contact is accompanied by a stinging
sensation that may persist for more than 12 h.49,94 Oliver et al.89 further characterized the cellular
and molecular mechanism of the stinging nettle urticaria. The cellular response of mononuclear
cells, polymorphonuclear cells, and mast cells was examined in 6 people at 5 min and 12 h following
contact with Urtica dioica. A significant increase in lymphocytes, plasma cells, eosinohil, or
neutrophil polymorphonuclear leukocytes was not observed at 5 min. Within 5 min, localized
separation of cells with intercellular exudate and fluid-filled vesicles in the cytoplasm of kerati-
nocytes were reported in the epidermis. During this time, the lymphatics and blood vessels are
dilated. The lymphatics are filled with exudate and no white cells are seen within the lumina of
the blood vessels. In addition, no evidence of diapedesis, perivascular infiltration, damage to
endothelial cells or their junctional contacts, and no evidence of vasculitis was reported in the blood
vessels 5 min following nettle contact. At 5 min, some mast cells had evidence of discontinuity of
the plasma membrance and discharge of granular contents from the cell surface with the loss of
the internal substance of deeper-lying granules.
The visible changes observed at the site of contact within minutes are no longer present at 2
h following contact. However, patients noted a persistent tingling sensation lasting for up to 12 h.
Following contact to the stinging hairs of U. dioica, mast cell numbers do significantly increase at
12 h in the papillary and reticular dermis. Microscopically, widespread areas of mitochondrial
swelling are observed in all types of epidermal cells and melanocytes at 12 h. Also at 12 h, continuity
of lymphatic endothelium is restored and general dermal exudate is decreased. Dilated blood vessels
are minimal and a minor degree of perivascular congregation of mast cells and lymphocytes are
observed at 12 h. Some mast cells with intact plasma membranes were depleted of granules or had
granules with an ill-defined internal substance at 12 h. Those mast cells with depleted granules had
large vesicles with an ill-defined internal substance. Mast cells were most frequently perivascular
and closely associated with cells having a dendritic appearance.
15.5.2.1 Other Evaluations of Urtica Extracts
The potential genotoxicity of Urtica dioica has been evaluated in the Salmonella typhimurium
microsomal activation assay (Ames test), in human lmphocytes in the alkaline single cell gel
electrophoresis (COMET assay), and in the somatic mutation and recombination test (SMART) in
Drosophila melanogaster.95,96 In the SMART assay, water extracts of Urtica dioica were prepared
and fed to larvae. Mitotic recombination or somatic gene mutation, deletion, or another mutational
change at one of the gene markers will result in a single or twin spot on wings of affected progeny.
The frequency of spots per wing were determined for the control and treated groups. Based on the
SMART assay, a weak genotoxic effect was observed with a standard tea preparation and with a
concentrated extract.96 In the Ames test, using strains TA98 and TA100, a saline extract and an
aqueous extract of the arial parts of U. dioica did not produce an increased frequency of revertants.95
In addition, a sugar rich, flavonoid rich, and chloroform fraction of the water extract had similar
findings. However, the Urtica extracts and chloroform and flavonoid fractions did produce a dose-
related increase in tail moments in the COMET assay, suggesting that a component or components
of the extracts or fractions can produce DNA damage by strand breakage.95 Some of the components

of plant extracts, the flavonoids, have been shown to have mutagenic and/or carcinogenic activity.97-
103The findings from these in vitro assays are not conclusive as human health hazards and additional
investigations would be required in order to predict the potential human mutagenic or carcinogenic
potential of Urtica.
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Section IV
Other Plant Families

16 Agavaceae
J. Juan Segura, C. Calzado Flores, and J. Del Valle Cantu
CONTENTS
16.1 Introduction
16.1.1 Taxonomy
16.1.2 Plant Family
16.1.3 Geographical Location
16.1.4 Genera
16.1.5 Species
16.1.6 Common Names
16.2 Chemistry
16.2.1 Family/Species
16.2.2 Chemical Structure of Active Principles
16.3 Biological Activity
16.3.1 Experimental Assays
16.3.2 Toxicological Assays
16.3.3 Clinical Effects
16.4 References
16.1 INTRODUCTION
16.1.1 TAXONOMY
Kingdom—Metaphyta (Plantae)
Phylum—Spermatophyta (Embriophyta Siphonogama)
Subphylum—Angiospermae
Division—Anthophyta
Class—Monocotyledones
Order—Liliales or Liliiflorae
Family—Agavaceae (Amaryllidaceae)
Genera—Agave, Yucca, Hesperaloè, Littaea, and large cacti which tend to be spherical in
shape
16.1.2 PLANT FAMILY

The Agavaceae is a monocotyledonous family with about 670 species in 20 genera. This family
was recognized formerly as Amaryllidaceae, and is abundant in temperate and tropical regions of
the world. A few species are herb or rosette trees, but most are shrubs or subshrubs. Some species
are cultivated as ornamental plants, Agave americana L. for example, and certain Yucca L. species.1

Plants from this family have a basal aggregation of leaves or a terminal aggregation of leaves
(when shrubby or arborescent). Leaves are evergreen, small to very large, and can either alternate
or spiral. The leaves are also flat or terete, leathery, fleshy, or leathery and fleshy, and sessile,
sheathing edgewise to the stem or with normal orientation with simple epulvinate; lamina entire,
linear or lanceolate, or subulate, parallel-veined without cross-venule; lamina margins entire, or
serrate (often sharp pointed and with lateral spines); leaves with a persistent basal meristem and
basi petal development. Their flowers are perianth showy with six similar segments; ovary
superior or inferior, with three locules, each one with many ovules; one style; six stamens;
inflorescence a panicle, raceme or umbel. Moreover, the Agavaceae family has fruits that can be
a capsule (loculus) or berry that are fleshy or nonfleshy, dehiscent or indehiscent. This family is
considered as xerophytic perennials and some species produce a tall flowering stalk that repro-
duces only once in a lifetime.2
Different Agave species represent an economic value for the population, especially for the
agriculture workers. From these plants, several products are obtained. These products include
various fibers (sisal hemp, henequen, pita, istle, ixtle, lechuguilla, etc.), pulque, and mescal derived
from the fermentation and distillation of Agave sap.3,4
16.1.3 GEOGRAPHICAL LOCATION

The Agavaceae family is believed to be a native of America. However, the plant has been exported
to other countries with semiarid and humid tropical climate regions such as Asia, Africa, and
Australia. The plant was exported to promote its commercial exploitation. Although the Agave
genera is distributed throughout the American continent, most plants of this family grow in arid,
subtropical, or tropical climates that are mainly found in the south of the United States, Mexico,
and Central America.5
16.1.4 GENERA
The Agavaceae family contains 20 genera which includes the following: Agave, Beschorneria,
Cordyline, Dracaena, Furacrea, Hesperaloë, Littaea, Manfreda, Nolina, Phormiun, Polianthes,
Prochnyanthes, Sansevieria, and Yucca. The Agave genera is the largest genera in this family where
about 300 species are cultivated for fiber and fermented drink.1
16.1.5 SPECIES
Of the 670 species found in the Agavaceae family, a review of the literature did not find any current
clinical use of these plants in humans. However, there are some experimental investigations in
laboratory animals using crude extracts from different species of Agave genera.6 Other reports
found the sap of Agave americana as producing an irritant contact dermatitis in humans.7 Also,
some studies have reported hepatotoxicity and photosensitivity reactions in animals that feed on
the aerial parts of the A. lecheguilla and A. americana.8-11 In addition, some Agave species have
been used in traditional medicine as remedies for healing aerobic wound infections.12 Recently, the
effectiveness of these species has been demonstrated in vitro on some species of bacteria and
fungi.12,13 In Figure 16.1, several specimens of A. lecheguilla are observed.
Other species have been used to obtain products with different commercial purposes. For
example, the Mescal brandy, which is a popular alcoholic beverage in Mexico, is distilled from the
fermented mash of the cooked stems of certain wild and cultivated Agave L. species, especially A.
tequilana, and A. Weber, A. pacifica Trel.4

FIGURE 16.1 Lechuguilla (Agave lecheguilla) can be found in the semidesert zone in the northeast of Mexico.
16.1.6 COMMON NAMES

Agave americana is known as American aloe or century plant. This species has been reported as
a plant capable of producing irritant dermatitis and conjunctivitis.7 Also when used as a hair restorer,
the sap of this plant produced a contact urticaria reaction followed by acute eczematous dermatitis.14
Nolina texana, also known as bunch grass or sucahuiste, is another plant from the Agavaceae
family that can cause irritant dermatitis.15 Following ingestion of this plant by goats and sheep,
photodermatitis reactions accompanied by hepatic and renal damage have been observed.8,9
Furcraea Vent (or figue) is capable of causing dermatitis in persons engaged in growing them,
persons processing the fibers to make bags, and in those persons handling the finished sacks used
for packing coffee.16
Sansevieria trifasciata Prain is also known as mother-in-law’s tongue. This species can cause
dermatitis. Both irritant and delayed-type hypersensitivity reactions have been observed.15 In addi-
tion, compounds found within this plant can produce vomiting, salivation, diarrhea, and hemolysis.7
The sap of A. lecheguilla Torrey, which is also known as Istle or Mexican fiber, has been
described as irritating16 and its ingestion has caused poisoning in sheep and goats.17,18 Camp et al.10
reported that sheep orally forced fed with ground A. lecheguilla for 14 days developed icterus and
hepatogenous photosensitization.10 The last observation about hepatic damage was also observed
in Angora goats fed with this plant.11
A. sisalana Perrine (syn. Agave rigida Miller var. sisalana Engelm.) is commonly known as sisal
agave, sisal hemp, or green agave. The raw sap of this plant is corrosive to metal and highly irritating
to the eyes and skin. It causes an instant, stinging red rash in gardeners who have occasion to cut
any part of the plant. It also affects factory workers exposed to the sap and the wet fiber in the process
of extraction. The odor of sisal (sisal being the fiber derived from this plant) in mattresses, generally
in combination with some other material, causes allergic reactions in sensitive individuals.5,19 In 1960,
Faninger and Markovic-Brisk20 described an occupational dermatitis caused by moldy sisal.

FIGURE 16.2 Smilagenin is a representative steroidal moiety of the sapogenins.
The aqueous extract of A. fourcryoydes (also known as henequen) decreased the cardiac
frequency in mollusks producing an ovicida mollusquicide effect.6
Yucca aloifolia L. is known as sword leaf or Spanish bayonet. Morton reported eye injury
caused by the short black spine at the leaf tip. The needle-sharp leaf tips of this species may
penetrate the skin and in or near bone may excite a reaction that simulates a neoplasm.21
16.2 CHEMISTRY
16.2.1 FAMILY/SPECIES
The Agavaceae family contains steroidal saponins and sapogenins recognized as precursors in the
production of medicinally used steroids.1 In addition, crystals of calcium oxalate have been reported
as part of the chemical composition of Agavaceae. These crystals have been related to irritants and
allergic effects following contact with members of this family.22
Saponins are a glycosides chemical group that produce a diminution of superficial tension in
water forming a considerable production of foam. Sapogenin (aglycone) and carbohydrates are
obtained after the hydrolysis reaction of saponin. The representative steroidal moiety of the sapo-
genins is the smilagenin (Figure 16.2).23
Approximately 200 steroidal saponins from the monocotyledons have been isolated. However,
fewer sapogenins were obtained when these compounds were hydrolyzed because the isolated
aglycone moiety can be the same compound for two or more saponins.23 All parts of the plant
generally contain steroidal saponins and steroidal sapogenins, more specifically hecogenin (C27 H42
O4), tiogenin (C27 H44 O3), and neotiogenin. Other sapogenins that have been isolated are sisalagenin,
gloriogenin, gentrogenin, gitogenin, delta 9-11-hecogenin, diosgenin, smilagenin, sarasapogenin,
and yamogenin.24-26 The content of each sapogenin can differ within the plant (i.e., leaves, stems,
roots) and the stage of growth.5,23,27 Yuccagenin and diosgenin were isolated in A. tubulata and A.
legrelliana.28 Later, a new steroidal sapogenin diol, ruizgenin (Figure 16.3), was isolated from the
leaves of A. lecheguilla29 and chlorogenin from A. cocui.30
Several steroidal sapogenins were isolated from leaves of eight species of cordyline: cannin-
genin, cordylagenin, brisbagenin, and ruscogenin.31 From the dried fermented residues of leaf juices
of A. sisalana, two new steroidal saponins tigogenin derivates, recognized as dongnosides, were
characterized.32
Another chemical group isolated from extract of leaves of different species of Agave correspond
to enzymes with proteolytic activity.33-35
16.2.2 CHEMICAL STRUCTURE OF ACTIVE PRINCIPLES

The steroidal sapogenin hecogenin is shown in Figure 16.4. This compound is isolated from different
species of the Agavaceae family and has been used in the synthesis of corticosteroids.1

FIGURE 16.3 Ruizgenin was isolated from the leaves of Agave lecheguilla.
FIGURE 16.4 Hecogenin is a natural steroid isolated from different Agavaceae species.
16.3 BIOLOGICAL ACTIVITY

16.3.1 EXPERIMENTAL ASSAYS
The antitumoral activity of constituents from Agave plants have been evaluated in rats. Effective
inhibition of the Walker carcinoma 256 (intramuscular) tumor system of the Cancer Chemotherapy
National Service Center was observed with extracts from Agave schottii Engelm.36 The antimicrobial
activity has also been observed with different products obtained from some Agave species. The
concentrated maguey sap inhibited growth of pyogenic and enteric bacteria such as Staphylococcus
aureus and Shigella sonnei, respectively.12 Also, the inhibitory growth effect on some opportunistic
pathogens such as Candida and Microsporum have been reported with the ethanolic extract from A.
lecheguilla Torr.13 In rabbits, a crude extract prepared from A. lecheguilla (amole) rhizomes caused
an effect on vitreous hemorrhage reabsorption.37 A group of investigators reported the influence of
crude extracts obtained from three different Agave species on cardiac frequency in mollusks.6
In a comparative study, a higher hemolytic activity in hamsters and mice provoked by saponin
administration was observed with steroid saponins from A. sisilana than with Periandra mediter-
ranea saponins.38 Recently, lyophilized aqueous extracts obtained from A. americana and some
genins isolated from them (hecogenin and tigogenin) were evaluated for their anti-inflammatory
properties in rats.39 The activity observed with these test substances was comparable in intensity
and duration to the effects produced by indomethacin, a known anti-inflammatory agent.39
16.3.2 TOXICOLOGICAL ASSAYS

The toxicological effects of ground A. lecheguilla have been evaluated in goats and sheep. Icterus
and photosensitization were observed in sheep following 14 days of feeding the animals with the
aerial part of this plant.10 In another study using Angora goats, the feeding of A. lecheguilla caused
an hepatogenous photosensitization.11

In addition to the toxicological reports with Agave, there are several reports in the literature
about the toxicological effects of Agavaceae. The acute toxicological evaluation of these plants
was performed in rats while the chronic effects of an aqueous extract of rhizome from A. lecheguilla
was evaluated in rabbits. In this study, a 1 g/kg dose of amole administered for 10 days had no
lethal effect on rats. In addition, no toxic effects were observed in rabbits following seven months
of administrations of amole.40
16.3.3 CLINICAL EFFECTS

There are a few investigations about the clinical use of Agavaceae. The majority of the curative
properties have been included as empirical knowledge within traditional medicine. Mainly, the use
of different Agave species had been reported to have irritating properties to the eyes and skin.
There have been two pharmacological properties attributed to Agavaceae:
1. Those effects produced following a previous dermal contact

2. The manifestations related with oral administration of the plant
The dermal manifestations include acute eczematous dermatitis followed by a contact urticaria
reaction when a shampoo derived from A. americana was used on the scalp, forehead, and wrist.14
Other dermal reactions have been observed in gardeners who have occasion to cut any part of the
plant and who have been exposed to the raw sap of A. sisalana and in factory workers exposed to
the sap and the wet fiber in the extraction process.5
In respect to the effects caused by the oral administration of Agave plants found in the literature,
a case of alimentary intoxication was observed after swallowing the juice from chewing the fibers
of cooked stem quiote of A. americana.41 In this patient, the symptomatology, mostly observed in
the abdomen, was treated with surgery.41 However, other outcomes have also been noted in indi-
viduals taking an oral administration of Agave. No adverse reactions were reported in healthy
normal volunteers following the oral administration of a single dose up to 6 g of crude extract of
rhizome from A. lecheguilla amole.42 In other clinical studies, no side effects nor any gastric,
cardiovascular, or respiratory symptoms were reported in patients treated with capsules containing
500 mg of amole every 12 h for 10 days.43 In the same clinical study, the clinical laboratory values
for blood from amole-treated and nonamole-treated patients did not differ significantly. These
observations were realized after 90 days of treatment.43
16.4 REFERENCES
1. Trease, G. E. and Evans, W. C., Tratado de Farmacognosia, Interamericana, México, 1987, chap. 19.
2. Watson, L. and Dallwitz, M. J., The families of flowering plants: descriptions, illustrations, identifi-
cation, and information retrieval, http://biodiversity.uno.edu/delta, 1992.
3. De la Cruz Campa, J. A. and Medina Torres, J. G., La Lechuguilla (Agave lecheguilla), Recursos
Naturales del Semidesierto, Serie: Plantas desérticas y el hombre, D.I.F. Coahuila, Mexico, 1988.
4. Bahre, C. J. and Bradbury, D. E., Manufacture of mescal in Sonora, México, Econ. Bot., 34, 391, 1980.
5. Morton, J. F., Major Medicinal Plants. Botany, Culture and Uses, Charles C. Thomas, Springfield,
IL, 1977, 67.
6. Diaz-Garces, R. and Ferrer López, J. R., Efecto de las dosis letales de plantas de la familia Agavaceae
sobre la actividad cardíaca y la oviposición de Biomphalaria havanensis (Mollusca: Planorbidae),
Rev. Cubana Med. Trop., 48, 6, 1996.
7. McCord, C. P., The occupational toxicity of cultivated flowers, Ind. Med. Surg., 31, 365, 1962.
8. Mathews, F. P., Poisoning in sheep and goats by sucahuiste (Nolina texana) buds and blooms, Bull.
Tex. Agric. Exp. Stn., 585, 1940.

9. Bridges, C. H., Camp, B. J., Livingston, C. W., and Bailey, E. M., Kleingrass (Panicum coloratum
L.) poisoning in sheep, Vet. Pathol., 24, 525, 1987.
10. Camp, B. J., Bridges, C. H., Hill, D. W., Patamalai, B., and Wilson, S., Isolation of a steroidal
sapogenin from the bile of a sheep fed Agave lecheguilla, Vet. Hum. Toxicol., 30, 533, 1988.
11. Burrows, G. E. and Stair, E. L., Apparent Agave lecheguilla intoxication in Angora goats, Vet. Hum.
Toxicol., 32, 259, 1990.
12. Davidson, J. R. and Ortiz de Montellano, B. R., The antibacterial properties of an Aztec wound
remedy, J. Ethnopharmacol., 8, 149, 1983.
13. Verastegui, M. A., Sánchez, C. A., Heredia, N. L., and García-Alvarado, J. S., Antimicrobial activity
of extracts of three major plants from the Chihuahuan desert, J. Ethnopharmacol., 52, 175, 1996.
14. Kerner, J., Mitchell, J., and Maibach, H. Y., Irritant contact dermatitis from Agave americana L.
Incorrect use of sap as “hair restorer,” Arch. Dermatol., 108, 102, 1973.
15. Mitchell, J. C. and Rook, A., Botanical Dermatology: Plants Injurious to the Skin, Greenglass Ltd.,
Vancouver, BC, 1979, 49.
16. Schwartz, L., Tulipan, L., and Birmingham, D. J., Occupational Diseases of the Skin, Henry Kimpton,
London, 1957.
17. Mathews, F. P., Lechuguilla (Agave lecheguilla) poisoning in sheep and goats, J. Am. Vet. Assoc., 93,
168, 1938.
18. Mathews, F. P., An experimental investigation of lechuguilla poisoning, Arch. Pathol., 25, 661, 1938.
19. Wilcox, E. V. and McGeorge, W., Sisal and the utilization of sisal waste, Bull. Hawaii Agric. Exp.
Stn., 35, 1912.
20. Faninger, A. A. and Markovic-Brisk, A., Occupational dermatosis caused by moldy sisal, Srp. Arch.
Celok. Lek., 88, 303, 1960.
21. Maylan, D. J., Thorn induced “tumors” of bone, J. Bone Jt. Surg., 34, 386, 1952.
22. Souder, P., Poisonous plants on Guam, in Venomous and Poisonous Animals and Noxious Plants of
the Pacific Region, Keegan H. L. and Macfarlane, W. V., Eds., Pergamon Press, New York, 1963, 15.
23. Domínguez, X. A., Métodos de Investigación Fitoquímica, Limusa, México, 1973, chap. 11.
24. Blunden, G., Yi-Yi, and Jewers, K., Steroidal sapogenins from leaves of Agavaceae species, Phy-
tochemistry, 17, 1923, 1978.
25. Khanna, P., Sharma, O. P., and Jain, S. C., Steroidal sapogenins from leaves of Agave wightii Dr. and
Prain., Indian J. Exp. Biol., 17, 446, 1979.
26. Matsuki, Y., Fukuhara, K., Yui, T., and Nambara, T., Determination of hecogenin in Agave sisalana
by gas-liquid chromatography, J. Chromatogr., 174, 451, 1979.
27. Higgins, J. W., A high-performance liquid chromatographic analysis of the benzoate esters of sapo-
genins isolated from Agave, J. Chromatogr., 121, 329, 1976.
28. Cuellar-Cuellar, A. and Diaz-Azcuy, S., Comparative study of some Agave grown in Cuba. Importance
in the hormone industry, Rev. Cuban Farm., 11, 257, 1977.
29. Blunden, G., Carabot, C. A., Cripps, A. L., and Jewers, K., Ruizgenin, a new steroidal sapogenin diol
from Agave lecheguilla, Steroids, 35, 503, 1980.
30. Blunden, G., Carabot, C. A., and Jewers, K., Steroidal sapogenins from the leaves of some species
of Agave and Furacrea, Phytochemistry, 19, 2489, 1980.
31. Blunden, G., Jaffere, J. A., Jewers, K., and Griffin, W. J., Steroidal sapogenins from leaves of Cordyline,
J. Nat. Prod., 44, 441, 1981.
32. Ding, Y., Tian, R. H., Yang, C. R., Chen, Y. Y., and Nohara, T., Two new steroidal saponins from dried
fermented residues of leaf-juices of Agave sisilana form Dong No. 1, Chem. Pharm. Bull. Tokyo, 41,
557, 1993.
33. Du-Toit, P. J., Isolation and partial characterization of a protease from Agave americana variegata,
Biochim. Biophys. Acta, 429, 895, 1976.
34. Schabort, J. C., Du Toit, P. J., and Kempff, P. G., An aminopeptidase from Agave americana varie-
gata—I, J. Biochem., 9, 161, 1978.
35. Schabort, J. C., Du Toit, P. J., and Kempff, P. G., An aminopeptidase from Agave americana varie-
gata—II, J. Biochem., 9, 171, 1978.
36. Bianchi, E. and Cole, J. R., Antitumor agents from Agave schottii (Amaryllidaceae), J. Pharm. Sci.,
58, 589, 1969.

37. Del-Valle, J., Segura, J. J., Medinilla, G., Zavala, A., Guerrero, A., and Cerda-Flores, R. M., Treatment
of vitreous hemorrhage with amole infusion administered orally to New Zealand rabbits, Proc. West.
Pharmacol. Soc., 34, 195, 1991.
38. Santos, W. R., Bernardo, R. R., Pecanha, L. M., Palatnik, M., Parente, J. P., and De-Sousa, C. B.,
Haemolytic activities of plant saponins and adjuvants. Effect of Periandra mediterranea saponin on
the humoral response to the FML antigen of Leshmania donovani, Vaccine, 15, 1024, 1997.
39. Peana, A. T., Moretti, M. D., Manconi, V., Desole, G., and Pippia, P., Anti-inflammatory activity of
aqueous extracts and steroidal sapogenins of Agave americana, Planta Med., 63, 199, 1997.
40. Segura, J. J., Zavala, A., Medinilla, G., Del-Valle, J., Puc-Dzul, M., Guerrero, A., and Calzado-Flores,
C., Preliminary toxicological evaluation of Agave sp. “amole,” Proc. West. Pharmacol. Soc., 34,69,
1991.
41. Villarreal, R., Martínez, O., and Berumen, U., Phytobezoar from the stem (“quiote”) of the cactus
Agave americana: report of case, Am. J. Gastroenterol., 80, 838, 1985.
42. Segura, J. J., Charles-García, F., Del Valle-Cantú, J., Zamudio, D., and Calzado-Flores, C., Clinical
testing of “amole” (Agave lecheguilla): phase 1-A, Proc. West. Pharmacol. Soc., 38, 71, 1995.
43. Segura, J. J., Charles-García, F., Del Valle-Cantú, J., Zamudio, D., and Calzado-Flores, C., Clinical
study of subacute administration of amole: clinical phase 1-B, Proc. West. Pharmacol. Soc., 39, 29,
1996.

17 Algae
Jose G. Camarasa
CONTENTS
17.1 Introduction
17.2 Botanical Classification and Distribution
17.2.1 Composition of Algae
17.2.2 Uses of Algae
17.3 Toxicology
17.3.1 Microcystins
17.3.2 Caulerpenyne
17.3.3 Iodine
17.3.4 Pheophorbide A
17.3.5 Phycocyanin
17.3.6 Phenolic Compounds
17.3.7 2-Hydroxyethyl Dimethyl Sulphoxonium Ion
17.3.8 Spirulina fusiforms
17.3.9 Fucoxanthin
17.3.10 Deoxylapachol
17.3.11 Arsenic
17.3.12 Sesquiterpene Lactones
17.3.13 Proteoglycans
17.3.14 Phocamadiene A
17.3.15 Hepoxilin B3
17.3.16 Domoic Acid
17.3.17 Gelidiella acerosa
17.3.18 General Compounds
17.4 Skin Pathology
17.4.1 Swimmer’s Itch
17.4.2 Dogger Bank Itch
17.4.3 Japanese Sargassum Fensholt
17.4.4 Frullania
17.4.5 Biotoxins
17.4.6 Protothecosis
17.5 References

17.1 INTRODUCTION
Algae are a large group of plants that grow in fresh or salt water and in damp zones of any place
in the planet. Also named seaweeds, the general knowledge refers to the algae as aquatic plants
located mainly in the ocean or large masses of fresh or salt waters. They can live in very hot waters
or in very cold, in the poles, including in the ice. Some are unicellular as a simple form of plant
life. Many others, as seaweeds, are long filamentous forms, branched or stranded.
17.2 BOTANICAL CLASSIFICATION AND DISTRIBUTION

The botanic classification of algae is very complex and probably not yet complete. Actually, these
plants are mainly divided in eukaryotic and prokaryotic (Eucarioti and Procarioti) (Table 17.1).
Eukaryotic and chlorophyllus organisms lack true embryos and vascular tissues made up of xylem
and phloem. The blue-green algae (cyanobacteria) are prokaryotic and are more related to bacteria
than eukaryotic algae.
More than 25,000 algae species are recognized and classified. Most of them have flagella and
can remain fixed in the soil or in rocks as grass of water. Others are floating, displaced over long
distances. There are many different sizes, shapes, and configurations. The unicellular forms are
microscopic. The largest forms can reach 200 or 300 ft (90 m). Some are saprophytic or live in
symbiosis with other plants or animal species. Some need light and contain chlorophyll. Other live
in the dark, very deep in the ocean at 15,000 ft (3,500 m). Some are toxic and others are not. Even
some strains of the same species can be toxic while others can be nontoxic.1-5
The most important habitat for algae is the ocean. More than 95 species of brown or red algae
live in the large seas. Near the coast, algae grow attached to coral reefs or rocks. Microscopic algae
live floating or suspended in waters near the surface and are named phytoplankton.
Sometimes algae can have an explosive growth, invading large areas in ponds, lakes, or seas,
contaminating the waters and, secondarily, shellfish and other creatures (pink tide).
17.2.1 COMPOSITION OF ALGAE

Some species of algae contain pigment. All pigmented algae contain chlorophyll, and beta carotene,
or variable amounts of other chlorophylls b, c, or d, xantophylls, and biliproteins.
Some eukaryotic algae contain low potential cytochrome C.550 and regions of sequence
similarity to cytochrome C-6. This cytochrome appears to be involved in a fermentation that sustains
the organisms during prolonged periods of dark and anaerobic conditions.6-7
TABLE 17.1
Classification of Algae
Procarioti Cyanophyceae (blue algae)
Eucarioti Rhodophyceae (pink algae) chlorophyll a; phycobilins
Chlorophyceae (green algae) chlorophyll a, b; carotenoids
Prasinophyceae
Charophyceae
Euglenophyceae chlorophyll a, b; carotenoids
Xantophyceae
Baciophyceae (diatomee)
Chrysophyceae (brown algae) chlorophyll a, c; fucoxanthin
Phaephyceae (brown algae) chlorophyll a, c; fucoxanthin
Dinophyceae (dinoflagellate) chlorophyll a, c; peridinin
Cryptophyceae chlorophyll a; phycobilins; carotenoids

According to their pigment, algae are distributed in brown, blue-green, green, and red. In fact,
algae can be classified into three categories based on their pigment.
The red algae (Rhodophyta) possess chlorophyll a or chlorophyll d and the biliproteins, phy-
cocyamin and phycoerythrin. The chlorophytes and euglenoids possess chlorophylls a and b. The
third group possesses chlorophylls a and c and includes brown, yellow, and other mixed colored
algae.8
The algae prokaryotic (Cyanophyceae) or blue algae contain biotoxins. Among the eukaryotic,
that release biotoxins, are the algae from the Dinophyceae group. Both species are of medical
interest.
Lyngbya majuscula is a Cyanophycea (blue algae) and belongs to the family of oscillatotiaceae.
It is composed of large hairy filaments that grow in rivers, ponds, lakes, and seas, very near to the
coast (tide zone), or deep, between 100 or 200 ft (30 m). It often causes skin troubles in swimmers.
In some brown and red algae, iodine is required for normal growth. Some kelps of the order
Laminariales contain 10,000 times greater concentrations of iodine than those found in the ocean
water. In addition, red and brown algae contain polysaccharides in the cell walls. From these,
mucilaginous substances called agar, carageenen, and algin are obtained.
17.2.2 USES OF ALGAE

Algae from the phytoplankton are consumed by fish. The oils produced are converted in cod-liver
and other liver oils that are sources of vitamins for humans and poultry for domestic animals.
Occasionally, green algae has been used for food. Sea lettuce is consumed in Asian countries. The
Chlorella species contain many of natural vitamins except vitamin C and is suitable as a nutritient.
Algin produced by giant kelps and brown algae is used in many products as foods, pharmaceutical,
cosmetics, and in brewing, and in many industries like textiles and paper, and in many other
industrial uses.
Algae has also been used as soil fertilizer and animal fodder. For this purpose, selected species
are cultivated in the sea as mariculture.
In the kelps of the order Laminariales that contain 10,000 times greater concentrations of iodine,
these plants are employed in the treatment of thyroid diseases. Red and brown algae can also
generate agar, carageenen, and algin. Agar that contain agarose and agaropectin is used in prepa-
rations of biological media for the growth of tissues and microorganisms. Agar can also be used
in the manufacture of cheeses, creams, jellies, ice cream, salads, canned fish and meat, ointments,
creams and lotions, and in the prevention of the formation of coarse ice crystals.
Finally, the so-called Diatomaceous earth is use as an abrasive in metal polishes, insulation of
boilers, as a medium in chromatographic columns, filtration of liquids, and in toothpaste.9-10
17.3 TOXICOLOGY
Toxicity of algae is well known and can produce undesirable effects, causing sanitary problems or
harmful changes in the marine coastal water. Some bioxins from algae can affect both marine
animals and man. Humans can be affected through the digestive, respiratory organs, and the skin.
Although the biointoxications are mainly produced from marine animals, blue and blue-green algae
blooms release bioxins which affect skin and respiratory apparatus. Biointoxications by dinoflagel-
lates can be produced in four main ways: paralytic shellfish poisoning (P.S.P.), diarrhoetic shellfish
poisoning (D.S.P.), venerupin-poisoning, amnesic shellfish poisoning (A.S.P.) and the blue algae
blooms affecting the skin. All these marine toxins must be considered and special attention paid
in order to improve the knowledge of the compounds’ chemistry, toxicology, tolerance limits,
therapeutical approach antidotes, and remarks on safety. The eutrophication phenomena in marine
coastal waters can be explained by anthropogenic or by natural causes and both need a scientific
worldwide sanitary control.11

Some purified toxins has been extracted from different algae. Debromoaphysiatoxin comes
from the algae Lyngbya majuscula. Lyngbyatoxin A has been isolated from the lipid extract of a
variety of Lyngbya majuscula Gomont and seems chemically related to Teleocidin B, a toxic
substance associated with strains of streptomyces.12,13
17.3.1 MICROCYSTINS
Microcystin L.R. is a potent cyclic heptapeptide hepatoxin that is produced by the blue-green algae
Microcystis aeruginosa. The algae is found in the Northern hemisphere and has been proven to be
one of the most potent inhibitors of type I and type II A protein phosphatases. Microcystin L.R.
induces alterations in the hepatocyte cytoskeleton, followed by hepatocyte disassociation, and cell
necrosis.
At the same time, Microcystin L.R. produces endothelial damage that allows the release of
cells and debris into the circulation system with microembolism occuring in the lungs and kidneys.
Rifampicin is effective against such toxicity when administered in animals (mice) at 25 mg/kg
dose, intraperitoneally, but only when injected close in time to exposure to the lethal toxin.14-16
The structures of Microcystins are unique with an unusual amino acid 3-amino-9-methoxy-10-
phenyl-2,6,8, trimethyl-deca 4 (E), 6 (E)-dienoic acid (Adda), that is thought to be significant for
the activity. Geometrical isomers at C-7 in the Adda portion of microcystins G (z) Adda microcystin
L.R. and R.R. have been isolated from Cyanobacteria. Both isomers bind to protein phosphatases
type I and type II A, inhibit their activities, and release glutamic pyruvic transaminase from rat
liver into serum in a very high proportion.
Microcystin L.R. is the best known microcystin. It is a heptapeptide containing leucine and
arginine. Microcystin L.R. has a potent tumor promoting activity in rat liver previously initiated
by experimental diethylnitrosamine. Microcystin L.R. inhibits protein activities of phosphatases.
This inhibition is similar to that of the known protein phosphatase inhibitor and tumor promoter
okadaic acid that is a tumor promoter factor in mouse skin, rat glandular stomach, and rat liver. In
fact, a natural product derived from a blue-green algae named microcystin is toxic and may produce
severe damage in the liver.17,18 That toxicity is completely abolished with a single dose of Silymarin,
a flavoliguane isolated from the wild artichoke Silybum marianum, L. Gaertn.19-21
Barcoo fever, Barcoo spews, Barcoo sickness, or simply the Barcoo is also a toxic disease that
looks like an infection illness produced by blue-green algae. The symptoms are similar to those
shown to be owing to the hepatotoxin of the tropical Cyanobacteria Cylindrospermopsis raciborskii
(Woloszynskn).22
17.3.2 CAULERPENYNE
Caulerpenyne is the most important of the bioactive secondary metabolites released by the algae
Caulerpa toxifolia (Vahl) and C. agardh. The extensive growth of that algae in the Mediterranean
Sea produces important quantities that justify the possible toxic effects of its bioactive metabolites.
These effects were studied in in vitro models. In these studies, primary cultured melanocytes,
keratinocytes, inmortalized keratinocytes (HaCaT), and (HESV) obtained from skin were used. In
addition, marrow cells and hemapoietic progenitors (CFU–GM) from bone were used. Hematopoi-
etic cells are more sensitive to caulerpenyne than skin derived cells. Nevertheless, the results suggest
that the risk for food intoxication or skin damage to humans from the invasive Mediterranean
Caulerpa toxifolia may be considered minimal based on the findings from these assays.23
Caulerpenyne was also tested against eight human cancer cell lines. The compound demon-
strated inhibitory growth effects in all cases with some variability between cell lines. The most
sensitive were cells of colorectal cancer. Cells in culture clearly exhibited an early and marked
shift into S phase followed by a blockade into the premitotic G.2.M. phase, although targets for
Caulerpa remain to be identified.24

17.3.3 IODINE
The order of Fucales are brown algae (Sargassum muticum) that contain high amounts of iodine,
up to 2500 mg/kg of dried material. The ingestion of products derived from brown algae can
produce an iodine eruption. Contact with these plants can produce irritant skin contact dermatitis.
As such, iodine can be considered a toxic product released by brown algae.25
17.3.4 PHEOPHORBIDE A
Pheophorbide A is a chlorophyll derivative present in the Chlorella algae speices. This compound
has been suggested to be a phototoxic and photoallergic substance. In Japan, where it is ingested
as an aphrodisiac in natural health food, phototoxic reactions have been reported in some
patients.26,27
17.3.5 PHYCOCYANIN
Phycocyanin is a blue pigment present in blue-green algae. This compound is considered to be a
contact sensitizer.28
17.3.6 PHENOLIC COMPOUNDS

Phenolic compounds are also present in Sargassum muticum and could be toxic. These compounds
have been reported in recent years in the Mediterranean area. They are developed in very large
amounts, mainly in the summer months. The brown algae (Phaeophyceae) or Sargassum muticum
Fensholt is originally from the Pacific Ocean, living in tropical and temperate seas. The plant may
have arrived in Europe with the import of Japanese oysters. Its presence was detected for the first
time in the 1970s near the coasts of Normandy, Brittany, the Netherlands, and Denmark. This
species of algae is found mainly on dyke supports, piers, and dams.29
17.3.7 2-HYDROXYETHYL DIMETHYL SULPHOXONIUM ION

The hapten (2-hydroxyethyl) dimethyl sulphoxonium ion is the first animal hapten identified. It
causes an allergic contact dermatitis known by the popular name of Dogger bank itch. As an
occupational skin disease, it was described in 1989 and was related for some time to contact with
algae. In fact, this compound is an animal product released by a marine bryozoan (Aclyonidium
gelatinosum L.) that contaminates water and algae.30,31
17.3.8 SPIRULINA FUSIFORMIS
Effects on proliferation of cultured cells and its relation to carcinogenesis have been evaluated.
The blue-green microalgae Spirulina fusiformis that is used in the daily diets of natives in Africa
and America, have been found to be a rich natural source of proteins, carotenoids, and other nutrients
like vitamin A, among many others. Studies have demostrated an inhibitory effect in animal
experimental oral carcinogenesis and reversing oral leukoplakia in pan tobacco chewers in India
by the oral intake of diet supplemented with Spirulina fusiformis.32
17.3.9 FUCOXANTHIN
Fucoxanthin, a natural carotenoid prepared from brown algae, inhibited the growth of GOTO cells,
a human neuroblastoma cell line. The amount of 10 mg per ml reduced the growth rate of GOTO
cells by 38 percent in the control by the arrest in the GO–G1 phase of the cell cycle.33

17.3.10 DEOXYLAPACHOL
Deoxylapachol, from a New Zealand brown algae Landburgia quercifolia, is active against P388
leukemia cells. Dimethoxy-methyl-butenyl naphtalene was the major component of this seaweed
that also contains naphtalendiones.34
17.3.11 ARSENIC
Some algae like the brown seaweed U. pinnatifida (Wakame) contain Arsenic compounds. The
major organic arsenic compounds, termed arseno sugars, in marine algae commonly contain 5-
deoxy-5-dimethylarsinyl-ribofuranoside. Arsenobetain is not detected in marine algae or in fish,
mollusca, or crustacea. Both derivates probably have biological normal functions in these animals.35
17.3.12 SESQUITERPENE LACTONES

Two new sesquiterpene hydroquinones, Peyssonol A and B from the Red Sea algae Peyssonelia
sp., have been shown to be potent inhibitors of the RNA-directed DNA synthesis of the reverse-
transcriptases (RTs) of human immunodeficiency virus HIV-1 and HIV-2.36,37
17.3.13 PROTEOGLYCANS
It was very well known for over 50 years that a great variety of sulfated polysaccharides (pro-
teoglycans) were present in a large number of marine algae. These compounds have been shown
to have pharmacological anticoagulant properties.37,39
17.3.14 PHOCAMADIENE A
Phocamadiene A is a polyhalogenated monoterpene isolated from red marine algae of the Phoca-
mium genus. This substance causes histamine release from most cells in rats and guinea pigs. The
H2 histamine receptor antagonists Cimetedine and Ranitidine potentiate the response of phocama-
diene A. This activity has been measured by the contractions produced by the substances in the
gastrointestinal tract of the animals and was insensitive to atropine but significantly reduced by the
H1 histamine receptor antagonists.38,40
17.3.15 HEPOXILIN B3
Hepoxilin B3 is a 12 lipoxygenase metabolite of arachinodic acid that has been found in various
mammalian tissues. Although lipoxygenase pathways are well documented in terrestrial plants,
these pathways have also been identified for the first time in two marine plants: the tropical red
marine algae Platysiphonia miniata (C. agardh) Borgesen and Cottoniella filamentosa Borgesen.39,41
17.3.16 DOMOIC ACID

Domoic acid was the primary neurotoxin in the blue mussels (Mytilus edulis) that caused poisoning
in humans. Further research showed that the algae Nitzschia pungens was the source of this toxin.40,42
17.3.17 GELIDIELLA ACEROSA
The oral administration of 1 g/kg per day of a crude extract of Gelidiella acerosa, a Sri Lankan
marine red algae, to rats caused a potential post coital contraceptive activity. This activity was due
to an elevated post implantation loss (by 89 percent) resulting from fetal death between 9–14 days
of pregnancy. The extract appeared to be antiprogestational (reduced ovarian progesterone output).

It is suggested that the crude extract may reduce the ovarian progesterone release, possibly via
antiplatelet and PGE-2-depressing activity.41,43
17.3.18 GENERAL COMPOUNDS

Different substances from different algae can produce diverse pharmacological effects. A relatively
high percentage of aqueous extracts from algae have exhibited activity in the National Cancer
Institute’s primary AIDS antiviral screen that are under further experimentation.36,42
Some species of marine algae have antibiotic activity. Various degrees of activity have been
detected in Rhodophyta, Phaephyta, and Chlorophyta algae. The species were tested against multi-
antibiotic resistant bacteria. Further examination of the potential antibiotic activity is still needed.38,43
From the past decade, we know of the presence of double-stranded DNA viruses that may
infect eukaryotic green algae. Yet, some people who recently traveled to the Caribbean Sea, suffered
from diarrhea due to the presence of spherical bodies in the stools. The spherical bodies resembled
coccidian oocysts of 8.0 to 9.0 microns in diameter. Some people had acquired immunodeficiency
syndrome. After properly studying the body, the bodies were species of blue-green algae.44-46
17.4 SKIN PATHOLOGY

17.4.1 SWIMMER’S ITCH
Skin pathology caused by algae is well recognized. Usually the dermatitis appears in people who
swam in waters of rivers, ponds, lakes, or in the ocean where the water was disturbed by fragments
of seaweed. Once the person finished swimming, the person would continue to wear the wet bathing
garment. In time, perhaps minutes or a few hours, a sudden itching or burning sensation would
begin. Immediately, an acute dermatitis was visible. Scrotum, perineum, and perianal regions are
some of the most affected areas. The eruption increases in intensity over three or four days and
evolves like contact dermatitis. A final desquamation is normal. In some cases, the dermatitis
persists for two to three weeks. The clinical manifestations of an algae dermatitis are similar to the
so-called swimmer itch. The pruritus and dermatitis caused by the organisms like platyhelmintes
(Cestoda, Trematoda, and Schistozome cercarial) or other aquatic animals or invertebrates, may
also be confusing in evaluating algae dermatitis. A differential diagnosis between both diseases
may be convenient.
17.4.2 DOGGER BANK ITCH

Contact dermatitis of the hands, arms, face, and thorax can occur in fishermen and occasionally
produce occupational contact dermatitis when fishing in waters during the season of maximum
growth of the seaweed. In 1939, Bonnevie31 in Denmark mentioned and studied a severe occupa-
tional skin disease in fishermen that afterward was reported continuously by the name Dogger bank
itch. The cause of the disease was confusing at the beginning. The etiology is not from algae, but
from a marine bryozoan that was especially abundant around the Dogger bank of the North Sea.
That disease has been also recognized in other geographical areas. The agents named Alcyonidium
hirsutum (Flem) or Alcyonidium gelatinosum (L.) belong to a large group of marine animals, not
to algae.30,31
17.4.3 JAPANESE SARGASSUM FENSHOLT

Japanese Sargassum Fensholt has been distributed all over the world with the export of the Japanese
oyster. Sargassum Fensholt is one of the brown algae of order Fucales, that has more than 100
species that grow in tropical temperate seas. In Japan, many fishermen suffer a contact dermatitis
on the hands, arms, face, and legs during the eel catching season. Across the world, other patients,

who also are mainly fishermen, suffer erythematous swollen, exudative dermatitis of the hands,
arms, and face when working during the fishing season. Patch tests with Japanese Sargassum in
tap water, Japanese Sargassum in 0.9 percent NaCl solution, and potasium iodide at a 20 percent
aqueous solution, reveal allergic positive reactions in some patients. Brown algae contain much
iodine. The results of patch testing suggest that iodine could be one of the substances causing the
Japanese contact dermatitis.25
17.4.4 FRULLANIA
The probable cause of contact dermatitis observed in fishermen of anemones is the exposure to the
allergic compounds (frullanias) found in the moss Losthecium that grows among the moss. Previ-
ously, the Microciona, an animal named Ked moss, had been reported as the causative agent only
by intuitive suspicion.47,48
17.4.5 BIOTOXINS
Seabathers itch or papulovesicular eruptions are also produced by blue-green algae. Biotoxins
produced are mainly irritant sustances. Lyngbyotoxin A and Dermoaplysiatoxin are the toxic
products of Lyngbya majuscula, a blue-green algae. A similar papulovesicular eruption is caused
by Anabena, an alga that contain phycocyanin.49,50 The penetration of Lyngbyatoxin A in the human
and guinea pig skin has been measured. The method included skin disks of excised skin, mounted
in diffusion chambers, exposing the epidermal face to the air and the dermal portion bathed in a
buffered salt solution containing gentamycin sulfate. The epidermal surface were dosed with 26
micrograms of Lyngbyotoxin A per square centimeter in 13 microliters of dimethyl-sulfoxide per
square centimeter. The skin penetration was calculated by summing the amount of the toxin
recovered from the dermis and the receptor fluid. Penetration expressed as percentage of dose (n=3)
in guinea pig and human skin was 23 and 6.2 percent, respectively, after 1 h of topical exposure.51
17.4.6 PROTOTHECOSIS
Protothecosis are uncommon infections caused by Prototheca, considered to be an achlorophylous
algae. The genus Prototheca comprises several species, the most prevelant of which is Prototheca
wickerhamii. It is really an achlorophylons algae. This algae is found in the slime flux of trees and
fresh environs. The first reports of skin infections owing to this algae were noted about 30 years
ago. Asymptomatic and stationary cutaneous plaques may be seen in otherwise healthy patients,
although some systemic disease has been confirmed. Characteristic morula are seen histologically.
Antifungal therapy is the most effective medication.52
Nearly 80 human cases are reported since the first case was described by Davis and Wakelin
in 1964 in Sierra Leone. The disease has been identified in Europe, Asia (Thailand, China, and
Japan), Oceania, and the United States. In North America, most of the cases come from the
Southwest.
The main clinical manifestations are cutaneous lesions of papules, plaques, papulo-nodular
areas, and eczematous plaques, mainly located in the extremities. Bursitis of the olecranon occurred
in 25 percent of the patients. A tenosynovitis that followed median nerve release for carpal tunnel
syndrome has been published. Systemic protothecosis attacks also have been reported when an
immunosuppresive factor is present.
The first description of algae meningitis was reported in a patient with AIDS in association
with Cryptococcus neoformans. The histopathology shows a dermic granuloma with endospores.
The characteristic feature of protothecosis, in tissues, is the presence of the specific matura sporangia
of Prototheca wickerhamii with the pattern of morula. It is PAS positive and Grocott and Muci-
carmin positive.

The ecology was studied by Clark, Pidoux, Pore, and Sudman. Prototheca wickerhamii are
ubiquitous inhabitants of sewages and are found in slime flux and animal wastes containing different
aquatic systems. The transmission is by traumatic inoculation. The pathogenecity and virulence are
moderate and are considered as rare opportunistic agents.53-55
Experimental granulomas has been induced in the skin of mice by intradermal or subcutaneous
injection of Prototheca wickerhamii in BALB/C and ICR mice. Granuloma nodules were shown
by six BALB/C mice whereas only three of six ICR mice developed granulomas. BALB/C mice
are susceptible and ICR strains are more resistant. In the early stages, the inflamatory infiltrate is
composed of polymorphonuclear leukocytes, lymphocytes, and macrophages. After months, the
granuloma is composed of hystiocytic cells and macrophages. Mast cells and scattered eosinophiles
also can be observed. Central necrosis and many endospores surrounded by the granuloma often
are seen. After six months, the cellular infiltrate is full of lymphocytes and plasma cells, between
many vacuolated epithelioid cells, leading to a degeneration of the granuloma.56,57
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55. Moyer, R. A., Bush, D. C., and Dennehy, J. J., Prototheca wickerhamii tenosynovitis, J. Reumathol.,
17, 701, 1990.
56. Horiuchi, Y. and Masuzawa, M., Epithelioid cell granulomas experimentally induced by Prototheca
in skin of mice: a light microscopic study, Hiroshima J. Med. Sci., 44, 21, 1995.
57. Iacoviello, V. R., de Girolami, P. C., Lucarini, J., Sutkerk, K., Williams, M. E., and Wanke, C. A.,
Protothecosis complicating prolonged endotracheal intubation: case report and literature review, Clin.
Infect. Dis., 15, 959, 1992.

18 Alstroemeriaceae
Lars P. Christensen, Kell Kristiansen, and Marian Ørgaard
CONTENTS
18.1 Introduction
18.1.1 Alstroemeriaceae
18.1.1.1 Taxonomic Position
18.1.1.2 Morphology
18.1.1.3 Cytogenetics
18.1.2 Alstroemeria L
18.1.2.1 Geographic Distribution and Ecology
18.1.2.2 Morphology
18.1.2.3 Systematics
18.1.2.4 Species of Horticultural Interest
18.1.2.5 Production
18.1.3 Bomarea Mirb.
18.1.4 Leontochir Phil.
18.1.5 Schickendantzia Pax
18.2 Chemistry
18.2.1 Anthocyanins and Other Flavonoids
18.2.2 Tuliposides
18.2.3 Extraction, Isolation, and Quantification of Tuliposides
18.2.4 Function and Biosynthesis of Tuliposides and Tulipalins
18.2.5 Reduction of Allergen Content
18.2.5.1 Genotypic Variation and Environmental Effects
18.2.5.2 Inheritance of Tuliposides and Breeding for Low
Allergen Content
18.3.1 Allergenic Principles
18.3.2 Dermatitis
18.5 References
18.1 INTRODUCTION
Within Alstroemeriaceae, only the genus Alstroemeria has major commercial interest. Interspecific
hybrids of Alstroemeria are cultivated in greenhouses for cut-flower production, increasing in
importance since the 1960s. In relation to the large scale cultivation of Alstroemeria, the attention

to allergenic reactions from handling the plants has emerged and a severe contact dermatitis known
as tulip finger appears more and more frequently. The responsive allergens have been identified as
tuliposides and tulipalin A, compounds also recorded within Liliaceae, for example, in Tulipa and
Erythronium. Several species within Alstroemeriaceae have been investigated for their content of
allergens and the results so far show that all examined species except Leontochir ovallei contain
tuliposides and tulipalin A, however, in very variable amounts according to the species.
18.1.1 ALSTROEMERIACEAE
18.1.1.1 Taxonomic position
Alstroemeriaceae (subclass Monocotyledonae; order Liliales) comprises four genera: Alstroemeria

L., Bomarea Mirb., Leontochir Phil., and Schickendantzia Pax counting approximately 200 species
where both Leontochir and Schickendantzia are monotypic genera. Dumortier established the family
in 1821 and today it includes the four genera. Differences in opinion as to the taxonomic position
of the family have occurred and the discussion has not been settled yet. The Alstroemeriaceae has
been included in Amaryllidaceae1-6 or in Liliaceae.7-10 The opinion now is that Alstroemeriaceae
constitutes an independent family within the order Liliales. Further resolution of phylogenetic
relationships is still debated. Within Liliales, Dahlgren et al.11 suggest an association of Alstroe-
meriaceae and the orchid families (Cyprepediaceae and Orchidaceae), however, they consider some
similarities resulting from convergent development with the orchid families being more advanced
in some characteristics. Takhtajan12 considers the tribe Haemantheae within Amaryllidaceae to be
the closest relative to Alstroemeriaceae whereas Hutchinson13 relates Alstroemeriaceae to Peter-
manniaceae and Philesiaceae in the order Alstroemeriales. Chemotaxonomically, the closest rela-
tives to Alstroemeriaceae seem to be within Liliaceae owing to the occurrence of tuliposides in
genera of both families (see Section 18.2.2). Based on analysis of the nucleotide sequences from
the plastid gene rbcL, Alstroemeriaceae appears as a sister group to the Colchicaceae.14
18.1.1.2 Morphology
Genera belonging to Alstroemeriaceae are morphologically characterized as erect or twining,

perennial petaloid herbs. Almost all species have slender sympodial rhizomes and tuberous roots
for storage of nutrients, starch, and water. Several species produce stolons (Figures 18.2 and 18.3).
Leaves are alternate, linear to lanceolate-ovate with petioles mostly twisted at the attenuated base
resulting in reversed (resupinate) leaves. Stomata found on the actual lower side are thus inverted
to the morphological upper side of the leaves. The leaves are simple with entire but often undulated
margins.
Most often, unbranched vegetative and generative stems are produced from the rhizomes, the
generative ones being higher than the vegetative. The inflorescences are terminal with solitary, few,
or numerous flowers arranged in umbels or umbel-like cymes subtended by bracts of various size.
Flowers are trimerous, epigynous, bisexual, protandrous, and regular (in Bomarea, Leontochir and
Schickendantzia) to somewhat zygomorph (in most Alstroemeria species). The perianth segments
are two whorled (3 + 3). The inner whorl in Bomarea and Alstroemeria often is darkly striated
and/or spotted having a more or less distinct yellow band. The outer whorl is less patterned and
often without a yellow band. Flowers of Leontochir and Schickendantzia are described as unicolored,
however, red flowers of Leontochir with a yellow basal blotch are observed.15 The flower color
ranges from white, yellow, orange, red, rose to purple, and violet. In some species, the outer whorl
is greenish, especially on the outer side. Nectaries are often present near the base of the inner
perianth segments.16 Normally, dichogamy (protandry) prevents self-pollination within flowers but
not within inflorescences. However, synchronized protandry within inflorescences has been
observed in both Bomarea acutifolia (Link & Otto) Herb.17 and in Alstroemeria aurea Graham.18
The three carpels form a unilocular (Schickendantzia and Leontochir) or trilocular (Alstroemeria

and Bomarea) ovary.11,19 The fruit is a capsule that open explosively or is indehiscent and berry-
like. Seeds are 2 to 3 mm in diameter and more or less round, yellow to red or dark brown, and
when germinating no coleoptile-like cotyledon is formed.11 The embryo sac development is of the
Polygonum type.11,20
Hummingbirds, bees, butterflies, and flies have been reported as pollinators of Alstroemeria
and Bomarea.17,21
18.1.1.3 Cytogenetics
Alstroemeria, Bomarea, and Leontochir are diploids with chromosome numbers 2n = 2x = 16 in

Alstroemeria and 2n = 2x = 18 in Bomarea and Leontochir.22-26 The chromosome number of
Schickendantzia has not been reported. Chromosomes of Alstroemeria vary between 4 and 20 mm
and are much larger than those of Bomarea.25,27,28 The chromosomes of Alstroemeria are among
the largest in the plant kingdom and have, therefore, been used frequently by cytologists in studies
of chromosome morphology.
The evolutionary relationships between Alstroemeria and Bomarea are rather controversial.
Whether Alstroemeria was derived from Bomarea by several cytogenetic modifications24,25 or
Bomarea has derived from Alstroemeria by addition of a pair of chromosomes22 is unclear.
Natural and induced genetic variation in Alstroemeria species and cultivars has been assessed
by the use of various molecular cytogenetic techniques, for example, the analysis of RAPD
markers29,30 and DNA hybridization.31,32 The results of these investigations clearly demonstrate
genome differentiation between Chilean and Brazilian species; further interpretations of species
evolution and relationships are less clear.
Both Alstroemeria and Bomarea have been used in traditional medicine,33-36 the storage roots as
food,3-5,33,36,38 the stems chewed as candy,39 and stems of Bomarea have been used in house
construction in Columbia.36 Extracts of leaves have been used against angina and hemorrhoids, the
roots have been used as a diuretic, and the tonic against cystitis,33 as well as against sterility.36 The
starch of the roots is easy to digest and should be good for children and people with digestive
problems.37 The roots are either cooked11,37 or roasted.33 The medicinal effects and food qualities
may depend on genera and species because different species are mentioned for different purposes.
However, the small qualitative differences in chemical compounds among species indicate that
several species might have similar effects. From the present chemical analyses of the family, it is
difficult to point out the compounds active against diseases. It may be saponins that have hemolytic
effects40 and/or chelodonic acid,41 both detected in Alstroemeria.
18.1.2 ALSTROEMERIA L.
Several of the popular names, for example, Inca Lily, Peruvian Lily, and Parrot Lily, reflect the
geographic origin of the genus and the vividly colored, showy flowers.
Alstroemeria with the type species A. pelegrina L. was first described by the French priest R.
P. Louis Feuillèe in 1714. Feuillèe described three species referring them to the genus Hemerocallis
(Day Lily): Hemerocallis salsilla (equivalent to Bomarea salsilla (L.) Herb.), H. pelegrina (now
Alstroemeria pelegrina L.), and H. ligtu (now Alstroemeria ligtu L.). The genus Alstroemeria was
established by Linneaus in 1761 in honor of one of his students, Claes von Alströmer (1736-1794),
who sent him seeds from the Swedish consulate in Cadiz, Spain.42
Looking through literature, more than 225 Alstroemeria epithets have been recorded.2,10,43-48
Most of these are synonyms and several of the names are now referred to the genus Bomarea. At
present, about 50 Alstroemeria species are recognized. Bayer44 recognizes 31 Alstroemeria species
from Chile (41 taxa), reporting 130 synonyms. Further, 18 Chilean species have been described by

Ravenna,45 who, however, does not take the work of Bayer44 into account. The number of species
of Alstroemeria from Brazil is rather uncertain. Baker2 and Uphof43 both describe 18 Brazilian
species, Aker and Healy21 recognize 30 Brazilian species, and Tombolato46 reports 26 species. A
taxonomical revision and description of the Brazilian Alstroemeria would be of great value. At
present, Brazilian Alstroemeria species are subjected to systematic investigations and the observed
variation within species raises questions to the previous species delimitations.46,47,49
In Argentina, 10 Alstroemeria taxa, including A. pygmaea Herb. (equivalent to Schickendantzia
pygmaea (Herb.) Speg.) have been reported recently and 2 further species probably also occur in
Argentina.50 Of these species, six also occur in Chile and the four other species are also found in Brazil.
18.1.2.1 Geographic Distribution and Ecology
Main centers of distribution for Alstroemeria are Central Chile and the southern and eastern parts
of Brazil with extensions into Paraguay, Argentina, and Peru.21,47 The distribution area of Alstro-
emeria covers different climates and ecological zones with many species adapted to rather specific
habitats.44,51 In Chile, Alstroemeria is found from 22° S in the north (A. graminea Phil. and A.
paupercula Phil.) down south to Patagonia (51° S) (A. patagonica Phil.), a distance of more than
3000 km. Some species are lowland plants growing at the shore of the Pacific Ocean (e.g., A.
hookeri Lodd. and A. pelegrina), whereas other species are alpine plants adapted to the Andes
at altitudes up to 3500 m (A. andina Phil. and A. spathulata C. Presl). Alstroemeria species grow
in sand, semishaded woodlands, at steep rocky slopes, at dry screes, and they are often found
in newly disturbed areas.44,51 In Brazil, some species are found in the rain forests of the tropical
Amazon and in river marshes;21,43 however, the largest number of Brazilian species is found in
the Cerrado (e.g., the province Minas Gerais) in the central and southeastern part at altitudes of
more than 1000 m.
Many of the Chilean species are adapted to short winter rainfalls presenting a limited growth
period with leaves often withering before seed set is accomplished. The rhizomes are in a dormant
stage during the summer drought, triggered to sprout only if sufficient precipitation falls during
winter time. In the arid desert areas of the northern Chile, the precipitation in some years is
insufficient for the plants to flower. They then survive as dormant rhizomes or as seeds. In Brazil,
the longer rainy season provides conditions enabling vegetative growth for a longer period with
some species even being evergreens.2,47 Several of the Brazilian species form large continuous and
dense populations,47 as do A. pelegrina in Chile and A. aurea in Chile and Argentina.44,50,51
In older literature1,2,52 and also in a recent checklist10 the species concepts remain diffuse and
confusing, obviously resulting in misinterpretations of species, for example, A. pelegrina and A.
ligtu have been considered as one species52 as have A. ligtu and A. pulchella L. f.43 Records of A.
pelegrina in the Peruvian Andes at altitudes of up to 3500 m10 may likewise refer to misidentified
species because A. pelegrina in Chile is restricted to altitudes below 300 m along the Pacific coast
around Valparaiso.44,51 The two Brazilian species A. inodora Herb. and A. pulchella are described
as being closely related to the Chilean A. haemantha Ruìz & Pav. (equivalent to A. ligtu ssp. simsii)
and A. aurantiaca (syn. A. aurea),2 but the two Chilean species are easily distinguished morpho-
logically from another and clearly differ from the two Brazilian species. The Chilean A. ligtu and
the Brazilian A. caryophyllea Jacq. have also been referred to as one species, but this misinterpre-
tation can be ascribed to a misstatement in The Botanical Magazine.1,43 There are also other incidents
of A. ligtu being misidentified.43
18.1.2.2 Morphology
The Chilean and Brazilian species are distinguishable both at the morphological and at the molecular
level. The Chilean species are most often slender plants with linear to lanceolate leaves and with
open cup-shaped, large, and showy flowers in bright colors. A. hookeri, A. pallida Graham, and

A. angustifolia Herb. have the most slender growth habit. A. revoluta Ruìz & Pav., A. schizanthoides
Grau, A. graminea, and A. andina have relatively small flowers (diameter less than 3 cm). Many
Brazilian species are stout, erect plants with large, dark green leaves, and tubular flowers in dull
and dark colors.2,43,47 A. sellowiana Seub. and A. caryophyllea from Brazil are fragrant species2,43,47;
the latter have been used in breeding programs producing fragrant cultivars.53,54 A. caryophyllea
was named by Jacquin with reference to the fragrance of a carnation (Dianthus caryophyllus Lem.).53
The rhizomes are of variable length according to species, for example, in A. andina; they are
less than 4 cm with very short internodes, whereas in A. aurea the rhizomes may be up to 12 cm
long with much longer internodes.44,50 The rhizomes are cylindrical and 0.5 to 1 cm in diameter.
The storage roots are fusiform (Figure 18.1a) and can be up to 60 cm long with a diameter of 2
cm. The stems may run below ground for more than 1 m, especially in gravel. For example, stems
of A. ligtu ssp. simsii and A. magnifica Herb. can reach a height of more than 1.5 m, whereas, for
example, in A. hookeri ssp. recumbens (Herb.) Bayer and A. patagonica the flowers are only 5 to
10 cm above the ground. Not all Alstroemeria species, for example, A. spathulata and A. patagonica,
have resupinate leaves44 which otherwise characterize the family. The leaves are up to 12 cm long
and 3 cm broad with often somewhat undulated margins. The inflorescences have from 1 (A.
patagonica) to more than 25 flowers (e.g., A. magnifica ssp. maxima (Phil.) Bayer, A. ligtu ssp.
simsii, and A. ligtu ssp. incarnata Bayer). The flowers are zygomorph (Figure 18.1b, c), except in
A. patagonica and A. kingii Phil.,44 with the perianth segments of the inner whorl darkly spotted
and/or striated. The median, inner segment is downward orientated, broad, and forms a lip. The
two other inner segments are narrower and upward pointed (Figure 18.1b, c) and have a yellow
transversal band. The Brazilian species are less zygomorph with their tubular flowers.
18.1.2.3 Systematics
Based on morphological data, Bayer44 groups A. pulchra Sims, A. magenta Bayer, and A. magnifica
and, likewise, A. hookeri, A. angustifolia, and A. pallida, as well as A. ligtu, A. aurea, and A.
presliana Herb., but Bayer does not find it possible to discuss the relationships between groups or
the phylogenetic evolution of the genus. From estimations of nuclear DNA content by flow
cytometry26 and by characterization of karyotypes by Giemsa C-banding,28 the investigated Alstro-
emeria species could be arranged in four groups: Group 1—A. magnifica, A. pelegrina, A. philippii
Baker, and A. pulchra; Group 2—A. angustifolia, A. aurea, and A. hookeri; Group 3—A. ligtu ssp.
ligtu and A. ligtu ssp. simsii; and Group 4—the Brazilian species (A. brasiliensis Spreng., A.
caryophyllea, A. inodora, and A. psittacina). The morphological, cytological, and chemical data
(see Sections 18.2.1 and 18.2.2) provides, however, no consistent systematic grouping of the genus
at present except that the Chilean and the Brazilian species seem to be distinct taxonomic units.
The differences in karyotypes suggest an early separation of the Chilean and the Brazilian species
after which speciation followed different evolutionary pathways.28
18.1.2.4 Species of Horticultural Interest
Alstroemeria aurea Graham (syn. A. aurantiaca D. Don)—the distribution area extends from
36° S to 42° S in Chile with extension into the Argentinean Andes.44,50,55 It is found from almost
sea level up to altitudes of 2000 m inhabiting arable areas, semishaded Nothofagus forests, and
open mountain screes.44,50,51,55 The inflorescence has up to 15 relatively large flowers in yellow to
red colors with a very variable patterning of dots and stripes. Leaves are up to 14 · 2 cm and
almost without undulated margins. Specimen selections (e.g., cv’s ‘Lutea,’ ‘Orange King,’ and
‘Splendens’) are cultivated as ornamental perennials in gardens throughout Europe and America.
A. aurea has been used in interspecific hybridizations to produce cut flower cultivars. ‘Walter
Fleming’ is a diploid, sterile hybrid between A. aurea and A. paupercula made in the 1930s. A
fertile, tetraploid sport was later crossed with other diploid species to produce the sterile triploid

FIGURE 18.1 Alstroemeria pelegrina (KK & MØ 93-24, Los Molles, Prov. Valparaiso, Chile). (a) Root
system with horizontal rhizome producing stems, fusiform storage roots, and fibrous roots. (b) Erect generative
stem with resupinate leaves and funnel-shaped, zygomorph flowers. (c) Flower; outer perianth segments
emarginated with a tooth; inner perianth segments with spots and stripes. (d) Fruit. — Bar equals 1 cm.
(2n = 3x = 24) Orchid hybrids.61 The first hybrid between A. aurea and A. pelegrina appeared in
early 1960s with the introduction of ‘Regina’ from the Dutch company van Staveren56; ‘Regina’
is still a cultivar of major importance.57
Alstroemeria pelegrina L. (Figure 18.1)—this generic type species was described by Linneaus
in 1761. Morphologically, it is distinguished by somewhat succulent leaves, large flowers (7 cm in

diameter) with a large pink blotch on the outer perianth segments that are emarginated with a tooth
in the middle. The inflorescence has 1 to 4 flower(s) and the stems reach a height of up to 50 cm.
It grows in coastal areas of the Chilean province Valparaiso, where rather large continuous popu-
lations can be found.51 A. pelegrina forms part of many cultivar hybrids. As mentioned, hybrids
with A. aurea are used as cut flowers. Hybrids with the Brazilian species are referred to as Butterfly
hybrids and are fertile tetraploids (2n = 4x = 32).
Alstroemeria ligtu L.—the epithet “ligtu” comes from the local Chilean word for the flour
produced from the starch of the storage roots.58 The species is characterized by the two upper inner
perianth segments being narrow, acute, and often with very pronounced purple stripes throughout.
It is found in Chile between the latitudes 32° 7¢S and 38° S at altitudes from sea level to 2000 m.
The species is now divided into three subspecies.44 A. ligtu ssp. ligtu has white to orange/red flowers
with purple stripes. A. ligtu ssp. simsii (Spreng.) Bayer (syn. to A. haemantha Ruìz & Pav.) has
orange flowers whereas A. ligtu ssp. incarnata Bayer has the largest flowers in rose shades with
yellow to red-brown stripes. Leaves are relatively large, especially in ssp. incarnata and ssp. simsii.44
The A. ligtu-hybrids are fertile, diploids (2n = 2x = 16), and they were earlier grown commercially
as cut flowers and are still used as garden plants. These hybrids can be dated back to 1927 (see
the paragraph below discussing the species for the garden).
Purple flowered Alstroemeria species—the cut-flower industry has also included species with
purple flowers in their breeding programs. A. violacea Phil. (equivalent to A. paupercula Phil.) is
stated as one of the parents in ‘Walter Fleming,’59 however, this is questionable.60 A. philippii Baker,
A. magenta Bayer, and A. magnifica Herb. may also form part of purple flowered cultivars. All
these species have relatively large leaves and large, bright purple flowers.
Brazilian species—Brazilian species mainly have been used in breeding programs because of
their vigorous vegetative growth, long lasting foliage, and long flowering period; however, few
Brazilian species have been used. A. pulchella L. f. (syn. A. psittacina Lehm) and/or A. inodora
Herb. have been considered as the Brazilian parent of the Butterfly hybrids.29,61,62 Because these
two species are difficult to distinguish, confusion of their involvement does exist.29 Smith56 states
that A. brasiliensis is the Brazilian parent of the Butterfly hybrids. The flowers of A. pulchella are
tubular in orange to red colors with green margins. The flowers have a diameter of approximately
1 cm and a length of 3 to 4 cm.
A. pulchella is reported from northern Brazil,2,21 however, Meerow and Tombolato47 suggest
that A. pulchella originates from the southern most states of Brazil and adjacent Argentina and
Paraguay and Sanso50 has also reported it from Argentina. The species have also been reported
from Mexico,63 but this is questionable.
Species for the garden—species from high altitudes and those from the southernmost latitudes
are most likely to fit into North European and American gardens. The alpine species may, however,
have special growth requirements making them rather recalcitrant. The hardiest species is A. aurea
which has been in cultivation since 183163 and was awarded by the Royal Horticultural Society in
1893. A. ligtu-hybrids are also suitable for the garden. These hybrids date back to 1927, where
plants of the ssp. ligtu and ssp. simsii hybridized frequently.63 However, the exact parentage and
origin are not precisely known and all three subspecies of A. ligtu may have been involved in the
A. ligtu-hybrids of today. Despite the tropical to subtropical origin of A. pulchella it also has been
grown successfully in temperate gardens. Nowadays, hybrids specifically suited for the garden are
also bred. Smith56 reports Alstroemeria hybrids (‘Princess Lilies’ and ‘Little Princesses’) that grow
well in English gardens.
18.1.2.5 Production
Alstroemeria has become an important cut flower because of its large, vividly colored, long-lasting
flowers. Since the 1990s, Alstroemeria has been among the first ten cut-flower species on the Dutch
market. The production area in The Netherlands was about 115 ha and 400 ha were grown in the

rest of the world.62 Each year more than 200 million stems are sold at the auctions in The Netherlands
and, in 1997, the production value was approximately 89 million Dutch guilders (approximately
equal to 42 million US$). Tulips (Liliaceae), that contain the same allergens (see Section 18.2.2),
are produced on a much larger scale than Alstroemeria and, in 1997, 1.1 billion tulips valuing 298
million Dutch guilders (approximately equal to 144 million US$) were sold in The Netherlands.57
A large number of Alstroemeria cultivars have been developed, but the 10 most popular cultivars
account for 50 to 60 percent of the production.57
Cut flower cultivation—Alstroemeria cut flowers are produced in greenhouses or in open
fields. If rhizomes are planted between May and June, flowering stems can be harvested in
September.64 Flower harvesting can be performed from the same plantings over several years.
Commercial cultivars may reach a height of more than 2 m. Alstroemeria plantings have to be
thinned by removal of thin and vegetative stems giving more light to upcoming flowering stems
and reducing the risk of Botrytis attacks owing to high air humidity. Alstroemeria is also susceptible
to the soil borne fungi Pythium and Rhizoctonia and pests like thrips, aphids, whiteflies, and snails.
The most severe diseases in Alstroemeria plantings are viruses such as the Tomato Spotted Wilt
Virus62 and Alstroemeria Mosaic Virus.64
Low temperatures (below 15°C) are necessary for flower induction that takes place in the
rhizome.59,65 Flower development is promoted by higher temperatures. However, temperatures that
are too high stop the induction of new flowering shoots. Temperatures during winter should be 15
to 16°C and during the summer kept as low as possible in order to have as long a flowering period
as possible.
Flowering stems are harvested by pulling or cutting them when two to three flower buds are
open. The stems are sorted after harvest and the bottom 10 cm of the stem are defoliated. During
the production, the easiest phases for the workers to get contact dermatitis are during thinning
shoots, harvesting flower stems, and leaf removal from the harvested stems. This work exposes the
skin of the hand to the plant sap containing the allergens. Ways to prevent contact dermatitis are
described in Section 18.3.2.
Breeding—the marketed cultivars are almost exclusively interspecific hybrids. Only a very
limited number of the species have been included in the breeding. Interspecific hybridizations
within Alstroemeria have been reported as far back as 1880,63,66 but the potentials of Alstroemeria
as a cut flower were not realized until the 1950s.66 Early advances in Alstroemeria breeding are
summarized by Robinson.63 Breeding today is mainly done in The Netherlands and the United
States by controlled crosses as well as by mutagenesis.67 Until 1995, more than 215 cultivars had
been registered.68 Most of the commercial cultivars are sterile triploids or fully fertile tetra-
ploids.23,69,70 The sterility prevents the triploid cultivars from being used in further cross breeding,
thus mutagenesis is an important tool in the breeding of Alstroemeria. Criteria for successful
cultivars are the production of large numbers of high quality flowering stems during a long period
of the year and new bright flower colors are welcomed. During the last decade, cultivars suited as
pot plants70,71 and vigorous cultivars for the garden56 also have been introduced.
The vast commercial potentialities of the Alstroemeria germ plasm have not all been utilized.
In vitro techniques such as ovule and embryo culture, increase the possibilities for successful
hybridizations62,70,72-74 enabling immature seeds and embryos to be grown in vitro where nutrients
necessary for embryo development, germination, and plantlet development are applied to the culture
medium. The techniques make it possible to cultivate embryos from interspecific crossings with
poorly developed endosperm. Two days after fertilization, the immature embryo can be rescued
and develop further in vitro.74
Hybrids between many Chilean species74 as well as between Brazilian and Chilean species72,73
have been obtained. The pollen viability of the hybrids vary considerably and to use these hybrids
in further breeding chromosome doubling may be needed to restore fertility.
For induction of mutations actively growing rhizomes are irradiated with low doses (3 to 5 Gy)
of X-rays.67 Shoots from the irradiated rhizomes are evaluated and the best selected and propagated

vegetatively for further evaluations of their potentials as new cultivars. Problems of chimerism,
often noticed after mutagenic treatments, are of minor importance in Alstroemeria75 probably owing
to the sympodial growth pattern of the rhizome.67
18.1.3 BOMAREA MIRB.

The genus Bomarea was named by Mirbel in honor of the French geographer, J. C. Valmont de
Bomare (1731–1807).76 The genus comprises more than 100 species,11,77 however, the exact number
is uncertain77 and additional species still are being described.78,79 TROPICOS48 lists 232 Bomarea
names of taxa including 205 species. Killip80 and Brako and Zarucchi10 report 78 species from Peru,
of which 37 should be endemic. Jørgensen and Ulloa Ulloa9 list 24 species from the high Andes
of Ecuador (8 endemic) and nine species from Costa Rica are recorded.81
Bomarea is widespread in Central and South America, from Mexico to Central Chile, Argen-
tina,82 and southern Brazil. Some species have a wide geographic distribution, for example, B.
caldasii (Kunth) Asch. & Graebn. is reported from Costa Rica, Ecuador, and Brazil, and B. edulis
(Tussac) Herb. is distributed from Mexico to Peru and in Brazil as well as on some islands in the
West Indies. Many Bomarea species grow within a broad altitudinal range,48 for example, B. edulis
is found at altitudes from 50 m in Costa Rica up to 3500 m in Peru and B. caldasii from altitudes
of 1000 m in Costa Rica up to 4600 m in Peru. Several alpine species grow above 4000 m and B.
ovata (Cav.) Mirb. is found at more than 5000 m.
Systematically, Bomarea is divided into three subgenera: subgen. Wichuraea M. Roem., subgen.
Sphaerine Herb., and subgen. Bomarea (syn. Eubomarea) of which subgen. Bomarea is the largest
one.2,77 Baker2 recognizes 3 species within Wichuraea and 20 within Sphaerine all alpine species
with erect to suberect stems, and 52 species in Bomarea that mostly are vines.
The flowering stem of B. dulcis (Hook.) Beauverd (subgen. Wichuraea) is only 10 to 30 cm
and that of B. pumila Griseb. (subgen. Sphaerine) is even smaller.2,80 The latter is very slender with
a prostrate stem of which only the upper 4 to 5 cm have leaves.80 Some of the erect species grow
on rocky slopes and cliffs.39 The vines of the subgenus Bomarea, for example, B. pardina Herb.,
may reach a length of 10 m,77 climbing in trees and shrubs, especially along the edge of closed
forest vegetation and cleared areas.17,48,77-79
The rhizomes and storage roots are generally not well known. Figure 18.2a shows the rhizomes,
stolon, and storage roots of a greenhouse grown B. edulis as well as stem roots;15 a characteristic
not previously reported in the Alstroemeriaceae. Several species have spherical storage roots about
the size of a walnut, thus being distinct from the fusiform storage roots in Alstroemeria. The
leaves vary from less than 1 cm (e.g., B. pumila) up to 25 · 10 cm in B. declinata (Poepp. &
Endl.) Kunth.
The flowers are regular (actinomorph, Figure 18.2b) or only slightly zygomorph appearing in
white, yellow, orange, and red colors often with purple, maroon, or black spots on the inner
perianth segments. Several species have greenish outer perianth segments. The outer and inner
perianth segments form a tube and are often of equal length, but the inner ones are often broader
than the outer. The largest flowers are found in B. involucrosa (Herb.) Baker (up to 6.5 cm long)
and the smallest in B. nematocaulon Killip, and B. pumila with flowers only 1 cm long. The
inflorescence may count as many as 100 flowers in an umbel-like cyme (e.g., B. edulis and B.
formosissima (Ruìz & Pav.) Herb.) or the flowers are solitary (e.g., B. pumila and B. filicaulis
Kraenzl.).
Horticulturists have made interspecific hybridizations as far back as 1910,83 but the hybrids
have never become popular significant ornamentals. However, enthusiasts do grow Bomarea species
and advice on how to grow them can be found on the Internet.84
Various Bomarea species have popular names, for example, Deer’s Potato, Jerusalem White
Artichoke, Jerusalem White Root, and Chile Arrowroot, referring to the edible roots.33,38,80 Coats38
and Peckolt33 even provide small recipes on how to cook the storage roots.

FIGURE 18.2 Bomarea edulis (cult. ex Royal Botanic Garden Edinburgh, 19691464). (a) Root system with
horizontal stoloniferous rhizome producing stems (some of which with stem roots), spherical storage roots,
and fibrous roots. (b) Twining generative stem with resupinate leaves and tubular, regular flowers. — Bar
equals 1 cm.
18.1.4 LEONTOCHIR PHIL.

Leontochir is derived from Greek and means lion hand, probably referring to the inflorescence with
the red flowers in dense umbels resembling the paw of a lion (Figure 18.3). This monotypic genus
with the species L. ovallei Phil. is found in coastal northern Chile around Carrizal Bajo, 28° S

latitude.85 Leontochir is becomming an endangered species because Chileans pick the flowers
because they are believed to have aphrodisiac effects.86 Hunziker85 refers Leontochir to Alstroemeria
as A. ovallei (Phil.) J. H. Hunz., but the lack of tuliposides and tulipalins in Leontochir (see Section
18.2.2) makes it distinct in this respect from Alstroemeria. The stoloniferous rhizome has spherical
storage roots, a characteristic different from Alstroemeria but similar to Bomarea. Stems are
procumbent, slender with a length of more than 1 m.2 The leaves have undulated margins and they
are shiny, sessile, oblong, and acute with a length of 7 to 10 cm and turned upwards on the
procumbent stem.15 Pedicels are very short and thick, and the flowers are in dense umbels on a
thickened peduncle. The flowers are regular, bowl-shaped, and unicolored red24 or red with a yellow
basal part.15 The outer perianth segments have large nectaries at the bowl-shaped basal parts with
the median segment producing less nectar than the two others. Thus, the position of the nectaries
also differs from that of Alstroemeria. All six perianth segments are of equal length, but the inner
three are broader than outer ones. Stigma and anthers are shorter than the perianth segments and
before anthesis the anthers are somewhat curled, bent down toward the median perianth segment.
Approximately one week after anthesis, the stigma divides apically into three.
18.1.5 SCHICKENDANTZIA PAX

The genus is named in honor of the German-born F. Schickendantz (1837–1896), who collected a
large number of plants in Argentina (Figure 18.4). It is also a monotypic genus with the species S.
pygmaea (Herb.) Speg. (syns. S. hyeronymi Pax, S. trichosepala Speg., and Y. Alstroemeria pygmaea
Herb.). The status as a separate genus is still debated and recently Sanso50 included it in Alstroe-
meria. It is reported from the Andes, from Peru down to Patagonia, at altitudes of 3000 to 4500
m growing among rocks and in grass.2,10,39,50 S. pygmaea is described as a tufted plant with stems
only scarcely produced above ground.2,52 Several stems are produced from a short rhizome that
also produces one to two elongated storage roots. Flowering stems have few leaves subtending the
flowers whereas the vegetative stems have more and larger leaves.50 The leaves are linear to
lanceolate, approximately 3 · 1 cm. The flowers are regular, funnel-shaped, unicolored,4 white to
yellowish or with purple dots in the throat50 and with a diameter of up to 4 cm and most often
solitary,5,50 but plants with branched flowering stems have been observed (Figure 18.4a).15 The
ovary is described as being unilocular4 as in Leontochir.
18.2 CHEMISTRY
The chemical investigations carried out so far on species in Alstroemeriaceae have primarily been
on anthocyanins, other flavonoids, and tuliposides. Other constituents present in this family are
sterols, hydrocarbons, caffeic acid, p-coumaric acid, and chelidonic acid, that so far has only been
isolated from Alstroemeria aurea.41,87,88 Furthermore, the presence of saponins in many Alstroeme-
riaceae species have been indicated, although their chemical structures still remain to be deter-
mined.40 Finally, alkaloids do not seem to be present in Alstroemeriaceae, although they are widely
distributed in Amaryllidaceae.89
18.2.1 ANTHOCYANINS AND OTHER FLAVONOIDS

Alstroemeria flowers appear in yellow, white, pink, red through scarlet-red to purple, and violet
colors. The pigments found in the genus are anthocyanins, flavone, and flavonol glycosides, as well
as carotenoids. The anthocyanins cause orange-red, red, and purple colors and they have been
identified as 3-rutinosides of 6-hydroxydelphinidin, 6-hydroxycyanidin, cyanidin, delphinidin, and
3-glycosides of 6-hydroxycyanidin, cyanidin, and delphinidin, some that are acylated with malonic
acid (Tables 18.1 and 18.2). Flavone and flavonol glycosides by themselves do not usually contribute
significantly to the flower color, but owing to co-pigmentation with anthocyanins they cause a

FIGURE 18.3 Leontochir ovallei (cult. ex M. Bridgen, Univ. Connecticut, USA). (a) Root system with
horizontal stoloniferous rhizome producing stems, spherical storage roots, and fibrous roots. (b) Twining
procumbent stem with flowers in an umbel. (c) Bowl-shaped, regular flower with nectaries at the base of the
perianth segments. — Bar equals 1 cm. (d) Flower in side view.
bathochromic wavelenght shift in the visible lmax of the anthocyanins which makes them appear
bluer.90 Although flavone and flavonol glycosides are present in relatively large amounts in the
flowers of Alstroemeria species, their chemical structures have not been determined.90 However,
they may be closely related to or even identical with some of the leaf flavonoids found in Bomarea
caldasiana Herb. and a few Alstroemeria species (see Table 18.1). The yellow flowers in some
Alstroemeria species and the intensively yellow patches in most species are caused by carotenoids.90
The chemical structure of the carotenoids have not been determined so far. Beside the leaf flavonoids
in Bomarea, pigments have only been investigated in the genus Alstroemeria (Table 18.1).

FIGURE 18.4 Schickendantzia pygmaea (Petersen & Hjerting, 810, 1952, Tafi del Valle, Tucuman, Argentina).
(a) Plant with horizontal rhizome, fusiform storage roots, fibrous roots, and a generative and vegetative stem.
The generative stem is branched, which is uncommon in the family. (b) Funnel-shaped, regular flower. — Bar
equals 1 cm.
The anthocyanins found in Alstroemeria are widely distributed in many other genera91,92 except
those having three hydroxy groups in the A-ring, i.e., 6-hydroxycyanidin 3-glucoside (3), 6-hydroxy-
cyanindin 3-rutinoside (6), and 6-hydroxydelphinidin 3-rutinoside (7) (Figure 18.5) that only seem
to be present in the genus Alstroemeria.90,93-96 The majority of the investigated Alstroemeria species
can be placed into three groups according to their content of major anthocyanins. The species in

TABLE 18.1
Distribution of Anthocyanins and Other Flavonoids in Alstroemeriaceae;
Alstroemeria Species Are Grouped According to Their Major Anthocyanins
Anthocyanins
Genus/Species a Major Minor Other Flavonoids References
Group 1
A. angustifolia ssp. angustifolia Herb. 4, 6 1, 2 90, 95
A. aurea Graham (syn. A. aurantiaca D. Don)b 4, 6 94, 95
A. exserens Meyen 4, 6 1c 95
A. garaventae Bayer 4, 6 95
A. ligtu ssp. ligtu L. 4, 6 94, 95
A. ligtu ssp. simsii Bayer 4, 6 94, 95
(syn. A. haemantha Ruìz & Pav.)
A. pallida Graham 4, 6 1c 95
A. presliana ssp. presliana Herb. 4, 6 1, 2, 5c 95
A. pseudospathulata Bayer 4, 6 95
A. versicolor Ruìz & Pav. 4, 6 2, 5 90, 95
Group 2
A. diluta ssp. diluta Bayer 1, 4 6 95
A. diluta ssp. chrysantha Bayer 1, 4 6 95
A. hookeri ssp. hookeri Lodd. 1, 4 5, 6 95
(syns. A. rosea Hook., A. hookeriana Schult.)
A. hookeri ssp. recumbens Bayer 1, 4 5, 6 95
A. leporina Bayer & Grau 1, 4 6c 95
A. magnifica Herb. ssp. maxima Bayer 1, 4 5c 95
A. pelegrina L. 1, 4 5, 6 90, 94, 95
Group 3
A. magenta Bayer 1, 2, 4, 5 7 95
(syn. A. violacea Phil.)
A. paupercula Phil. 1, 2, 4, 5 94, 95
A. philippii Baker 1, 2, 4, 5 7 95
A. polyphylla Phil. 1, 2, 4, 5 95
A. pulchra ssp. pulchra Sims 1, 2, 4, 5 7 8–12 95, 174
A. pulchra ssp. maxima Phil. 1, 2, 4, 5 7 95
A. revoluta Ruìz & Pav. 1, 2, 4, 5 7 95
A. werdermannii Bayer 1, 2, 4, 5 7 95
Beyond groups
A. brasiliensis Spreng. Kaempferold 175
A. hookeri ssp. cummingiana Bayer 4 1, 6c 95
A. pelegrina var. alba Quercetin,d 175
Kaempferold
A. presliana Herb. ssp. australis Bayer 1, 4, 6c 95
A. pulchella L. f. (syn. A. psittacina Lehm) Kaempferold 175
A. schizanthoides Grau 2 1, 4, 5 95
Bomarea caldasiana Herb. Kaempferold 175
a Author names (Alstroemeria) in accordance with Bayer.44
b Synonyms are given in parentheses when they are necessary to prevent confusion.
c Contains an acylated 6-hydroxycyanidin 3-rutinoside also.
d Isolated as a glycoside, but the glycoside part has not been identified.

TABLE 18.2
Distribution of Anthocyanins in Alstroemeria Cultivars
Anthocyanins
Alstroemeria Cultivars Major Minor References
‘Stalluc’ Luciana®, ‘Stablaco’ Mona Lisa®, ‘Pascal’®, 4, 5 94

‘Staltang’ Tango®
‘Apple Blossom’®, ‘Atlas’®, ‘Stadoran’ Campfire®, 4, 6 93, 94, 96
‘Helios’®, ‘Starodo’ King Cardinal®, ‘Starosella’
Rosita®, ‘Stajello’ Yellow King®
‘Amanda’®, ‘Madonna’® 4, 6, 7 96
‘Stamako’ Red Sunset®’, ‘Stacova’ Red Sunrise® 3, 4, 6 93
‘Cindrella’®, ‘Fiona’®, ‘Stalilac’ Jubilee®, ‘Patricia’®, 4–7 94, 96
‘Zelido’ Rita®, ‘Rosello’®, ‘White Libelle’®,
‘Zeranon’®
‘Cana’® 1, 4, 6a 2, 5 95
‘Regina’® 1, 2, 4, 5 6, 7a 94, 95
a Contains an acylated 6-hydroxycyanidin 3-rutinoside also.
the first group contain cyanidin 3-rutinoside (4) and 6-hydroxycyanidin 3-rutinoside (6), whereas
the second group is characterized by having cyanidin 3-malonylglucoside (1) and cyanidin 3-
rutinoside (4) as major anthocyanins. The major anthocyanins in the third group are the 3-rutinosides
and 3-malonylglucosides of cyanidin (1, 4) and delphinidin (2, 5) (Table 18.1; Figure 18.5). From
a chemotaxonomic point of view, species in the first group seem to be related as 6-hydroxycyanidin
3-rutinoside is only found as a minor anthocyanin in the third group and in a few species beyond
this grouping (Table 18.1). The presence of cyanidin 3-malonylglucoside as a major anthocyanin
in the second group indicates a relationship between species of this group, because the ability to
produce acylated anthocyanins seems to be limited to about 1/2 of the investigated species (Table
18.1). The species in the third group seem closely related because, for example, they produce
delphinidin glycosides that are present only sporadically as minor constituents in the first and
second group (Table 18.1). A. hookeri ssp. cummingiana (Herb.) Bayer, A. presliana ssp. australis,
and A. schizanthoides do not fit precisely in the preceding grouping. However, A. presliana ssp.
australis seems to be related to species of the first group owing to the presence of 6-hydroxycyanidin
3-rutinoside as one of the major anthocyanins, whereas the anthocyanin composition in A. hookeri
ssp. cummingiana indicates a relationship to the species in the second group. A. schizanthoides is
different from the other species because it only contains delphinidin 3-malonylglucoside as a major
anthocyanin (Table 18.1). The anthocyanin composition of the majority of the Alstroemeria cultivars
do not fit into the grouping, probably because they are interspecific hybrids (Table 18.2). 6-Hydroxy-
cyanidin 3-glucoside (3) has only been detected in cultivars, for example, and not in the species.
The flower color is one of the most important characteristics in the breeding of ornamental
plants. In order to create desired flower colors it is an advantage to know the relationship between
the color and the contents of the pigments and their inheritance. Nørbæk et al.90 recently determined
the major anthocyanins in 28 Alstroemeria species and 183 interspecific hybrids, and a model
describing the effects of anthocyanin and co-pigments on Alstroemeria flower color was established.
The model includes four chemical characteristics: the total anthocyanin concentration, the ratio of
anthocyanins to flavonoids, the relative content of different aglycones, and the percentage of
malonated anthocyanins. Regarding the inheritance of these characteristics a high correlation
between parents and hybrids was found for the relative contents of different aglycones. For example,
the percentage of 6-hydroxycyanindin 3-glycosides in the offspring corresponded to the average

FIGURE 18.5 Chemical structures of anthocyanins (1–7) and flavonoids (8–12) isolated from species in
Alstroemeriaceae.
in their parents. For malonated anthocyanins, most often the average percentage in parents was
found in offspring. The anthocyanin concentration in the hybrids was somewhat lower than the
average of their parents. The inheritance of these three characteristics seems mainly to be controlled
by additive genes. The anthocyanin/flavonoid ratio in a hybrid often deviated strongly from the
average of the parents and no systematic tendency was apparent. Thus, the inheritance could not
be determined for this characteristic. The previous investigation could be quite valuable for selection
of parents in the breeding of new cultivars with specific colors and thereby expand the market for
Alstroemeria cut flowers.

18.2.2 TULIPOSIDES
Contact dermatitis from Alstroemeria and Tulipa (Liliaceae) is one of the best known occupational
dermatoses in the field of plant production. The causative agents have been identified as tuliposide
A and tulipalin A (see also Section 18.3.1 and 18.3.2).97-101 Tuliposide A and its b-hydroxy derivative
(tuliposide B) were first isolated from leaves, stems, and pistils of Tulipa gesneriana L. by Tschesche
et al.102,103 and identified as 1-tuliposide A (13) and 1-tuliposide B (14), respectively, (Figure 18.6).
Both compounds turned out to be very unstable as they readily rearranged by an acyl migration
into 6-tuliposide A (15) and 6-tuliposide B (16). Tschesche et al. 102,103 also demonstrated that 1-
tuliposide A and 1-tuliposide B hydrolyzed easily into b-D-glucose and their respective unsaturated
lactonized aglycones, tulipalin A (19) and (-)-tulipalin B (20) under acidic conditions or in aqueous
solution at room temperature. While the 1-acyl derivatives are very unstable, the corresponding 6-
acyl derivatives are quite stable in aqueous solution (pH » 55), showing only a slight tendency for
cleavage into b-D-glucose and tulipalin A and B, respectively.101
Since the work of Tscheshe et al.,102,103 tuliposide A and B have often been associated with the
1-acyl derivatives when found in other plants even though the position of the acyl group was not
determined.100,101 Tuliposide A has been found in all investigated species of Alstroemeriaceae, except
Leontochir ovallei, (Table 18.3) and in several Liliaceae species,102-106 whereas tuliposide B only
seems to be present in Liliaceae.104,107-112 Recent investigations of the Alstroemeria species for
tuliposide A revealed only the presence of the 6-acyl derivative.107-112 The absence of 1-tuliposide
A or other intermediate acyl derivatives (e.g., 3- and 4-tuliposide A) in the HPLC chromatograms
of various extracts of the Alstroemeria species (Figure 18.7, 18.8a, and 18.8b ) and in the 1H- and
13C NMR spectra of 6-tuliposide A clearly indicate that 6-tuliposide A is not an artefact formed
from 1-tuliposide A during extraction and isolation.101,107-111 The NMR data of 6-tuliposide A showed
that it exists both as the b- and a-anomer.101,107-109 From the integrals of the two anomeric C-1
protons appearing at d 4.62 (b) and 5.17 (a) in the 1H NMR spectrum (recorded in D2O), the
anomeric equilibrium was determined to be 3:2 at room temperature. This is consistent with the
RP–HPLC chromatograms shown in Figure 18.7, 18.8a, and 18.8b. 6-Tuliposide A may, therefore,
be the only natural acyl derivative of tuliposide A in species of Alstroemeriaceae, although the
presence of 1-tuliposide A cannot theoretically be excluded. Recent investigations of several Tulipa
cultivars and species by RP–HPLC gave similar results as only the 6-acyl derivatives of tuliposide
A and B were detected.112 Several papers on the distribution of tuliposides in Liliaceae have
appeared,104-106 but because only Tschesche et al.102,103 investigated the position of the acyl group
on D-glucose, it is still uncertain which acyl derivative of tuliposide A and B is most common in
Liliaceae. The presence of a third tuliposide (tuliposide C) in T. gesneriana have also been
indicated,102,103 but this compound has not been identified. A tuliposide with a 4-hydroxy-2-meth-
ylenebutanoate moiety in both the 1- and 6-position of b-D-glucose (tuliposide D, 17) have recently
been found in Alstroemeria species together with a closely related derivative (tuliposide E, 18)
(Figure 18.6).107-111 However, we also have been able to detect tuliposide D in some Tulipa species
of which T. patens contained relatively large amounts of this compound.112 The presence of
tuliposide D and E in Alstroemeriaceae and tuliposide D in Liliaceae is interesting from a biogenetic,
chemotaxonomic, and allergenic point of view.
Tulipalin A was isolated in 1946 from Erythronium americanum (Liliaceae)113 and later from
tulips.97,114 It has been considered only to be formed from tuliposides after excision of plant parts.98,99
However, the concentrations of tuliposides and tulipalin A immediately after homogenization of
fresh plants have recently been shown not to change over several days, clearly indicating that
tulipalin A is present in situ in the plants.101,108,110,111 This is also in accord with the different amounts
of tulipalin A found in leaves, stems, and flowers (Table 18.3).101,108,110,111 The content of tulipalin
A in the plants is probably influenced by the environment (e.g., development stage, pest attatcks,
drought), although it cannot be excluded that tulipalin A is formed after cutting and that a high

FIGURE 18.6 Chemical structures of tuliposides (13–18) and tulipalins (19, 20).

tulipalin A content is owing to high levels of a tuliposide-cleaving enzyme in the particular plant
part yielding large amounts of tulipalin A.101,108,110,111
The highest contents of tuliposides and tulipalin A in leaves, stems, and flowers of individual
plants of the species of Alstroemeriaceae are given in Table 18.3. Roots and rhizomes also contain
tuliposides104,105,112 but are not included in Table 18.3 because they have not been intensively
investigated. Roots and rhizomes are also of less importance from an allergenic point of view
because people working with Alstroemeria do not normally come into contact with these plant
parts. 6-Tuliposide A has been found in leaves, stems, and flowers of nearly all species investigated
from the Alstroemeriaceae, with a large variation among plant parts and species (Table 18.3; Figure
18.9). In most Alstroemeria plants, the content was lowest in leaves and highest in flowers (Figures
18.9 and 18.10; Table 18.3). Plants with relatively large amounts of 6-tuliposide A in stems and
flowers have been found within most species, with more than 1.5 percent of fresh weight in A.
revoluta, A. presliana ssp. presliana, and A. presliana ssp. australis, for example. These species
also contained relatively large amounts in leaves, whereas the leaves of A. angustifolia ssp.
angustifolia, A. magenta, A. magnifica ssp. magnifica, A. modesta Phil., A. pelegrina, and A. pulchra
ssp. maxima only contained 6-tuliposide A in minor amounts (Tables 18.3 and 18.4). The content
of 6-tuliposide A in one plant part was positively correlated with that in the other plant parts; that
is, plants with a high content of 6-tuliposide A in leaves often had a high content in stems and
flowers.111
The content of tuliposide D also varied among species and plant parts and ranged from not
being detectable in A. pulchella to more than 0.7 percent of fresh weight in the leaves of A. presliana
ssp. presliana. The content of 6-tuliposide A was higher than that of tuliposide D in all plants
(Table 18.3) with no correlation between the content of these two compounds.111 Alstroemeria
species may be divided into three groups regarding their content of tuliposide D (Table 18.3). In
the first group, tuliposide D occurs in very minute amounts and species belonging to this group
are for example, A. diluta ssp. chrysantha Bayer, A. ligtu ssp. simsii, A. magenta, and A. polyphylla
Phil. In the second group, for example, A. angustifolia ssp. angustifolia, A. pallida, A. pulchra ssp.
pulchra, and A. versicolor Ruìz and Pav., tuliposide D is found in moderate amounts. Finally, in
the third group consisting of A. hookeri ssp. cummingiana, A. presliana ssp. presliana, A. pseu-
dospathulata Bayer, and A. revoluta, tuliposide D is present in relatively large amounts. For species
in groups two and three, tuliposide D may contribute to the allergenic properties of these plants.
Tuliposide E has only been detected in a few species and only A. presliana ssp. presliana and
A. revoluta contained this compound in relatively high amounts (Table 18.3). It is, therefore, not
likely that tuliposide E contributes significantly to the allergenic properties of Alstroemeria.
The highly allergenic tulipalin A is mainly present in the flowers, ranging from trace amounts
in A. pulchella to more than 0.7 percent of fresh weight in A. polyphylla. In leaves and stems,
tulipalin A constitutes less than 0.3 percent of fresh weight in all Alstroemeria plants investigated
(Table 18.3). Positive correlations between 6-tuliposide A and tulipalin A in the different plant parts
were found even though the relation between the two compounds varied considerably among plants
and plant parts (Figure 18.9).111
In the genus Bomarea, only 6-tuliposide A and tulipalin A have been found except for very
small amounts of tuliposide D in the stems and flowers of B. caldasii (Table 18.3). The highest
amounts of 6-tuliposide A in Bomarea were detected in stems and flowers, whereas tulipalin A
were mainly found in the flowers. The leaves contained only very minute amounts of 6-tuliposide
A and tulipalin A, so the distribution of allergens in Bomarea follows the same pattern as in
Alstroemeria. Compared to Alstroemeria, the concentrations of 6-tuliposide A and tulipalin A seem
to be considerably less in Bomarea, although only a few species from this genus have been
investigated (Table 18.3). The presence of the same tuliposides in Bomarea and Alstroemeria and,
especially the absence of tuliposide B, clearly indicate that these two genera are closely related.
In Leontochir, tuliposides and tulipalin A appear to be absent indicating that the genus has a
special position in the family being only distantly related to the other genera (see Section 18.1.4).

TABLE 18.3
The Highest Concentrations of 6-Tuliposide A (15), Tuliposide D (17), Tuliposide E (18), and Tulipalin A (19) in Leaves (L), Stems (S) and
Flowers (F) of Species Belonging to the Genera Alstroemeria, Bomarea, and Leontochir108
6-Tuliposide A Tuliposide D Tuliposide E Tulipalin A
Genus/Speciesa and Cultivars L S F L S F L S F L S F References
Alstroemeria angustifolia ssp. angustifolia Herb. tb 7+ 7+ t 4+ 4+ n n n n 3+ 4+ 101, 108–110, 112

A. aurea Graham 8+ 8+ 7+ 1+ 2+ 3+ n n n 2+ 2+ 4+ 101, 104, 105, 108–112
A. diluta ssp. chrysantha Bayer 2+ 3+ 4+ t t t n n n t t 6+ 101, 108, 110, 112
A. exserens Meyen 4+ 6+ 4+ — — — — — — 2+ 2+ 5+ 101, 110
A. gayanac (= A. magnifica Herb.?) 2+ 4+ 7+ — — — — — — — — — 105
A. graminea Phil. 6+ 5+ 6+ 4+ 4+ 6+ — — — 2+ 1+ 4+ 110, 112
A. haemanthac (= A. ligtu ssp. simsii Bayer?) 2+ 4+ 7+ — — — — — — — — — 105
A. hookeri ssp. hookeri Lodd. 5+ 6+ 7+ — — — — — — 2+ 2+ 2+ 105, 112
A. hookeri ssp. cummingiana Bayer 5+ 7+ 7+ 4+ 5+ 5+ t t t 2+ 2+ 2+ 108, 110, 112
A. inodorac (= A. pulchella L. f.?) 4+ 4+ 7+ — — — — — — — — — 105
A. ligtu ssp. ligtu L. 6+ 7+ 7+ t 1+ 2+ n n n t 2+ 2+ 101, 104, 105, 108–112
A. ligtu ssp. simsii Bayer 3+ 7+ 6+ n n t n n n t 1+ 1+ 101, 108-110, 112
A. magenta Bayer 1+ 5+ 7+ t t 1+ — — — t 2+ 5+ 101, 108-110, 112
A. magnifica ssp. magnifica Herb. (syn. A. gayana Phil.) 1+ 6+ 7+ n 1+ 2+ n n n n 2+ 2+ 110, 112
A. magnifica ssp. maxima Bayer 1+ 5+ 6+ — — — — — — n 1+ 2+ 112
A. modesta Phil. t 7+ 7+ n 1+ 2+ — — — n 2+ 2+ 110, 112
A. pallida Graham 7+ 7+ 8+ 2+ 3+ 4+ n t t 1+ 1+ 3+ 101, 108, 110-112
A. pelegrina L. t 4+ 6+ n 2+ 3+ n t t t 2+ 3+ 101, 105, 108, 110, 112
A. philippii Baker 2+ 5+ 6+ — — — — — — 1+ 2+ 5+ 101, 105
A. polyphylla Phil. 3+ 5+ t t 1+ t n n n 2+ 2+ 6+ 101, 108, 110, 112
A. presliana ssp. presliana Herb. 8+ 8+ 8+ 6+ 5+ 5+ 3+ 2+ 1+ 2+ 2+ 2+ 108, 110, 112
A. presliana ssp. australis Bayer 8+ 8+ 8+ — — — — — — 3+ 3+ 1+ 101

A. pseudospathulata Bayer 8+ 5+ 6+ 4+ 5+ 5+ t t t 2+ 2+ 3+ 108, 110, 112
A. psittacinac (= A. pulchella L. f.?) 4+ 4+ 4+ — — — — — — — — — 105
A. pulchella L. f. 5+ 6+ 2+ n n n n n n 1+ 1+ t 108, 110, 112
A. pulchra ssp. pulchra Sims 6+ 7+ 8+ 2+ 3+ 3+ — — — 2+ 2+ 3+ 101, 105, 110, 112
A. pulchra ssp. maxima Phil. 1+ 5+ 7+ t 3+ 3+ — — — 2+ 1+ 3+ 110, 112
A. revoluta Ruìz & Pav. 8+ 8+ 8+ 5+ 5+ 5+ 2+ 2+ 3+ 3+ 3+ 4+ 101, 105, 107–112
A. versicolor Ruìz & Pav. 2+d 8+ 8+ t 4+ 3+ n t t t 2+ 3+ 101, 105, 108, 110–112
A. violaceac (= A. paupercula Phil.?) 1+ 4+ 4+ — — — — — — — — — 105
‘Rosy Wings’® 4+ 6+ 6+ — — — — — — 1+ 1+ 2+ 112
‘Carmen’® 5+ 6+ 6+ — — — — — — 1+ 1+ 2+ 112
‘White Libelle’® 4+ 4+ 5+ — — — — — — 1+ 1+ 2+ 112
Bomarea acutifolia (Link & Otto) Herb. t 3+ — n n — n n — 1+ 2+ — 112
B. caldasii (Kunth) Asch. & Graebn. t 4+ 4+ n 1+ t n n n 1+ 2+ 3+ 112
B. carderic t 2+ — — — — — — — — — — 105
B. edulis (Tussac) Herb. 4+ 4+ 3+ n n n n n n 1+ 1+ 3+ 105, 112
B. glaucescens (Kunth) Baker 1+ 3+ — n n — n n — 1+ 2+ — 112
B. simplex Herb. 2+ — n n — n n — n 2+ — 112
Leontochir ovallei Phil. [syn. Alstroemeria ovallei (Phil.) J. H. Hunz.] n n n n n n n n n n n n 112
—: not investigated; n: not detectable; t: trace; 1+ between 0.01 and 0.05 percent; 2+ between 0.05 and 0.15 percent; 3+ between 0.15 and 0.3 percent; 4+ between 0.3 and 0.5 percent;
5+ between 0.5 and 0.7 percent; 6+ between 0.7 and 1.0 percent; 7+ between 1.0 and 1.5 percent; 8+ more than 1.5 percent in fresh plant tissue.
a Author names (Alstroemeria) in accordance with Bayer.44 Synonyms of species are given in parentheses (see also Table 18.1).
b The highest concentration of 6-tuliposide A, tuliposide D, E, and tulipalin A in the investigated species of Alstroemeria, Bomarea, and Leontochir is given. However, as a large genotypic
variation is found within most species, the content in individual plants are most likely smaller at least for some of the compounds.
c The identity of the species investigated is uncertain. The most probable identity and synonym are given in parentheses.
d The content of 6-tuliposide A is much higher in this plant part according to Slob et al.105
FIGURE 18.7 An analytical HPLC chromatogram of an aqueous extract of Alstroemeria revoluta Ruìz &
Pav. stems separated on a LiChrospher 100 RP-18 (5 mm; 244 · 4 mm) column using a gradient solvent
system consisting of solvent A (distilled water — MeOH, 80:20) and solvent B (distilled water — MeOH,
50:50); elution profile: 0–6 min 0 % B, 40 min 100 % B, 45–60 min 0 % B; flow:0.6 ml min-1.
Tuliposides so far have been found only in Alstroemeriaceae and Liliaceae and these com-
pounds, therefore, seem to be useful in chemotaxonomic evaluations. To discriminate between
Alstroemeriaceae and Liliaceae tuliposide B seem to be a valuable taxonomic marker due to its
absence in the former family.
18.2.3 EXTRACTION, ISOLATION, AND QUANTIFICATION OF TULIPOSIDES

The contents of tuliposides and tulipalins have been determined by analytical methods such as thin-
layer chromatography (TLC),99-101,104,105,107-110 paper chromatography (PC),102-104 column chroma-
tography (CC),100,102,103,107,109 gas chromatography (GC),104-106 and reversed phase high performance
liquid chromatography (RP–HPLC).101,108,110,111 The later method has some clear advantages com-
pared to the other methods. RP-HPLC is very sensitive with a detection limit of approximately 0.2
mg ml-1 for tuliposides and 0.1 mg ml-1 for tulipalins. Second, the method allows in the same analysis
to detect both tuliposides and tulipalins and to determine the amounts of these compounds. Third,
the compounds can be isolated in relatively large amounts directly from aqueous extracts by using
a preparative column. Finally, RP–HPLC is fast, making it possible to investigate a large number
of plants within a minimum of time and at low cost. Thus, this method is preferred for the
quantification of the allergens in Alstroemeriaceae and Liliaceae.
Samples for analytical RP–HPLC are prepared as follows. Fresh or freshly frozen plant material
(fresh weight from 1 to 2 g) is grounded in distilled water (20 ml) with an Ultra-Turrax T25 and
stored in the dark at 4°C for 24 h before filtering. Samples (2 ml) are pressure-filtered through
cellulose acetate membranes (0.2 mm) before analysis.101,108,111 Tuliposides and tulipalins are sepa-
rated at room temperature on an analytical LiChrospher 100 RP-18 column, with a particle size of
5 mm and dimensions of 119 · 4 mm or 244 · 4 mm.101,108,111 6-Tuliposide A, tuliposide D and E,
and tulipalin A are easily separated on a LiChrospher 100 RP-18 (5 mm; 244 · 4 mm) column by
using a gradient solvent system consisting of solvent A (distilled water — MeOH, 80:20) and
solvent B (distilled water — MeOH, 50:50) with the elution profile: 0 to 6 min 0 percent B, 40
min 100 percent B, 45 to 60 min 0 percent B (Figure 18.7). The flow rate is 0.6 ml min-1 and 25
ml sample are injected. The compounds are detected at 208 nm by a UV or a photodiode array
detector. A refractive index detector can also be used, but it is about 30· less sensitive compared
with detection by UV. 6-Tuliposide A, tuliposide D, and tulipalin A also are separated easily by

FIGURE 18.8 Analytical HPLC chromatograms of an aqueous extract of Alstroemeria revoluta Ruìz & Pav.
stems separated on a LiChrospher 100 RP-18 (5 mm; 244 · 4 mm) column by simple isocratic elution. (a)
Flow rate: 0.6 ml min-1; mobile phase: distilled water — MeOH (80:20). (b) Flow rate: 0.8 ml min-1; mobile
phase: distilled water — MeOH (90:10).
simple isocratic elution. A mobile phase of 20 percent MeOH and a flow rate of 0.6 ml min-1 give
a good separation as shown in Figure 18.8a. For determination of the contents of 6-tuliposide A,
tuliposide D, and tulipalin A, this method is preferable compared to the gradient elution owing to
its simplicity and speed. If many samples are to be analysed, speed can be increased further by
only analyzing for 6-tuliposide A and tulipalin A. From an allergenic point of view this can be
justified as tuliposide D and E most often only are present in small amounts (Tables 18.3 and 18.4).
The contents of 6-tuliposide A and tulipalin A in extracts can be analyzed within 15 minutes on a
LiChrospher 100 RP-18 (5 mm; 244 · 4 mm) column using isocratic elution with 10 percent MeOH
and a flow rate of 0.8 ml min-1 as shown in Figure 18.8b. This method is not only fast but also
gives a very good separation of the two isomers of 6-tuliposide A. Furthermore, it separates
tuliposide B from tuliposide A and other components in extracts. Thus, this method would be the
one to choose for the determination of tuliposide A and B in the Tulipa species, for example.
Tuliposides and tulipalin A are quantified in extracts by using pure compounds for calibration.
The compounds are isolated by preparative HPLC or CC from crude water extracts. Isolation of
each component by preparative HPLC follows almost the same procedures as for analytical

FIGURE 18.9 Variation of the 6-tuliposide A and tulipalin A content within populations of Alstroemeria ligtu
and A. aurea. L: Leaves, S: stems, F: flowers. Each assembling of L, S, and F describe one plant. Plants were
grown in a greenhouse from seeds collected at different locations. Lowest part of each column is the content
of 6-tuliposide A and the upper part the content of tulipalin A.
separation, although the flow and injection volume are much higher.101,108 Tuliposides also can be
isolated easily by CC over silicagel using a gradient consisting of different proportions of chloro-
form, methanol, and water.107,109
18.2.4 FUNCTION AND BIOSYNTHESIS OF TULIPOSIDES AND TULIPALINS

Bergman et al.114 were the first to recognize the antibiotic properties of tulipalin A. They isolated
the compound from the white skin of young tulip bulbs and found it to inhibit the growth of several
fungi, including Fusarium oxysporum Schlecht f. sp. tulipae Apt, which causes Fusarium Bulb Rot
in tulips.114,115 Almost simultaneously, Tschesche et al.102,103 showed 1-tuliposide A and B and their
corresponding cyclized aglycones tulipalin A and B to exhibit a broad spectrum of bactericidal and

FIGURE 18.10 Relationships between the allergen content in offspring and their parents in leaves (c),
stems (V ), and flowers (2 ). Concentrations are expressed as tulipalin A equivalents, defined as the
concentration of tulipalin A in percent fresh weight that would result after total hydrolysis of the tuliposides.
Fresh weight percent of 6-tuliposide A and tuliposide D corresponds to 0.36 and 0.52 tulipalin A equivalents,
respectively.111
fungicidal activity, whereas 6-tuliposide A and B did not possess antibiotic properties. The antibiotic
activities of tulipalin A and B have recieved much attention and their role as fungitoxic agents is
now well documented.114,116-122 They appear, however, ineffective against the fungus Botrytis tulipae
that causes gray mould disease of tulips.118 Although the antibiotic properties of tuliposide D and
E have not been investigated, the present results indicate that the tuliposides in Alstroemeriaceae
are not directly involved in resistance against diseases. It is more likely that they are storage products
for the antibiotic tulipalin A that is formed from tuliposides by enzymatic hydrolysis in vivo.116,117,119
This has been confirmed in experiments where cold stored cut flowers attacked by fungi had a very
low content of 6-tuliposide A but an extremely high content of tulipalin A as compared to nonat-
tacked flowers.112 Tulipalin A may, therefore, be regarded as a post inhibitin that is present only in
relatively small amounts in uninfected plant tissue but is released in large amounts upon infection
in order to express full toxicity. The high concentrations of 6-tuliposide A and tuliposide D (total
up to 3.8 percent fresh weight) are found in some plants112 and their simple chemical structure also
indicate other functions; they may be primary metabolites functioning as storage compounds for
D-glucose or regulators of osmolarity.
The biosynthesis of tuliposides has not been investigated directly, but their chemical structure
indicates it to be rather simple. It is reasonable to assume that tuliposides are biosynthesized from
b-D-glucose and 4-hydroxy-2-methylenebutanoic acid (HMBA). A condensation between b-D-
glucose and HMBA with the loss of water would give 6-tuliposide A or 1-tuliposide A (Figure
18.11). Further condensation with HMBA leads to tuliposide D and E as shown in Figure 18.11.
Enzymatic hydrolysis of the tuliposides leads to tulipalin A and b-D-glucose and tuliposides are,
therefore as previously stated, precursors to tulipalin A. The latter has been confirmed in a

TABLE 18.4
Alstroemeria Species with Individual Plants with Concentrations of 6-Tuliposide A (15),
Tuliposide D (17), or Tulipalin A (19) Less Than 0.05% (Fresh Weight)112
Compound Leaves Stems Flowers
6-Tuliposide A t: A. ligtu ssp. ligtua t: A. polyphylla

A. modesta
A. pelegrina
1+: A. angustifolia ssp.
angustifolia
A. magenta
A. pulchra ssp. maxima
A. versicolor
Tuliposide D n: A. ligtu ssp. simsii n: A. ligtu ssp. simsii n: A. ligtu ssp. simsii
A. modesta A. pulchella A. polyphylla
A. pelegrina A. pulchella
A. pulchella
t: A. aurea t: A. aurea t: A. diluta ssp. chrysantha
A. diluta ssp. chrysantha A. diluta ssp. A. ligtu ssp. ligtu
chrysantha
A. ligtu ssp. ligtu A. excerens A. magenta
A. magenta A. ligtu ssp. ligtu
A. magnifica ssp. magnifica A. magenta
A. philippii A. modesta
A. polyphylla A. pallida
A. polyphylla
1+: A. angustifolia ssp. 1+: A. pelegrina 1+: A. aurea
angustifolia
A. pallida
A. pulchra ssp. maxima
A. versicolor
Tulipalin A Plants with concentrations less than t: A. diluta ssp. t: A. ligtu ssp. ligtu
0.05% have been found within chrysantha
nearly all species
A. excerens A. magnifica ssp. magnifica
A. graminea A. pulchella
A. ligtu ssp. ligtu
A. ligtu ssp. simsii
A. magnifica ssp.
magnifica
1+: A. angustifolia ssp. 1+: A. aurea
angustifolia
A. aurea A. excerens
A. hookeri ssp. A. ligtu ssp. simsii
cummingiana
A. pallida A. hookeri ssp. cummingiana
A. pulchella A. presliana ssp. presliana
A. pulchra ssp. A. presliana ssp. australis
maxima
A. versicolor
a Lowest concentration found in individual plants; n: not detectable; t: trace amounts (less than 0.01 percent); 1+ between 0.01
and 0.05 percent.

FIGURE 18.11 The possible biosynthesis of 6-tuliposide A, tuliposide D, and E, and tulipalin A from D-
glucose and 4-hydroxy-2-methylenebutanoic acid (HMBA). Dotted arrows indicate that the pathway is unlikely
to occur in Alstroemeriaceae but cannot theoretically be excluded.
biosynthetic study of tulipalin A performed by Huchinson and Leete.123,124 By investigating the

incorporation of radioactivity from [1-, 2-, and 3-14C] pyruvic acid into the lactone in separate
feeding experiments performed on Tulipa gesneriana, they found that tulipalin A is most likely
biosynthesized from one molecule of pyruvate and acetate. Condensation of pyruvate and acetate
yields citramalic acid that by simple reduction and dehydration leads to HMBA and then to
tulipalin A via the tuliposides (Figure 18.11). The verification of the biosynthesis of tulipalin A,
therefore, indirectly delivers the biosynthesis of tuliposides. However, as 4-methyleneglutamic
acid is a predominant amino acid in Tulipa and other Liliaceae genera, it cannot theoretically be
excluded that tuliposides are also biosynthesized from this amino acid or its decarboxylation
product (2-methylene-4-aminobutanoic acid) and b-D-glucose.125,126
18.2.5 REDUCTION OF ALLERGEN CONTENT

The allergenic action of plants can often be avoided by using proper protection such as gloves (see
Section 18.3.2). Another possibility to decrease the incidence of contact allergy by plants is to
breed cultivars with low contents of allergens. In Primula obconica, plants free of the allergen
primin have been found and the production seems to be controlled by one gene.127 To validate the
possibilities of a breeding program with the aim to decrease the allergen content, it is valuable to
have a knowledge of the genetic variability of the characteristics, environmental effects, how the
characteristics are inherited, and the biological functions of the allergens.
18.2.5.1 Genotypic Variation and Environmental Effects
The concentrations of 6-tuliposide A and tulipalin A in different plant parts of Alstroemeria species
vary considerably among genotypes.111 The largest variations have been found so far in A. aurea,
A. ligtu ssp. ligtu, and A. pallida where the coefficients of variation in the 6-tuliposide A and

tulipalin A content were generally above 40 percent within populations and much higher among
populations (Figure 18.9).111 In one A. ligtu ssp. ligtu population, the leaves did not contain allergens
whereas plants from other populations had moderate amounts. Furthermore, in one A. aurea
population the content of 6-tuliposide A and tulipalin A was generally much lower in all plant parts
when compared to the other A. aurea populations (Figure 18.9).
Patch tests with tuliposide A or tulipalin A are usually performed with safe concentrations, that
is, between 0.01 to 0.1 percent (see Section 18.3.3). Individual plants with such low contents have
been found within many Alstroemeria species (Table 18.4). Plants with a 6-tuliposide A concen-
tration below 0.05 percent fresh weight in the leaves have been found in, for example, A. ligtu ssp.
ligtu, A. pelegrina, A. magenta, and A. pulchra ssp. maxima, whereas such a low concentration
very seldomly was detected in stems and flowers. Plants within many species contained low amounts
of tuliposide D and/or tulipalin A for example, concentrations of tulipalin A below 0.05 percent
fresh weight have been detected in nearly all Alstroemeria species investigated (Table 18.4).
Environmental effects on plant chemical composition are well documented and with respect to
allergens it is known that season, irradiance, temperature, and plant age affect primin concentration
in Primula obconica Hance (Primulaceae).127,128 With respect to environmental effects, the 6-
tuliposide A content was investigated in one Alstroemeria clone transplanted monthly from in vitro
cultures and brought into flower from April to September.111 Coefficients of variation for 6-tuliposide
A were found to be 11, 20, and 29 percent in leaves, stems, and flowers, respectively, showing that
seasonal effects are less than the genotypic variation. The developmental stage of the shoot also
seems to have a large effect on the tuliposide content in Alstroemeria, as young developing shoots
had a significantly lower content when compared to flowering shoots.112
18.2.5.2 Inheritance of Tuliposides and Breeding for Low Allergen Content
The antibiotic activities of tulipalin A indicate that tuliposides at least indirectly are involved in
resistance against fungi (see Section 18.2.4) and changes in allergenic properties may, therefore,
affect resistance. Tulips contain the nonallergenic tuliposide B that is also the precursor to the
antibiotic tulipalin B, so it is theoretically possible to breed tulip cultivars with low tuliposide A
and high tuliposide B/tulipalin B content. In Alstroemeria, the situation is more complicated as
tuliposide B and tulipalin B are not present and it seems not possible, therefore, to produce
nonallergenic Alstroemeria cultivars without affecting resistance. However, as the risk for sensiti-
zation increases with allergen concentration, it should be possible to produce relative nonsensitizing
cultivars with low content of tuliposides and tulipalin A.
The inheritance of tuliposides in Alstroemeria and the possibility to produce Alstroemeria
cultivars with low content of allergens by cross breeding have recently been investigated.111 The
inheritance of tuliposides was investigated by testing the resemblance between parents and their
offspring for tulipalin A, 6-tuliposide A, tuliposide D, and total allergen content (Figure 18.10).
Narrow sense heritability of the different allergens in the different plant parts was estimated by
linear regression of the offspring value on the average of the parents. Significant heritabilities were
found for the concentration of 6-tuliposide A and tuliposide D, as well as for the total allergen
content.111 The heritability of tulipalin A was not significant, supporting the assumption that the
content of tulipalin A is controlled mostly by the environment (see Sections 18.2.4 and 18.2.5.1).
The significant and high heritabilities indicate that the production of tuliposides is controlled by
additive genes that also are expected considering the variability found within Alstroemeria species.
Several breeding generations will, therefore, be necessary before relatively nonsensitizing cultivars
can be introduced to the market. Furthermore, it also has been shown that it is possible to reduce
the allergen content by mutagenesis.111 However, to produce Alstroemeria cultivars totally without
allergens must be considered very difficult or even impossible.

FIGURE 18.12 Nucleophilic addition (Michael addition) of a skin protein on tulipalin A (hapten) forming
a protein-hapten complex (antigen).

18.3.1 ALLERGENIC PRINCIPLES
6-Tuliposide A and tulipalin A are strong sensitizers and it has been shown that these compounds
are the causative agents for allergic contact dermatitis (type IV delayed allergic reaction) in
Alstroemeria.98-100,129,130 Patients reacting positive to 6-tuliposide A and tulipalin A give negative
reactions when tested with lactones closely related to tulipalin A such as g-methylene-g-butyrolac-
tone, suggesting that a methylene group in a position is important for the allergenic activity.100
This is also in accordance with chemical considerations because the methylene group in tulipalin
A, for example, is activated by the electron withdrawing carbonyl group, making it suitable for
attack by nucleophils (rich in electrons) such as thiol (–SH) and amino (–NH2) groups in skin
proteins generating sensitizing antigens. For example, this is the type of reaction that can occur
between tulipalin A and a protein nucleophile, one of the most common haptenation reactions found
with naturally occurring sensitizers (Figure 18.12).131,132
Sesquiterpene lactones that account for most cases of allergic contact dermatitis in Asteraceae
(Compositae)129,133-135 and Frullaniaceae (liverworts)129,136 also contain the a-methylene-g-butyro-
lactone entity as part of their chemical structure, but there is no evidence of cross-reactivity between
tulipalin A and sesquiterpene lactones137,138 People sensitive to Alstroemeria and tulips, therefore,
are not normally sensitive to Asteraceae and Frullaniaceae species, and vice versa.
Tulipalin B, the cyclized aglycone of the nonallergenic tuliposide B, is able to sensitize guinea
pigs and cross-react with tulipalin A.139 The allergenic properties of tulipalin B appears to be
enantiospecific, because only the naturally occurring (–)-tulipalin B and not its enantiomer (+)-
tulipalin B is able to sensitize guinea pigs.140 The allergenic activity of tuliposide D and E have not
been investigated so far. Their structural relationship to 6-tuliposide A indicates that they have
allergenic properties and will most likely cross-react with 6-tuliposide A and tulipalin A. However,
if tuliposide D and E are not allergenic themselves, their presence still cannot be ignored because
they are very likely sources for 6-tuliposide A and tulipalin A in the plants and after deposition on
the skin.
18.3.2 DERMATITIS
All genera of the Alstroemeriaceae, except Leontochir, contain tuliposides and tulipalin A (Table
18.3), so it is reasonable to assume that the allergenic potential characterize the family. So far only
Alstroemeria have been shown to be a strong sensitizer and several cases of occupational contact
dermatitis owing to Alstroemeria have been reported.99,100,141-159 Allergic contact dermatitis to Alstro-
emeria appears to have a latent onset. Hausen et al.99 reported a delay of 19 months to 3 years

between the first exposure to the plant and development of dermatitis, and similar latency periods
have been recorded by Thiboutot et al.157 The latency period is most likely dependent on the
exposure intensity. In already sensitized persons, a minimal exposure to Alstroemeria may result
in an allergic reaction as demonstrated by Kanerva et al.159 From the stems of Alstroemeria, two
drops of sap were dripped onto the skin of a sensitized patient and immediately wiped off. This
brief skin contact for a few seconds was enough to induce an allergic edematous contact dermatitis
reaction.
Contact dermatitis owing to Alstroemeria is caused by recently damaged plant parts and
normally gives rise to eczematous dermatitis of the hands, a condition known as tulip fingers.98,160,161
Patients with tulip fingers typically present hyperkeratosis, fissuring, erythema, scaling, and ten-
derness of the fingers and fingertips.98,160-162 The forefingers and thumbs are those normally affected
as they are used mostly during flower handling.157 The clinical pattern is identical to that found in
workers handling tulips and their bulbs.160-166 Contact dermatitis to tulips is well known with many
clinical reports of tulip fingers already appearing in the 1920s and 1930s.160,162-164
The first observations of allergic contact dermatitis caused by Alstroemeria were described
by Rook141 and Cronin142 around 1970, and since then many cases have appeared with increasing
regularity up to the present day. The reasons for the sudden appearance and increasing incidence
is owing to the fact that the plants were introduced to the market in 1960s and have since become
very popular as cut flowers. The popularity of this ornamental plant is still increasing, thus, more
cases of occupational dermatitis to Alstroemeria are to be expected. The first full description of
Alstroemeria dermatitis were given by van Ketel et al. in 1975.144 There were four floriculture
workers who had allergic contact dermatitis due to Alstroemeria with positive patch tests to
different plant parts, tulip bulbs, and tulipalin A. A few years later, Rook147 reported two florists
with tender, erythematous, fissured, and hyperkeratotic fingertips, the typical clinical presentation
of tulip fingers. Many other case reports with allergic contact dermatitis owing to Alstroemeria
have since appeared describing typical cases of tulip fingers and cross-reactivity to
tulips.99,100,146,147,149,152-156
There also exists reports of patients without the typical clinical presentation of tulip fingers.
Rycroft and Calnan146 reported one patient, suffering from psoriasis, as having tulip fingers and an
onycholysis condition also. This patient was only sensitive to Alstroemeria and not to tulips. It was
concluded that not all patients allergic to Alstroemeria will cross-react with tulips, although the
possibility of a false negative reaction was considered. Björkner148 reported a case where a patient
working as gardener had strong test reactions to A. ligtu ssp. ligtu leaves and tepals. The test
responses were accompanied with depigmentation and the depigmented areas remained unchanged
for at least 1 year after test application. The reported depigmentation must be considered as a false
positive reaction (primary toxic), because of a too high allergen concentration after testing with
fresh plant material (Table 18.3).99 Hausen et al.99 reported six cases where nursery workers had
allergic contact dermatitis to Alstroemeria. The dermatitis began on the fingertips simulating the
clinical appearance of tulip fingers; later the dermatitis spread to the hands, forearms, and also to
the face. Patch tests with Alstroemeria ether extracts, tulipalin A and tuliposide A were positive.
A possible case of airborne contact dermatitis to Alstroemeria has been described by Illuminati et
al.151 The patient (florist) presented redness, scaling, and fissuring on the hands, the skin of the
face was red and scaly, and the eyelids were swollen. The involvement of the eyelids and face
especially suggested airborne contact dermatitis. Patch tests with Alstroemeria, Tulipa, and chry-
santhemum were positive and the clinical symptoms improved only after the patient avoided all
offending genera in these families. Airborne contact dermatitis caused by tulip bulbs has been
described with tuliposide A as the sensitizer.167 It is, therefore, not unlikely that Alstroemeria and
Tulipa caused the dermatitis, although chrysanthemum airborne contact dermatitis is well docu-
mented with sesquiterpene lactones as probable sensitizers.135 The observed airborne contact der-
matitis, in fact, also may have been caused by handborne allergen contamination of the eyelids and

facial skin.159 Because minimal exposure to Alstroemeria may cause an allergic reaction in sensitized
persons,159 it cannot be excluded that a possible Alstroemeria airborne contact dermatitis really is
handborne.
Alstroemeria also may cause immediate allergic reactions (Type I allergy). Piirilä et al.168 have
described two cases where one patient had respiratory symptoms and the other an allergic rhinitis.
The patient with respiratory symptoms showed a slightly positive reaction in prick tests to Alstro-
emeria pollen and the patient with allergic rhinitis showed a slightly positive specific IgE test to
Alstroemeria. Tulips may also cause Type I allergy with asthma, rhinitis, and conjuctivitis as the
most common allergic reactions.168-171 The findings about immediate allergy caused by Alstroemeria,
therefore, are important, considering the increasing popularity of the plant.
Working with Alstroemeria or tulips imply the risk of active sensitization in developing allergic
contact dermatitis such as tulip fingers. Gloves may offer protection even in already sensitized
persons, but the material with which the glove is made is important.99 Marks152 noted that tuliposide
A penetrated vinyl but not nitrile gloves. Barrier creams may also be beneficial. Thiboutot et al.157
reported that Kerodex barrier cream did not protect against dermatitis. However, a barrier cream
containing cysteine may offer protection because a mixture of cysteine and tulipalin A gave negative
patch test reactions in sensitive objects.161 Furthermore, we have been informed of a quite interesting
case of a gardener whose sensitivity to Alstroemeria disappeared after eating fresh Alstroemeria
leaves.172 Although this case has not been thoroughly investigated, it could be of importance with
regard to preventing or even curing contact dermatitis caused by these plants. At present, treatment
should be based on avoidance of Alstroemeria for affected persons.

Due to the high concentrations of tuliposides and tulipalin A in Alstroemeria (Table 18.3), direct
testing with fresh plant material carries the risk of false positive reactions and active
sensitization99,129 and thus cannot be recommended. To avoid primary irritant reactions and sensi-
tization, a safe concentration of Alstroemeria extracts or sensitizing constituents should be used
for patch testing. Patch test concentrations between 0.01 percent and 0.1 percent for all allergens
(primarily 6-tuliposide A and tulipalin A) are considered to be safe.99,100,129
Hausen and associates99,129 have indicated that incorporation of tulipalin A in petrolatum is not
suitable for patch tests because the test preparations lose their activity after two weeks storage even
at low temperature. Although tulipalin A is sensitive to heat, air, and light, we have not detected
any degradation of tulipalin A after several weeks storage in the dark at 5°C.112 Thus, tulipalin A
is quite stable if properly stored and it also is used regularly for patch testing in investigations of
Alstroemeria and Tulipa dermatitis.99,100,152,157,166,173 Tulipalin A is commercially available and patch
tests are normally carried out with a concentration of 0.01 percent in petrolatum.99,100
6-Tuliposide A is relatively stable in petrolatum even at room temperature and is therefore very
suitable for patch testing.99 Patch tests are normally carried out with tuliposide A concentrations
between 0.01 to 0.1 percent in petrolatum.99,100,151,156 As tuliposide A is not readily available,
although it can be isolated easily from fresh plant material (see Section 18.2.3), patch tests are
most often performed with tulipalin A, as described above, or with suitable extracts, for example
1 to 5 percent ethanol extract in petrolatum.99,100
Plant material of Bomarea and Tulipa were provided kindly by the botanical gardens of Missouri,
Edinburgh, Munich, and Copenhagen as well as the Royal Veterinary and Agricultural University,
Copenhagen. Plants of Leontochir were obtained from Prof. M. Bridgen, University of Connecticut.
The chemical analyses of the allergens were partly financed by the Danish Agricultural and

Veterinary Research Council, the Directorate for Agricultural Development, and the Danish Working
Environment Fund. Niels Jacobsen, the Royal Veterinary and Agricultural University, Copenhagen
is thanked for his advice and assistance. The assistance of Peter M. Jørgensen, Missouri Botanical
Garden, for extracting data from TROPICOS is greatfully acknowledged. Line K. Jacobsen, Copen-
hagen skillfully has made the line drawings.
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132. Roberts, D. W. and Lepoittevin, J.-P., Hapten-protein interactions, in Allergic Contact Dermatitis. The
Molecular Basis, Lepoittevin, J.-P., Basketter, D. A., Goossens, A., and Karlberg, A.-T., Eds., Springer-
Verlag, Berlin, 1998, chap. 6.
133. Mitchell, J. C. and Dupuis, G., Allergic contact dermatitis from sesquiterpenoids of the Compositae
family of plants, Br. J. Dermatol., 84, 139, 1971.
134. Evans, F. J. and Schmidt, R. J., Plants and plant products that induce contact dermatitis, Planta Med.,
38, 289, 1980.
135. Paulsen, E., Compositae dermatitis: a survey, Contact Derm., 26, 76, 1992.
136. Benezra, C., Stampf, J.-L., Barbier, P., and Ducombs, G., Enantiospecificity in allergic contact
dermatitis. A review and new results in Frullania-sensitive patients, Contact Derm., 13, 110, 1985.
137. Schlewer, G., Stampf, J.-L., and Benezra, C., Synthesis of a-methylene-g-butyrolactones: a structure-
activity relationship study of their allergenic power, J. Med. Chem., 23, 1031, 1980.
138. Benezra, C. and Ducombs, G., Molecular aspects of allergic contact dermatitis to plants. Recent
progress in phytodermatochemistry, Dermatosen, 35, 4, 1987.
139. Barbier, P. and Benezra, C., Allergenic a-methylene-g-butyrolactones. Study of the capacity of b-
acetoxy- and b-hydroxy-a-methylene-g-butyrolactones to induce allergic contact dermatitis in guinea
pigs, J. Med. Chem., 29, 868, 1986.

140. Papageorgiou, C., Stampf, J. L., and Benezra, C., Allergic contact dermatitis to tulips: an example of
enantiospecificity, Arch. Dermatol. Res., 280, 5, 1988.
141. Rook, A., Alstroemeria causing contact dermatitis in a florist also allergic to tulips, Contact Derm.
Newslett., 7, 166, 1970.
142. Cronin, E., Sensitivity to tulip and Alstroemeria, Contact Derm. Newslett. 11, 286, 1972.
143. Mitchell, J. C., Contact sensitivity to Tulipa and Alstroemeria, Contact Derm. Newslett., 16, 506, 1974.
144. van Ketel, W. G., Verspyck Mijnssen, G. A. W., and Neering, H., Contact eczema from Alstroemeria,
Contact Derm., 1, 323, 1975.
145. Hoffmann, H., Schulsinger, C., and Hamann, K., Alstroemeria-eksem. Et nyt erhvervseksem i Dan-
mark, Ugeskr. Læger, 143, 754, 1981.
146. Rycroft, R. J. G. and Calnan, C. D., Alstroemeria dermatitis, Contact Derm., 7, 284, 1981.
147. Rook, A., Dermatitis from Alstroemeria: altered clinical pattern and probable increasing incidence,
Contact Derm., 7, 355, 1981.
148. Björkner, B. E., Contact allergy and depigmentation from Alstroemeria, Contact Derm., 8, 178, 1982.
149. Hausen, B. M. and Schubert, H., Sensibilisierende Wirkung und Vorkommen von Tuliposiden in
Alstroemeria-Hybriden (Alstroemeriaceae), Allergologie, 6, 60, 1983.
150. Hausen, B. M. and Oestmann, G., Untersuchungen über die Häufigkeit berufsbedingter allergischer
Hauterkrankungen auf einem Blumengrobmarkt, Dermatosen, 36, 117, 1988.
151. Illuminati, R., Russo, R., Guerra, L., and Melino, M., Occupational airborne contact dermatitis in a
florist, Contact Derm., 18, 246, 1988.
152. Marks, J. G., Jr., Allergic contact dermatitis to Alstroemeria, Arch. Dermatol., 124, 914, 1988.
153. van der Willigen, A. H., Stolz, E., and van Joost, T., Alstroemeria dermatitis, Bull. Contactderm., 2,
46, 1988.
154. de Groot, A. C., Meijer, P., van Joost, T., and Hausen, B. M., Contactallergie voor Alstroemeria
(incalelie), Ned. Tijdschr. Geneeskd., 134, 1261, 1990.
155. Apted, J. H., Contact dermatitis due to Alstroemeria (Peruvian lily), Aust. J. Dermatol., 31, 111, 1990.
156. Adams, R. M., Daily, A. D., Brancaccio, R. R., Dhillon, I. P. S., and Gendler, E. C., Alstroemeria. A
new and potent allergen for florists, Dermatol. Clin., 8, 73, 1990.
157. Thiboutot, D. M., Hamory, B. H., and Marks, J. G., Jr., Dermatoses among floral shop workers, J.
158. Lamminpää, A., Estlander, T., Jolanki, R., and Kanerva, L., Occupational allergic contact dermatitis
caused by decorative plants, Contact Derm., 34, 330, 1996.
159. Kanerva, L., Estlander, T., and Jolanki, R., Minimal Alstroemeria exposure during skin testing causing
an allergic contact dermatitis reaction, Eur. J. Dermatol., 4, 616, 1994.
160. Bertwistle, A. P., “Tulip fingers,” Br. Med. J., 2, 255, 1935.
161. Hjorth, N. and Wilkinson, D. S., Contact dermatitis IV. Tulip fingers, hyacinth itch and lily rash, Br.
J. Dermatol., 80, 696, 1968.
162. Rappaport, B. Z. and Welker, W. H., Tulip bulb dermatitis, J. Allerg., 8, 379, 1937.
163. Overton, S. G., Dermatitis from handling flower bulbs, Lancet, 2, 1003, 1926.
164. Caulfield, A. H. W., Report of the investigation and successful treatment (prevention) of dermatitis
resulting from the handling of tulip bulbs, J. Allerg., 8, 181, 1936.
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85, 798, 1962.
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338, 1959.
170. Lahti, A., Contact urticaria and respiratory symptoms from tulips and lilies, Contact Derm., 14, 317,
1986.
171. Krüsman, W. and Hausen, B. M., Tulpenallergie vom Soforttyp mit Asthma Bronchiale und Rhinocon-
junktivitis, Allergologie, 10, 549, 1987.
172. Paulsen, E., personal communication, 1998.

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growers, Contact Derm., 29, 11, 1993.
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aceae, Biochem. Syst. Ecol., 3, 229, 1975.

19 Aristolochiaceae
Luisa Pistelli
CONTENTS
19.1 Introduction
19.1.1 Morphological Characteristics of the Plant Family
19.1.2 Geographical Location
19.2 Chemical Constituents
19.2.1 Aristolochia Spp
19.2.1.1 Nitrogenated Constituents
19.2.1.1.1 Phenanthrene Derivatives
19.2.1.1.2 Alkaloids
19.2.1.2 Constituents without Nitrogen
19.2.1.2.1 Terpenoids
19.2.1.2.2 Lignoids
19.2.1.2.3 Flavonoids
19.2.2 Asarum Spp
19.2.3 Heterotropa Spp
19.2.4 Asiasarum Spp
19.2.5 Thottea Spp
19.2.6 Pararistolochia Spp
19.2.7 Hexastylis Spp
19.2.8 Saruma Spp
19.3 Pharmacology and Clinical Use
19.3.1 Aristolochia Spp
19.3.1.1 Pharmacology
19.3.1.1.1 Antitumor Activity
19.3.1.1.2 Immunomodulating Activity
19.3.1.1.3 Antibacterial and Antifungal Action
19.3.1.1.4 Antifertility Activity
19.3.1.1.5 Hypotensive Action
19.3.1.1.6 Miscellaneous Actions and Toxicity
19.3.1.2 Clinical Use
19.3.1.3 Dermatological Use
19.3.2 Asarum Spp
19.3.2.1.1 Sedative and Analgesic Effects
19.3.2.1.2 Antipyretic and Anti-Inflammatory Effects
19.3.2.1.3 Local Anesthetic Activity
19.3.2.1.4 Antibacterial and Antifungal Activity
19.3.2.1.5 Antihistaminic and Anti-allergic Effects

19.3.2.1.6 Effect on the Respiratory System
19.3.2.1.7 Effect on the Cardiovascular System
19.5 References
19.1 INTRODUCTION
Aristolochiaceae (the Birthwort family) is a family of twining shrubs, lianes, vines, perennial herbs,
that usually are rhizomatous and fragrant. The family consists of 7 to 8 genera and 450 to 600
species, mainly widespread in the Tropics, with a few species in subtropical and temperate regions
of the Old and the New World.
The common name of the family seems to be derived from two Greek words: aristos meaning
best or, excellent, and lochia meaning delivery. This name concerns the genus Aristolochia that is
used as a medicinal herb during childbirth.
The common name of Aristolochia L. is Dutchman’s pipe vine, referring to the unusually
shaped, curved flowers that resemble a Dutch pipe. Asarum L. is the scientific name for wild ginger,
while the scientific name for Hexastylis Raf. is heartleaf.
More than 100 taxa of Aristolochiaceae plants have been studied chemically, and many of these
are widely used in traditional medicine. The purpose of this chapter is to review the chemistry,
pharmacology, and clinical use of plants belonging to this family.
19.1.1 MORPHOLOGICAL CHARACTERISTICS OF THE PLANT FAMILY

Leaves are simple, petiolate, without stipules, alternate (subopposite in Asarum), entire, generally
cordate, palmately nerved. Flowers are solitary, racemose or in clusters, axillary (terminal or sub-
terminal in Asarum and Saruma), pedicellate, hermaphrodite, zigomorphic or rarely actinomorphic,
and usually 3-merous. Perianth in one whorl is approximately petaloid. Calyx is absent in Aristolo-
chia, Euglypha and Holostylis, synsepalous, trilobed, and frequently regular in Asarum, Saruma,
and Thottea. Petals are missing or much reduced in some Asarum spp., well developed and alternate
with the calyx lobes in Saruma, in Aristolochia, Euglypha, and Holostylis form a tube, are 3-lobed
at the apex or have a single unilateral and entire lobe that is often highly colored and fetid. There
are 5, 6, or 12 stamens, in 1 or 2 rows. The stamens are either free or adnate to the stylar column
to form a gynostemium. Anthers are dithecal, tetrasporangiate, and open longitudinally.
The ovary is inferior, rarely semisuperior, and usually forms 6-carpellar or, rarely, 4- to 5-
carpellar that usually are united or partially distinct, placentation is axillary or parietal. There
usually are six styles that are short and thick and free or fused in a gynostemium. Stigmas radiate
and there usually are six. Fruit usually has a septicidal capsule and a follicle in Saruma. Seeds are
numerous, usually flat, with minute embryos.
19.1.2 GEOGRAPHICAL LOCATION

From a systematic point of view, Hegnauer reported that the Aristolochiaceae family was subdivided
into two subfamilies and five tribes1:
I. Asaroideae.
1. Sarumeae: Saruma.
2. Asareae: Asarum.
3. Bragantieae: Apama, Thottea.

II. Aristolochioideae.
4. Aristolochieae: Aristolochia, Holostylis.
5. Euglypheae: Euglypha.
More recently, Brummitt subdivides Aristolochiaceae in eight genera2:
Aristolochia L.
Asarum L.
Euglypha Chodat and Hassl.
Holostylis Duch.
Isotrema Raf.
Pararistolochia Hutch. and Dalziel
Saruma Oliv.
Thottea Rottb.
The Asarum genus occurs in Europe with 1 species, A. europaeum although 13 Aristolochia species
are listed.3 In the flora of tropical Africa, the genus Pararistolochia is reported along with Aristolo-
chia, the first being the predominant in the west countries (with 12 species),4 while in the eastern
regions of Africa, Aristolochia species are the most abundant and only Pararistolochia triactina
(Hook. f.) Hutch. and Dalz. is reported.5
In North America, the Aristolochiaceae family is present with three genera: Aristolochia L.
(Dutchman’s pipe), Asarum L. (wild ginger), and Hexastylis Raf. (heartleaf).6 The Aristolochia
genus predominates in South of America,7 although in Argentina, there are two classified Aristolo-
chiaceae genera: Euglypha Choda et Hassler and Aristolochia L.,8 and three in Brazil: Aristolochia
L., Euglypha Choda et Hassler, and Holostylis Duch.9
More than 100 Asarum species are known and about 30 species are distributed in Japan,10
where only 4 Aristolochia occur (A. kaempferi Willd., A. onoei Fr. et Sav., A. debilis Sieb. et Zucc.,
and A. contorta Bge).
China is certainly the country where Aristolochiaceae genera and species are well represented,
about 50 species of Aristolochia and 50 species of Asarum, along with a few other species of
Heterotropa, Saruma, and Thottea.11 Some species of Aristolochiaceae are also reported in
Australia.12
19.2 CHEMICAL CONSTITUENTS

19.2.1 ARISTOLOCHIA SPP.
The genus Aristolochia is distributed in a wide area from the tropics to temperate zones and consists
of about 400 to 600 species. Only 70 species were chemically investigated until now.
The chemical constituents of the Aristolochia species may be divided into two general groups:
1- nitrogenated constituents:
phenanthrene derivatives
alkaloids
2- constituents without nitrogen:
terpenoids
lignoids
flavonoids

FIGURE 19.1 Main aristolochic acids and aristolactams isolated from the Aristolochia species.
19.2.1.1 Nitrogenated Constituents
19.2.1.1.1 Phenanthrene Derivatives

The so-called aristolochic acid (AAs) and aristoloctam (AMs) derivatives, recognized as special
and the main chemical constituents of this genus, belong (beside chloramphenicol and a few other
natural compounds) to substances rarely found in nature that contain a nitro group. The aristolochic
acids are derived from the phenanthrene system and bear a carboxyl function and a nitro substituent.
When the nitro group is replaced by an amino group, the carboxyl function forms a lactam ring,
giving a number of aristolactams. AAs are biosynthetically derived from aporphine-type alkaloids
by oxidative degradation; probably intermediates are involved that are hydroxylated at position 4.13
Oxygenate functions often occur in the positions 6, 7, 8; 6 and 8 or 7 and 8. Sometimes it is
possible to found glycosidic derivatives of AAs and AMs, more C-glycoside than N-glycoside.14
The structures of the main aristolochic acids and aristolactams are isolated from Arsitolochia plants
and are shown in Figure 19.1.
Aristolochic acids have been found only among the Aristolochiaceae plant family,15 and among
the butterfly that feed on such plants.16,17 The botanical range of the aristolactams is somewhat
broader; most of them are still found in the Aristolochiaceae, although there are also well

authenticated reports of their occurrence in some members of the Annonaceae, Menispermaceae,
and Monimiaceae.15 The botanical occurrence of AAs and AMs are reported in the Reference 18.
Recently, Houghton and Ogutveren19,20 isolated an AA with an unexpected oxygenated function
at C-9 (9-methoxyaristolochic acid II). Another unusual compound is debilic acid (Figure 19.1)
that represents an homo-aristolochic acid because it incorporates a carboxymethyl side chain at
C-1.21 From the roots of A. indica L., phenanthrene derivatives without the characteristic nitro
group in position 10 are also isolated.22 Aristolide-A and aristolide-B (Figure 19.1) are two novel
compounds isolated from the roots and stems of Aristolochia heterophylla Hemsl. They represent
the first isolation of dihydrophenanthrenelactones from a natural source.23
Compounds with nitro groups are rare among natural products, with the exception of the AAs
and AMs just examined. Therefore, 9-methoxytariacuripyrone and 7,9-dimethoxytariacuripyrone
with the new 5-nitro-2H-benzo[h]chromen-2-one skeleton, isolated from the rhizomes of Aristolo-
chia brevipens Benth. (common name of tacopate or guaco in Mexico) might be considered new
natural compounds (their cyclic skeleton might originate from a corresponding AA).24
19.2.1.1.2 Alkaloids
All alkaloids isolated from Aristolochia spp. have an isoquinolinic nucleus and may be devided
into four groups (Figure 19.2):
Aporphinoids
Tetrahydroprotoberberine alkaloids
Benzylisoquinoline and bis-benzylisoquinoline alkaloids
Protopine
One of the most common aporphinic alkaloids that occur in many Aristolochia spp. is magno-
florine which is structurally and phylogenetically related to aristolochic acid derivatives18; it is a
quaternary ammonium base with hypotensive activity.25-26 Other aporphine alkaloids isolated from
Aristolochia plants are corituberine, with a formula consistent with magnoflorine but with a tertiary
nitrogen (from A. clematitis L.),18 (-)-N-acetylnornuciferine, isolated from A. bracteata Retz. (um-
galegel or erg-el-agrab is the popular Indian name),27 cepharadione-A, 4,5-dioxodehydroasimi-
lobine, and aristolodione obtained from the aerial parts of Aristolochia chilensis Miers. (vernacular
name oreja de zorro or hierba de la virgen),28 tuberosinone and its derivatives, isolated and identified
from A. tuberosa C. F. Liong et S. M. Hwang,29 and N-formylnornantenine and its 6a,7-dehydro
derivative from A. brevipens Benth. rhizomes.30 Recently, two other alkaloids have been isolated
and identified from Aristolochia triangularis Cham. et Schletch. roots (mil hombres is its trivial
name) named triangularine A and triangularine B.31
Among the tetrahydroprotoberberine alkaloids, cyclanoline represents the only one extracted
for the first time from A. debilis Sieb. et Zucc.,32 while ten 8-benzylberberine-type alkaloids were
extracted from A. gigantea (Hook.) Klotzsch, eight of which are glycosidic derivatives.33 A novel
(-)-8b-(4¢-hydroxybenzyl)-2,3-dimethoxyberbin-10-ol was isolated from aerial parts of A. constricta
Mutis ex H. B. K. along with new protopine-type alkaloids 3,5-di-O-methylconstrictosine, 5,6-
dihydro-3,5-di-O-methylconstrictosine, 5,6-dihydroconstrictosine, constrictosine, and 3-O-methyl-
constrictosine. All the protopine derivatives significantly reduce, in a dose dependent manner, the
electrical, acetylcholine, and histamine contractions of the isolated guinea-pig ileum.34
Bis-benzylisoquinoline alkaloids (11,12¢-linked 1-benzyltetrahydroisoquinoline dimer) appear
to be rare in Aristolochia species. The first isolated was (-)-curine from A. indica L., then tetrandrine
from roots of A. debilis Sieb. and Zucc., (-)-temuconine was obtained from A. elegans of Egyptian
origin, then (-)-pampulhamine, (-)-geraldoamine, (-)-pedroamine (alkaloids with one diphenyl ether
link between rings C and C¢) were isolated from defatted leaves of A. gigantea Mart.,18 along with
the recently isolated alkaloids of this type, named dimethylgrisabine, O-methyldauricine, from the
bark of A. gigantea Mart.35

FIGURE 19.2 Alkaloids from Aristolochia spp.
Among nitrogenated constituents various amides, N-2-(4-hydroxyphenyl)ethyl-4-hydroxy-

cinnamide derivatives, and allantoin were also isolated from several species of Aristolochia.18,36
For all the chemical structures cited in the section on alkaloids, see Figure 19.2.
19.2.1.2 Constituents without Nitrogen

19.2.1.2.1 Terpenoids
There are few references in the literature about the components of the essential oils of Aristolochia
spp. The main constituents are monoterpenes, sesquiterpenes hydrocarbons, and oxygenated ses-
quiterpenes extracted by steam distillation of the aerial parts and roots of the examined species.
Sesquiterpenes are the predominated components in the volatile oils of seven Brazilian species18;
sesquiterpene hydrocarbons, in particular b-caryophyllene, isocaryophyllene, and bicyclogerma-
crene, are abundant also in the oil obtained by hydrodistillation from the leaves of A. elegans Mast.,
whereas the amounts decrease in the essential oils obtained from the other plant parts (stems and
roots) in which the oxygenated sesquiterpenes, mainly E-nerolidol, were the main constituents.37
The composition of the essential oil from A. asclepiadifolia Brandg. root was investigated over a
period of four years by gas chromatography–mass spectrometry: the freshly prepared essential oil

had a characteristic pleasant aroma. Linalol and its oxides, borneol and its oxides, and guaiol and
its isomers were found as the major components, along with a-bisabolol, ledol, terpineol, and
limonene and its oxides, with vanillin being a minor but important component for the aroma and
quality of essential oil.38
Further studies on the volatile constituents were carried out on A. debilis Sieb. and Zucc.,39 A.
longa L.,40 A. ringens Vahl.,41 A. indica L.,42 and A. chilensis Miers.43 Among the sesquiterpenes,
aristolone was isolated from the underground parts of A. debilis Sieb. and Zucc. (a plant used in
Chinese traditional medicine) together with several aristolane-type sesquiterpene derivatives.44 9-
aristolene, 1(10)-aristolene and their related compounds possess a 1H-cyclopropan[a]naphtalene
skeleton. New sesquiterpene hydrocarbons, ishwarane and aristolochene, were isolated from the
roots of A. indica L.; another of these compounds was also isolated from A. debilis Sieb. and Zucc.
(3-oxoishwarane).44,45 In A. indica L., further isolated were the (12S)-7,12-secoishwaran-12-ol, an
antifertility active principle, and the first aromadendrane derivative meet in this species, (+)-ledol.46
The previous unknown (+)-isobicyclogermacrenal was isolated from the petrol-ether (1:1) extract
of the stems of A. manshuriensis Kom.47 Investigation of the root and stem of A. cucurbitafolia
Hayata resulted in the isolation of seven sesquiterpenes, aristolactone, manshurolide, and five new
compounds namely madolins A–E.48
Sesquiterpene lactones are well represented in the Aristolochia species: aristolactone (from A.
reticulata Nuttal), isoaristolactone (from A. versicolar S. M. Hwang), mollislactone and neoaris-
tolactone (A. mollissima Hance),49 and the versicolactone A–D series, where versicolactone A has
a 12-C ring skeleton, versicolactone B is a germacranolide, versicolactone C, with an hydroazulene
skeleton, versicolactone D, as a dimeric compound, and yindailactone B, all isolated from A.
versicolar S. M. Hwang.50-52 Other sesquiterpene lactones, manshurolide and melampolide, were
also isolated from A. manshuriensis Kom. and A. yunnanensis Franch., respectively.53-54 Figure 19.3
showed the sesquiterpene constituents isolated from Aristolochia spp.
Diterpenes belonging to the kaurane, clerodane, and labdane skeleton types were isolated from
leaves, stems, and roots of some species of Aristolochia, especially of Brazilian origin. These
compounds were identified as clerodane derivatives from stems of A. brasiliensis Mart. et Zucch.,
roots of A. esperanzae Kuntz., roots of A. galeata Mart. et Zucch., and roots of A. cymbifera Mart.
and Zucc.41,55-57; ent-kaurane type located only in A. elegans Mast. and A. triangularis Cham. et
Schletch.58-59; and ent-labdane diterpenes isolated from A. cymbifera Mart. and Zucc. and A. galeata
Mart. et Zucc.41,56
A furanoid diterpene lactone, columbin, was also isolated for the first time in the Aristolochi-
aceae family from the rhizomes of Aristolochia albida Duch.60 while argentilactone, a skin irritant
compound, was isolated as a new constituent from rhizomes of A. argentina Gris.61 Diterpene
structures, columbin, and argentilactone are reported in Figure 19.4.
19.2.1.2.2 Lignoids
From the chemical point of view, members of the Aristolochiaceae are known by their ability
to synthesize phenanthrene alkaloids and arylpropanoids. The latter include lignans and neolig-
nans. Such lignoids are reported to possess antitumor, antifungal, antibacterial, and insecticide
properties.62
Eupomatenoids are 3-methyl-2-phenyl-5(E)-propenylbenzofuran derivatives that fall within the
general chemical class of lignans and, more specifically, have been proposed as neolignans. They
owe their name to the family of Eupomatiaceae that is a rich source of these compounds. (±)-
Licarin A (or dehydrodiisoeugenol), (–)-licarin B (or eupomatenoid-8), eupomatenoid-7, and eupo-
matenoid-1 were isolated from roots and stems of plants of the Aristolochia genus (A. maxima L.
or A. taliscana Hook. and Arn.), popularly known as guaco or raiz de guaco in Mexican folk
medicine.63-64 Also, 7 lignoids 1 to 7 were also isolated and identified from A. birostris Duchtre, a
plant used in Brazilian folk medicine (common name capivara or angelicó or jarrinha).65

FIGURE 19.3 Sesquiterpenes and sesquiterpene lactones from Aristolochia spp.
From seven Brazilian Aristolochia species (A. brasiliensis Mart. et Zucc., A. cymbifera Mart.
et Zucc., A. esperanzae Kuntz., A. triangularis Cham. et Schletch., A. birostris Duchtre, and A.
galeata Mart. et Zucc.) and from A. indica L. were isolated many dibenzylbutyrolactone type lignans.
Among these constituents, the formulas of cubebin and hinokinin56,58,62,65-67 are listed in Figure 19.5.
The 2,5-diaryl-3,4-dimethyltetrahydrofuranoids are a group of lignans found mainly among
members of the botanical families belonging to the order Magnoliales and were also found in the
botanically related family Aristolochiaceae. (+)-Zuonin-A, (+)-aristolignin, and nectandrin-B are
three examples of these tetrasubstituted tetrahydrofuran derivatives isolated from roots of A. chil-
ensis Miers., A. ponticum, and A. birostris Duchtre.19,65,68,69 These lignan type constituents were
described only in the Aristolochia species whereas neolignans, structurally related to asatone, were
also isolated from the Asarum and Heterotropa species.62
Another class of lignans that also occurred in many Brazilian Aristolochiae were the furofuran
type lignans: where asarinin and fargesin18,56 represented two examples of these compounds.
The 4-aryltetralones are a small group of lignans found previously in Virola sebifera (Myris-
ticaceae) and in Schisandra spp. (Schisandraceae). (-)-Aristotetralone was obtained as a minor
component in A. chilensis Miers.70,71 Figure 19.5 shows the main lignoid structures isolated from
Aristolochia species source.

FIGURE 19.4 Diterpene structures, columbin, argentilactone, and flavonoids from Aristolochia spp.
19.2.1.2.3 Flavonoids
Only few flavonoids were reported from leaves, stems, roots, or rhizomes of the Aristolochiaceae
species: isorhamnetin-3-O-b-D-robinobioside,72 kaempferol-3-O-b-D-robinobioside,73 rutin, quer-
cetin-3-b-glucoside (quercitrin), isorhamnetin, and 3,3¢,4¢,6,8-pentahydroxyflavone18.
From the extracts of the roots of A. indica L. was reported the isolation and characterization
of a new naphtoquinone, aristolindiquinone.74 Chemical structures of these compounds are reported
in Figure 19.4.
19.2.2 ASARUM SPP.

The genus Asarum of Aristolochiaceae with about 100 species has a wide distribution in Asia,
Europe, and North America. The genus has its center of distribution in eastern Asia, especially
Japan and China. Because all Asarum spp. show similar morphological characteristics according
to the Engler’s classification, all the Asiatic species are placed in one genus Asarum. In contrast,
in Maekawa’s and Bromquist’s systems, the genus is divided into five subgenera: Asarum L.,
Asiasarum F. Maekawa, Heterotropa Morr. et Decne., Geotaenium F. Maekawa, and Hexastylis
Raf.75 Either theory is acknowledged in Japan. In 1983, Cheng and Yang reported that there were

FIGURE 19.5 Lignoids from Aristolochia spp.
31 Asarum species in China, divided into two subgenera, Asarum and Heterotropa.76,77 Hitherto,
the systematic classification of this genus resulted were debatable.
The chemical composition of the essential oils obtained from many Asarum species were
investigated by gas chromatography–mass spectroscopy (GC–MS) to identify the bioactive com-
pounds responsible for the local anaesthetic, analgesic, antipyretic, sedative, and hypotensive
activity proved in the popular medicine of other countries. So 1,8-cineole, asaricin, methyleugenol,
croweacin, b-pinene, a-thujene, myrcene, terpinen-4-ol, a-terpineol, safrole, and myristicin were
identified in A. sieboldii Miq. (common name Huaxixin), while from four Chinese medicinal
species, A. siebolii var. soeulensis Nakai, A. forbesii Maxim., A. inflatum, C.Y. Chen and C. S.
Yang, A. magnificum var. dinghugense, C.Y. Chen and C. S. Yang, and A. caudigerum Hance var.
cardiophyllum, 3,5-dimethoxytoluene, safrole, methyleugenol, elemicin, and 2-undecane were
found in all species, together with several mono and sesquiterpenes.25,75
The fragrant volatile oils of Asarum canadense L. (common name Canada snakeroot, wild
ginger), obtained from the pentane extract was subjected successively to stem distillation,78 con-
tained monoterpene hydrocarbons, alcohols and esters, aromatic compounds, such as linalool,
geraniol, a-terpineol, eugenol and methyl eugenol,79 and the sesquiterpene ketone, aristolone.80,81

Rhizome oils of Asarum europaeum L. (trivial name hazelwort, asarabacca) was investigated
for a long time, so that these plants existed in four populations based on the essential oil compo-
sitions (chemovar. trans-isoasarone, chemovar. trans-isoeugenolmethylether, chemovar. trans-iso-
elemicin, chemovar. eudesmol).82 A tricyclic compound, a-agarofurane83 and furopelargon-A, a C15-
ketone were also isolated from the same source84; while from the nonvolatile oil, large amount of
trans-aconitic acid was detected. This compound showed anticancer effect in vitro.85-88
Subterranean parts of Asarum caulescens Maxim. furnished an essential oil where sesquiter-
penoid compounds were the main components89-93: caulesol and germacrone-4,5-epoxide,90 dihy-
drofuranocaulesone and caulesone,91 furanocaulesone A-C and (+)-aoifuranone93 along with eucar-
vone, borneol or estragole1,8-cineole, b-pinene, methyeugenol, safrol, saishinone, croweacin,
elemicin, 1-allyl-2,3,4,5-tetramethoxybenzene and 1-allyl-2,4,6-trimethoxybenzene.81
The oil of A. petelotii O. C. Schmidt contained phenol ethers in higher amounts than terpenes;
a unique phenol ether, apiole was present in the leaves (28.6 percent) and roots (30.4 percent)
together with considerable amounts of elemicin (26.44 percent) in the leaves and b-himachalene
(20.72 percent) in the roots.94 Then 7-methoxyaristolactam IV was identified together with 1,2,3,4-
tetramethoxy-5-allylbenzene, b-sitosterol and daucosterol. This was the first time that one aristo-
lactam alkaloid was obtained from the genus Asarum.95
Others studied Asarum spp. to evaluate the essential oil composition are listed here: A. caudi-
gerellum C. Y. Cheng and C. S. Yang,96 A. forbesii Maxim.,97 A. heterotropoides F. Schmidt,80,96,98,99
A. himalaicum Hook f. and Thomson et Klotzsch,80,100-102 A. ichangense C. Y. Cheng and C. S.
Yang,80 A. infaustum C. Y. Cheng and C. S. Yang,103 A. inflatum C. Y. Cheng and C. S. Yang,103 A.
insigne Diels,104,105 A. leptophyllum Hayata,81 A. macranthum Hook f.,106 A. porphyronotum C. Y.
Cheng and C. S. Yang,96 A. sieboldii Miq.,96,105 and various Asarum spp.75,77,107-109 The presence of
asatone, an unusual lignan, that occurs in n-hexane extract of various Asarum taxa was also
investigated and the results showed that asatone was more widespread in Asaurum sensu lato even
if it occurred in several sections of Heterotropa.110,111
Chingchengenamide A and B, two novel amides, were isolated from the ethyl acetate extract
obtained from rhizomes of A. chingchengense C. Y. Cheng and C. S. Yang,112 while in A. sagittar-
ioides C. F. Liang a similar compound, N-isobutyl-3,4-methylenedioxybenzamide, also was isolated
and proved to be an anti-allergic substance by pharmacological studies.113 Roots of A. maculatum
have been used as a substitute for A. sieboldii Miq. and A. sieboldii var. seoulensis Nakai that are
employed in Chinese medicine to treat halitosis, pain, cough, and asthma. From this plant material,
l-asarinin and N-isobutyl-(2E, 4E, 8E, 10E)-2,4,8,10-dodecatetraenamide was isolated.114,115
Polyphenolic compounds were also detected from Asarum spp.: quercetin, quercetin 3-O-b-D-
glucopyranoside, kaempferol 3-O-b-D-galactopyranoside, and kaempferol 3-rutinoside were iso-
lated from A. europaeum L.,116 while naringenin, 5,7-di-O-b-D-glucopiranosyl-2(S)-naringenin, and
2¢,4¢-di-O-b-D-glucopiranosyl-4,6¢-dihydrochalcone were isolated from the whole plant of A. mac-
ranthum Hook f. The latter substance was isolated for the first time in the genus Asarum.106 Peonidin
3-gentiobioside and cyanidin 3-gentiobioside acylated separately with p-coumaric and caffeic acids
were identified in the dark purple flower of A. asaroides (Morr. et Decne) Makino.117 The structures
of the main constituents isolated from Asarum spp. are shown in Figure 19.6.
19.2.3 HETEROTROPA SPP.

Heterotropa is known for its characteristic ornamental and medicinal value. More than 40 species
belonging to the subgenus Heterotropa grow in far eastern Asia. Because it is difficult to distinguish
each species on morphological data, some workers have reported the analysis of the essential oil of
several Heterotropa spp. for chemosystematic purposes. Large amounts of phenylpropanes, terpenes,
and a paraffin were found as the main components in the volatile oil of Heterotropa takaoi F. Maek.76
However, the main components of all Heterotropa species were terpene (monoterpenes and sesquit-
erpenes) and phenolether constituents, such as elemicin, safrole, ATMB, and apiole.39,77,118-121

FIGURE 19.6 Main structure of constituents isolated from Asarum spp.
Asatone, a neolignan compound, was isolated in many species of Heterotropa,110 while new neo-
sesquilignans, a heterotropanone, and a sesquiterpene, heterocurvistone, were isolated from H. takaoi
F. Maek.122-124 and H. curvistigma F. Maek., respectively.125
Many of the swallowtail species (Papilionidae, Lepidoptera) are associated either with Rutaceae
or Aristolochiaceae. Two papilionid butterflies, Luehdorfia puziloi and Luehdorfia japonica are
regarded as sibling species, but a distinctive characteristic between the two species is manifested
by the difference in host plants. Luehdorfia japonica feeds on a large variety of Heterotropa plants
and is also able to perform well on other aristolochiaceous plants such as Asiasarum or Asarum.
In contrast, Luehdorfia puziloi is restricted to Asiasarum plants. A feeding deterrent against larvae
of a papilionid butterfly Luehdorfia puziloi was isolated from Heterotropa aspera. One of the
antifeedant agents was identified as a neolignan compound, asatone.126 From the leaves of the same
host plant was isolated an oviposition stimulant component of Luehdorfia japonica and identified
as isorhamnetin 3-O-b-glucosil-(1fi 6)-b-galactoside-7-O-b-glucoside.127

19.2.4 ASIASARUM SPP.
Asiasari radix (Saishin in Japanese) prepared from the roots of Asiasarum sieboldi F. Maekawa,
or A. heterotropoides var. mandshuricum (Maxim.) F. Maek. is one of the most important crude
drugs in Chinese medicine and it was used as an analgesic antitussive or anti-allergic remedy.
Although several compounds were isolated from the roots of Asiasari radix, as two new phenyl-
propanoid glycosides (1-O-feruloyl-b-D-xylopranosyl-(1fi 6)-b-D-glucopyranoside and 1-O-p-
coumaroyl-b-D-xylopyranosyl-(1fi 6)-b-D-glucopyranoside), very little information was obtained
on their biological activity.128 The methanolic extract of the roots of A. sieboldi Miq. was evaluated
for anti-allergic effects on various experimental models in vitro and in vivo. A bioassay-guided
fractionation of that extract resulted in isolation of suppressive compounds in the PCA test:
methyleugenol, elemicin, g-asarone and sesamin. Furthermore, elemicin and (2E, 4E, 8Z, 10E)-N-
isobutyl-2,4,8,10-dodecatetraenamide were found to exhibit an inhibitory action on 5-lipoxygenate
(5-LOX) from RBL-1 cells.129 The alkamides form a distinct class of natural products in which
different amine parts are combined by an amide linkage with various unsatured fatty acids. The
latter may be derived from oleic acid and contain an unbranched alkyl chain of 9 to 18 carbon
atoms with one or more double bonds frequently accompanied by one to three acetylenic linkages.
Several olefinic isobutylamides were shown to possess considerable insecticidal activity, particularly
against house flies, sometimes surpassing that of the pyrethrins; furthermore alkamides were used
medicinally as sialogogue, antitussive, and analgesic remedies. Because N-isobutyldodecatetraena-
mide was one of the antitussive principles, other amides (as pellitorine) were isolated from A.
heterotropoides var. mandshuricum (Maxim.) F. Maek.130,131 Further studies on chemical composi-
tion of the essential oils of Asiasarum spp. were also reported.81
19.2.5 THOTTEA SPP.

Thottea is known only from tropical Asia.132 Only two Malaysian species were studied, Thottea
tricornis Maingay ex Hookerf. and T. dependens (Planch.) Klotzsch., where the presence of aris-
tolochic acids in the leaves was demonstrated for the first time since the larvae of two troidine
swallowtail butterflies, Troides (Troides) amphrysus and Pachliopta (Losaria) neptunus sequestered
these compounds in the osmeterial glands133
19.2.6 PARARISTOLOCHIA SPP.

Pararistolochia flos-avis (A. Cheval) Hutch. and Dalz. were reported to contain aristolactam I, AM-
AII, and two new derivatives, AM-FI and AM-FII.134 Furthermore, a new tetralone derivative,
namely flossonol, and a new lignan, (–)-phillygenin, were also obtained.135
19.2.7 HEXASTYLIS SPP.

The essential oils of three species of Hexastylis: H. arifolia (Michx.) Small, H. minus (Ashe), and
H. virginica (L.) Small were investigated and large amounts of safrole and elemicin were identified
together with several mono- and sesquiterpenes. It was found that the American Hexastylis is
phytochemically very similar to Japanese Heterotropa.136
19.2.8 SARUMA SPP.

Only one report on the chemical constituents of essential oil of Saruma henryi Oliv. was cited in
the literature.137

19.3 PHARMACOLOGY AND CLINICAL USE
19.3.1 ARISTOLOCHIA SPP.
The genus Aristolochia comprises approximately 600 species, some of which have found wide use
in traditional medicine (Table 19.1). The Chinese Pharmacopoeia lists the following drugs:
• Madouling (fructus) referred to the ripe fruit of Aristolochia contorta Bge. or A. debilis
Sieb. et Zucc. and used in the treatment of respiratory diseases as an antitussive and anti-
asthmatic.
• Tianxianteng (herba) is the dried aerial part of A. contorta Bge. or A. debilis Sieb. et
Zucc. used as a diuretic against edema and as an antirheumatic.
• Qingmuxiang (radix) constituted by roots of A. contorta Bge. or A. debilis Sieb. et Zucc.,
therapeutically prescribed in diarrhea owing to enteritis, rheumatoid arthritis, hyperten-
sion, eczema, and snake bite.
• Guangfangji (radix) is the dry root of A. fangchi Y. C. Wu ex L. D. Chou et S. M. Hwang
used as antirheumatic and diuretic.
• Guanmutong (caulis) referred to dry vine of A. manshuriensis Kom., used as a diuretic
and antiphlogistic for treatment of edema and rheumatic arthralgia, eczema, and hyper-
tension.25,78
Besides these official species, several other Aristolochia spp. used in traditional medicine were
investigated pharmacologically. The biological activities of aristolochic acids were studied exhaus-
tively also.
19.3.1.1.1 Antitumor activity

An alcoholic extract of A. indica L. showed reproducible activity against adenocarcinoma 755 test
system and the principle active result was aristolochic acid I.138 Aristolochic acid I (AA-I) was reported
as a potential antineoplastic agent. It inhibited the experimental tumour growth in animals and
destroyed malignant human tumor cell growth in tissue cultures at low concentration. Complete
inhibition of sarcoma-37 cells in mice was also observed after incubation with 100 to 200 mg of AA-
I for 3 h; 5 days of subcutaneous injection of AA-I to mice with sarcoma-37 markedly prolonged
the survival period of the animals.139 Also AAs isolated from A. tagala Champ. showed antitumor
activity.140 Recently, however, AAs were reported to be a potential carcinogen, so the mutagenic
activity of AA-I was extensively studied using the Ames’ test.141,142 Carcinogenic activity was dem-
onstrated in experimental animals. Male and female rats treated orally with aristolochic acid I at daily
doses of 0.1, 1.0, or 10.0 mg/kg developed a high incidence of tumors, dependent on dose and time.
Aristolochic acid I was used in clinical trials in cancer therapy; however, it was abandoned
owing to liver and kidney toxicity. Aristoloside, one of the active components, purified from A.
manshuriensis Kom. (Guanmutong, a plant material previously shown to have a marked anticancer
potential) showed antitumor activity.138,143,144 The dichloromethane extract of Aristolochia triangu-
laris Cham. et Schletch (from Argentina) was demonstrated to be toxic to brine shrimp (Artemia
salina) (LC50 is less than 200 mg/ml) using the brine shrimp microwell cytotoxicity assay in order
to search for antitumor activity.145
19.3.1.1.2 Immunomodulating Activity
Application of Aristolochia extracts, at various dilutions (1:100,000), in rabbits or guinea pigs
showed marked stimulation of phagocytic activity of the leukocyte. Aristolochic acid I was the
active principle. It also normalized the phagocytic activity in guinea pigs that was diminished by

TABLE 19.1
Aristolochiaceae Plants Used in Traditional Medicine
Aristolochia albida Duch.
Used traditionally against dysentery, gonorrhea, abdominal colic, and other gastro-intestinal disorders, arrow
poisoning, and snakebites by the Hansa tribe in Nigeria (also utilized against malaria); root is a stomachic, an
allergic, and an ingredient in Guinea worm remedy; rhizomes are used in skin diseases and against snakebites 60,176,177
Aristolochia argentina Gris. (charruga)

Used in Argentinean folk medicine as an emmenagogue and in the treatment of arthritis, poisoning, and pruritus 153,178-
181
Aristolochia asclepiadifolia Brandg. (guaco)

The root is very aromatic and some Mexican people use it in alcoholic infusion to combat injuries caused by
scorpions and snakes and to treat dysentery38
Aristolochia baetica L. (local name: Smora in Morocco)

Fresh leaves are used to prepare friction against warts157
Aristolochia birostris Duchtre (common name: capivara, angilicó or jarrinha)

A brazilian species66
Aristolochia bracteata Retz.

(Sudan common name: Um-galegel or Erg-El-Agrab equals scorpion root)
Used in folk medicine as a purgative, for its efficacy as an antihelmintic, an emmenagogue, for expelling round
worms, an antipyretic, a scorpion antidote, and to induce contractions to facilitate labor26,27
Aristolochia bracteolata Lam.

Molluscicidal activity182,183
Aristolochia brevipens Benth. (guaco or tacopate in Mexico)

Used by the local Tarasc people to treat arthritis and diarrhea; also applied to cure wounds from snakebites 24,30
Aristolochia chilensis Miers (oreja de zorro or hierba de la Virgen)

A decoction of its roots is used to reduce abundant lochia (puerperal secretions)28,43,68-71,184,185
Aristolochia cinnabarina C.Y. Cheng and J.L. Wu (Sichuan Zhusalian)

The roots are used in folk medicine as a painkiller186-189
Aristolochia clematitis L. (birthwort)

Showed irritant property190
Aristolochia constricta Mutis ex H.B.K.

The aerial parts are used empirically in folk medicine as an antispasmodic, an emmenagogue, and against snakebites 34
Aristolochia cucurbitafolia Hayata

Used in traditional Chinese medicine as anodyne, antiphlogistic, antitussive, expectorant, and antiasthmatic agent,
also for treatment of snakebites and lung inflammation191
Aristolochia elegans Mast. (brazilian species)

Contain alkaloids causing contraction of the uterus; the extracts shows mitotic activity and antiviral activity;
commonly used in folk medicine in Brazil and other countries as abortifacient, emmenagogue, and against snakebite
poisoning (also Aristolochia gigantea Mart.)37,192-194
Aristolochia fangchi Y. C. Wu ex L. D. Chou et S. M. Hwang (guang fang ji or Southern Fangchi root)

Commonly used in traditional Chinese medicine for the treatment of edema with oliguria, eczema, rheumatic arthritis,
and hypertension195

Aristolochia gigantea Mart

Is an ornamental species; in popular medicine is used as an abortifacient and in the treatment of wounds and skin
diseases33,196
Aristolochia grandiflora Sw
Used in Mexican traditional medicine as an uterotonic, cytotossic, and antimicrobial agent, and to treat snakebites 36
Aristolochia heterophylla Hemsl.

The roots and fruits are used as expectorant, antitussive, analgesic, anti-asthmatic, and for treatment of snakebites
and lung inflammation23
Aristolochia indica L. (godidha gadapa or Indian birthwort)

Medicinal plant possessing significant antifertility activity; in folk medicine it is used as an emmenagogue and
abortifacient, to treat snakebites, to increase the contractions of the uterus during labor, given for intermittent fever
and worms, given in syphilis and gonorrhea; aristolochic acid was characterized as the principal tumor inhibitor,
antifertility activity; aristolochic methyl ester is active as interceptive and anti-implantation agent22,42,46,66,74,197-200
Aristolochia kankuaensis Sasaki

The fruits and roots are used as an alternative for the famous folk medicine Madouling and are used as an expectorant,
antitussive, analgesic, anti-asthmatic, moreover for the treatment of snakebite and lung inflammation 201
Aristolochia longa L. (local name barraztam in Morocco)

Used in folk medicine in the Mediterranean area to provoke contraction of the uterus or to reduce abundant lochia
(puerperal secretion); aristolochic acids are inhibitory against carcinoma CA 755 and show antimicrobial activity
vs S. aureus and B. subtilis40,202; dried powdered roots mixed with Lawsonia inermis L. are used in the treatment
of dermatitis157
Aristolochia manshuriensis Kom. (Kwan-Mu-Tong crude drug)

Antihypertensive effects in traditional medicine47,203
Aristolochia maurorum L. (zarand in Iraq)

Roots are used for antiseptic and wound healing properties204
Aristolochia papillaris Mast. (jarrinha or angelicó in Brazil)

Used in popular medicine for the treatment of asthma, snakebites, fever, general infections, menstrual disturbances,
and to induce abortion149
Aristolochia serpentaria L. (snakeroot, Virginia snakeroot)

Used as a cancer cure, also used for leukemia and skin cancer; roots infusion gargled for malignant sore throat;
stimulant tonics promote perspiration, used to alleviate stomach pain, and for snakebites; used also in amennorhea,
bilious fever, dyspepsia, emmenagogue, expectorant, sudorific, and vermifuge205
Aristolochia taliscana Hook and Arn. (guaco or raiz de guaco)

Stems, leaves and flowers are used as anticancer agent63
Aristolochia triangularis Cham. and Schletch (mil hombres in Argentina)

Used in the treatment of wounds and skin disease, but also as antirheumatic and antiseptic for external use,
emmenagogue, antidote against snakebite, and abortive58,59,62,145
Aristolochia tuberosa C.F. Liong and S.M. Hwang

Used for treatment of sore throat, venomous snakebites, and tuberculosis in Chinese folk medicine 29

Aristolochia yunnanensis Franch. (Chinese Yunnan Ma Don Ling)

Used in traditional medicine (drug name is Nan Mu Xiang) to treat gastro-intestinal diseases, trichomoniasis, and
various pain conditions54
Asarum caudatum Lindl.

Extracts are active against fungi160
Asarum chingchengense C.Y. Cheng and C.S. Yang

Used for diaphoresis and as emetic75,113
Asarum europaeum L. (asarabacca)

Local anaesthetic activity of two phenylpropanoids: t-isoasarone and t-isoeugenolmethyl ester with an intensity
nearly equal to benzocaine; is used as an emetic, expectorant, anti-asthmatic, emmenagogue remedy 48,86-
88,161,165,166,168,206-209
Asarum heterotropoides Fr. Schmidt var. mandshuricum Kitag (manchurian wild ginger)
Antipyretic, analgesic, sedative, and hypotensive activity100,164,210
Asarum maculatum (kai-chogduri)

Used to treat halitosis, pain, cough, and asthma115
Asarum sagittarioides
Showed strong antihistaminic activity; amide is the active principle and it is proved to be an anti-allergic substance 114
Asiasarum heterotropoides F. Maek. var. mandshuricum F. Maek (Saishin)

The roots are used as an analgesic, antitussive, or expectorant or anti-allergic remedy, as anodyne131,211
Asiasarum sieboldii Miq.

Used as an analgesic, antitussive, expectorant, or antiallergic remedy, as an anodyne129,130
injection of chloramphenicol, prednisolone, or cyclophosphamide.138 Oral administration to man

also increased phagocytic activity, thereby increasing body resistance.139 This explains the clinical
observation that AA-I is particularly beneficial in the treatment of persistent suppuration from
fistulas, for example, anal and dental fistulas. A sodium salt of AA-I was put on the market
(Tardolyt®, Madaus®). It soon proved its value in the treatment of wounds with poor healing
tendencies, foruncolisis, leg ulcers, and osteomyelitis, and moreover, given besides antibiotic
therapy. However, these aristolochic acid preparations, used as an antiinflammatory, were cancelled
owing to its potential carcinogenicity.138
19.3.1.1.3 Antibacterial and Antifungal Action
Aristolochia extracts (Madouling) showed in vitro inhibitory action of various degrees against
pathogens commonly found in the respiratory tract, such as Hemophilus influenzae, Streptococcus
pneumoniae, but also Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, and
Proteus vulgaris.139 A number of Gram-positive bacteria including Staphylococcus, Streptococcus,
Diplococcus, Bacillus, Sarcinia and Mycobacterium were inhibited by AA-I at concentration of 50
to 200 mg/ml. The concentration of AA-I needed to inhibit Gram-negative bacteria and fungi was
higher than 200 mg/ml.25,78 Rats with wounds infected with Staphylococcus aureus, treated intra-
peritoneally or orally with AA-I, recovered much faster when compared to controls.
The aqueous extract of Madouling showed in vitro inhibitory activity against skin fungi
Schlemm’s Dermatomyces favolosa, Microsporum audouini, and Microsporum lanosum.139

1(10)-Aristolen-13-al, a sesquiterpene aldehyde isolated from the roots of Aristolochia debilis
Sieb. and Zucc. showed moderate antimicrobial activity against Staphylococcus aureus by the
bioautography method,45 and a new acylated N-glycoside of aristolactam, isolated from the roots
of Aristolochia contorta Bge., showed relatively significant antibacterial activity against Gram-
positive bacteria, based on disk diffusion and dilution methods.146
Using tissue culture method, A. debilis Sieb. and Zucc. showed higher antiviral action against
the herpes simplex virus among 472 traditional medicinal herbs.147
19.3.1.1.4 Antifertility Activity
The roots of Aristolochia indica L. (common name Indian birthwort) were used in Indian folk
medicine as an emmenagogue and as an abortifacient; the crude petroleum ether, chloroform, and
alcoholic extracts showed 100 percent interceptive activity in mature femal mice at the single dose
of 100 mg/kg body weight without tossic effects at the dose levels used.138,148 AA-I has contraceptive
activity in female mice. When given orally to mice, it showed significant anti-implantation and
early pregnancy interrupting effects that were not observed in rats. In addition, intraamniotic
injection of AA-I into mid-term pregnant dogs and rats led to termination of pregnancy.25
19.3.1.1.5 Hypotensive Action
Intravenous injection or oral administration of the crude preparation of Qingmuxiang to various
animal species resulted in hypertension. The decoction preparation had a stronger action. In
anaesthetised animals, the intravenous injection often caused a sudden drop in blood pressure. The
action of the intramuscolar injection was slower and that of oral dose was the slowest. Magnoflorine
is the active hypotensive principle. When administered by intravenous injection in anesthetized
cats, it significantly lowered blood pressure. Magnoflorine did not show a muscarinic action, but
it had a nicotinic action.25,139
Both, ethanolic extracts of Aristolochia papillaris Mast. and a fraction of this extract containing
tertiary alkaloids and three isolated pure compounds exhibited tracheal muscle relaxant activity.
This may indicate a use of the plant in asthma as a bronchodilator and needs to be verified by test
using in vivo models of asthma. These results do not support the use of the plant as an abortive
agent if its mechanism of action is by increased uterine activity.149
Many reports are present in the literature about the use of Aristolochia plants as remedies
against the poisonous effects of snakebite, especially about the capacity of these plants to inhibit
phospholipase A2 or other enzymes, aristolochic acid inactivated snake venomous as Vipera rus-
selli.150,151
Aristolochic acid was tested in the clinical treatment of cancer; however, it was found to produce
toxicity in kidney and liver. Rabbits, treated with intravenous injection of the 100 percent decoction
at the dose of 1 g/kg, developed generalized spasm, mydriasis, and then miosis, muscle relaxation,
respiratory depression, and finally cardiac arrest. The crude extract of Qingmuxiang produced an
emetic action, whereas the purified extract had no emetic action and was very low in toxicity.139
Refined fluid extract of Qingmuxiang in tablets (each tablet corresponding to 6 g of the herb, dosage
of 4 to 12 tablets 3 to 4 times daily) was effective in stage II hypertension, particularly for the
systolic pressure, but it was ineffective in stage III hypertension. In 50 cases treated with fluid
extract of the herb, diastolic pressure was lowered by than 20 mmHg in 20 cases.139 The Aristolochia
mixture (Fructus Aristolochiae) was effective in treatment of 94 cases of chronic bronchitis; the
sputum became thin and was easily expectorated.
Analgesic effect was achieved with tincture or powder of A. contorta Bge. root for pain owing
to peptic ulcer, gastritis, gastric spasm, or gastric pain of other etiologies.139

Aristolochic acid tablet (0.15 mg per tablet) was effective in the treatment of chronic
osteomyelitis, chronic abscess, and fistulae. It also hastened epithealization of burns, cleared
wound surfaces, and healed ulcers. AA markedly decreased the incidence of puerperal infection.
It was also reported that the occurrence of tonsillitis in children was markedly reduced after
administration of AA with antibiotics or sulfonamides when compared with the standard without
AA [139].
Many Aristolochia spp. were used in traditional medicine for dermatological purposes. Skin care
products containing biological stimulators such as human placental extracts and optionally with
Aristolochia spp. extracts in polyethylene glycol (mol. wt. 1500) are effective against oversize
pores, pustules, acne, sunburn and its peeling, and are not irritating. The placental/Aristolochia
extracts are used in a ratio of 1:10 to 20.152
Aristolochia argentina Gris. was used in the treatment of pruritus,153 but argentilactone, a new
rhizome’s constituent, showed a skin irritant action. Several plants of the Aristolochia genus,
popularly known as guaco or raiz de guaco, according to Mexican folk medicine, were used in the
treatment of dermatological affections. The active components were four closely related compounds
of the lignan type (eupomatenoids): (±)-licarin A, (-)-licarin B, eupomatenoid-7 and eupomatenoid-
1.64 In Europe, A. clematitis L. was used not only for its emmenagogue and febrifugal properties,
but also for its cicatrizing activity (in the treatment of wounds with poor healing tendency, leg
ulcers, fistulae, foruncolisis, and refractory acne), although there was a report that this species was
an irritant.154 The isolation of AA-I from A. clematitis L. and the recognition of its mechanism of
action as a stimulant of phagocytosis activity made it possible to use this substance to enhance the
defense capacity of the body. Little result was seen in acute pyodermas and leg-ulcers.155 Tardolyt®
was used with good results by itself or in combination, in cases of pyodermia, deep folliculitis,
sweat gland abscesses, fistulae, and varicose crural ulcers.156
A. fangchi Y. C. Wu ex L. D. Chou et S.M. Hwang, A. moupinensis Franch. and A. tagala
Champ. were used in Chinese folk medicine in the treatment of eczema,25 and A. baetica L. and
A. longa L. were used as warts and dermatitis remedies, respectively.157
Dried A. debilis Sieb. et Zucc. extracted with alcohol or with a mixture of water and alcohol
may be used for the preparation of lotions such as hair growth stimulants and therapeutics for
prostate gland disease.158
19.3.2 ASARUM SPP.

Xixin, Asari Herba, is the dry whole plant of Asarum heterotropoides Fr. Schmidt var. mandshuricum
(Maxim.) Kitag. or A. sieboldii Miq., collected in summer or when fruits are ripening. It is cited
in the Chinese Pharmacopoeia and used as analgesic and antitussive agent for treatment of influenza,
headache, rheumatic pain, and asthma.25 Xixin volatile oils showed antipyretic, analgesic, anticon-
vulsivant, sedative, and hypotensive activities. Asarum extract and plants are used in folk medicine
as a cough remedy.
19.3.2.1.1 Sedative and Analgesic Effects

In the literature, there are many reports about the therapeutic use of the volatile oil of Xixin.
Intraperitoneal injection of this oil produced a significant depressant effect; sleep was induced in
mice 5 min after the medication and the righting reflex was lost. Oral administration of essential
oil 0.5 ml/kg to rabbits produced analgesia against pain owing to electrical stimulation of the dental
nerve, producing an effect comparable to that of 0.5 g/kg of antypirine.139

19.3.2.1.2 Antipyretic and Anti-Inflammatory Effects
Intragastric administration of the volatile oil to rabbits with experimentally induced fever produced
an antipyretic effect. Furthermore, the oil also lowered the body temperature of normal animals.139
19.3.2.1.3 Local Anaesthetic Activity

An anesthetic effect was shown by ethanolic extract of Asarum sieboldii Miq. on the sciatic nerve
of frogs, the intradermal ending of guinea pigs, and the human glossal mucous membrane.139 Both
phenylpropanoids, isoasarone and isoeugenol methyl ester, of A. europaeum L. showed a local
anesthetic activity with respect to benzocaine; isoasarone showed local anesthetic activity with an
intensity nearly equal to benzocaine.159
19.3.2.1.4 Antibacterial and Antifungal Activity

In vitro studies proved that essential oil and ethanol extract of Xixin inhibited Gram-positive
bacteria, Bacillus subtilis and Salmonella typhi.25
Extract prepared from Asarum caudatum Lindl. (whole plant) exhibited antifungal activity
against Aspergillus flavus, A. fumigatus, Candida albicans, Fusarium tricuictum, Microsporum
cookerii, M. gypseum, Saccharomyces cerevisiae, Tricoderma viridae, and T. mentagrophytes. The
disk diffusion assay was used to screen for antifungal activity and this extract gave zones of
inhibition comparable to that of the positive control.160 Methyleugenol, isolated from Asarum
sieboldii Miq. completely inhibited toxin production by Aspergillus versicolor and three other
Aspergillus strains at 100 and 200 mg/ml.25
19.3.2.1.5 Antihistaminic and Anti-Allergic Effects

From the insoluble fraction of the methanolic extract of Asarum heterotropoides F. Schmidt, four
components, methyleugenol, kakuol, N-isobuthyldodecatetramina, and higenamine, showed marked
inhibition of the histamine-induced contraction of isolated guinea pig ileum. An anti-allergic activity
was exhibited by the aqueous or ethanol extracts of Xixin that reduced by more than 40 percent
the total amount of allergic mediators released in immediate hypersensitivity reaction.139 Also, N-
isobutyl-3,4-methylendioxybenzamide, isolated from methanolic extract of A. sagittarioides C. F.
Liang was proven to be an anti-allergic substance by pharmacological studies.114
19.3.2.1.6 Effect on the Respiratory System

Ethanol extract of A. sieboldii Miq. by intravenous injection to rabbits, antagonized respiratory
depression caused by morphine; methyl eugenol relaxed the isolated guinea pig bronchi, while 1-
pipecolic acid, isolated from A. hexalobum F. Maek. exhibited an antitussive effect on SO2-induced
cough in guinea pigs. The leaf extract of A. europaeum L., or the flavones of related species growing
in Europe, injected intravenous in cats, reduced or completely abolished bronchial spasm induced
by neostigmine (the extract was more effective than the crude flavone fractions).139,161
19.3.2.1.7 Effect on the Cardiovascular System

The volatile oil of Xixin produced stimulation at low dosage and inhibition at high dosage on the
isolated frog heart, stopping at the diastolic phase. A. heterotropoides F. Schmidt extract had a
significant stimulant effect on the isolated heart of rabbits and guinea pigs, but increased the
coronary flow only in the isolated guinea pig heart. Intravenous injection of the oil to anesthetized
dogs produced hypotension and as in anesthetized cats. The left ventricular pump function and
myocardial contractility in dogs were markedly improved by intravenous injection of A. het-
erotropoides F. Schmidt extract that contains higenamine as its active ingredient.162,163 The leaf
extracts of A. europaeum L. injected intravenous to anesthetized cats elevated the blood pressure
whereas the flavone fraction lowered it.139

The volatile oil isolated from A. forbesii Maxim. produced a dose dependent antihyperlipemic effect
in mice when given orally, and kakuol was identified as the active principle.
Antitumor promoting activity were confirmed for asarinin and xanthoxylol, two lignans isolated
from the radix of Asiasarum heterotropoides F. Schmidt var mandshuricum (Maxim.) Kitag. that
is a component of a kampo prescription, Shouseiryu-to.164 It is important to mention that safrole,
contained in the volatile oil, is known to be carcinogenic in mice and rats. It produced liver and
lung tumor after subcutaneous injection or after oral administration.139
The main use of Xixin in Chinese medicine was as headache and cough remedy. The decoction of
1 to 3 g of vegetal material may be given per os. In toothache and gengivitis, it was applied as a
locally patent medicine, Yatongshui®, a toothache liquid containing Herba Asari and other plant
material. Xixin also provided an anaesthetic effect that is useful in tooth extraction.
A 3 percent volatile oil of Xixin was used as a local infiltrative anesthesia and nerve blocker
in 33 cases of otorhinolaryngological and ophthalmic operation with good effect in 33 cases,
relatively good effect (occasional local pain) in 17 cases, and no effect in 2 cases.139
Many pharmaceutical preparations containig trans-isoasarone were formulated, Escarol® having
bronchospasmolytic, secretolytic, and antibacterial properties. This active compound was isolated
from Asarum europaeum L. roots. Of note are three forms of application: tinctura rhizomae Asari
recentis, dragees with dry extract, and tablets with the isolated effective substance. The Rhizoma
Asari europaei drug is noted also as an emetic remedy.165-168
Asarum spp. also found wide applications in folk medicine for dermatologic purposes. Asarum
enters in the formulation of antibacterial, low-irritation cosmetics along with N-long chain acyl
basic amino acid derivatives and their salts and/or polyhydric alcohols with their alkyl ester. Plant
extracts synergistically enhanced the antibacterial activiy of these chemical compounds.169,170
Asarum extracts (10 to 20 ml/100 kg) entered in facecare soap composition for treating acne along
with soap in 95 to 97 parts, essence of 1 to 2 percent, and powdered Chinese medicine (120 mesh)
in 1 to 3 parts.171
Asarum heterotropoides F. Schmidt forms part of a tincture formulated for treating scar together
with many other plant extracts,172 while a hair tonic was prepared from Asarum sieboldii Miq. or
Asarum heterotropoides F. Schmidt. Plant material (1 kg) was extracted with 95 percent of ethanol
(5 l) and water (5 l) for 4 days to give a macerate that was mixed with menthol 0.2, perfume 0.3,
95 percent ethanol 48 and water 48.5 parts to give a satisfactory hair tonic.173
A. canadense L. are the source of the perfumery raw material known as wild ginger oil. No
irritancy, allergenicity, nor phototoxicity on application to the skin of various animals, including
man, could be demonstrated.174 The leaves can cause dermatitis in some humans.175
I wish to express my special thanks to Prof. G. G. Leitao (Nucleo de Pesquisas de Produtos Naturais,
Universidade Federal do Rio de Janeiro, Brazil) for the useful material provided in this work. I am
also grateful to Prof. C. Vosa and Dr. A. Costa for their botanical advice (Department of Botanical
Science, University of Pisa). I wish to thank Dr. Laura Pistelli, Dr. A. Bertoli, and Dr. F. Morganti
for their technical assistance throughout this work.

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128. Hashimoto, K., Katsuhara, Nitsu, K., Ikeya, K., Okada, M., and Mitsuhashi, H., Two glycosides from
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20 Bignoniaceae
Oluwatoyin A. Binutu and Geoffrey A. Cordell
CONTENTS
20.1 Introduction
20.2 Paratecoma
20.3 Tabebuia
20.4 Tecoma
20.5 Jacaranda
20.6 Campsis
20.7 Catalpa
20.8 Conclusions
20.9 References
20.1 INTRODUCTION
The Bignoniaceae (Scrophulariales) family consists of trees, shrubs, often climbers or twiners, or
very rarely, herbaceous plants. The family is found chiefly in the tropics, especially in the tropical
part of South America, and includes about 120 genera and 700 to 750 species.1 Some of the genera
that are vines include Podranea, Pandorea, Tecomanthe, Doxantha, Pithecoctenium, Phaedranthus,
Pyrostegia, Clytostoma, Campsis, Pseudocalymma, Distictis, and Anemopaegma. Examples of
shrubs include Tecomaria, Stenolobium, and Tecomella, while the tree members include Catalpa,
Crescentia, Jacaranda, Radermachera, Oroxylum, Millingtonia, Dolichandrone, Spathodea,
Markhamia, Newbouldia, Stereospermum, Heterophragma, Kigelia, Parmentiera, Tabebuia, and
Godmania.
The leaves of family members are opposite and decussate, rarely alternate, simple or mostly
pinnately compound with the terminal leaflet sometimes tenderil-like; stipules absent; inflorescence
a panicle or raceme or cyme; flowers bisexual, zygomorphic, often showy; calyx generally with 5
lobes, campanulate; corolla with 5 lobes, sometimes bilabiate, campanulate, or funnelform, imbri-
cate; stamens 5, but often only 4 or 2 perfect, the others staminodes, alternate with the lobes of
the corolla; anthers 2-locular, dehiscing longitudinally, distinct or more usually connivent in pairs;
disk usually present, hypogynous; pistil 1; carpels 2; ovary superior, 2-locular; style simple and
terminal; stigma 2 lobed; placenta axile and bilocular or unilocular with 2 parietal bifid placentas;
ovules numerous; fruit a capsule; seeds often winged; embryo straight; endosperm absent.
Several species are extensively cultivated for their horticultural value and some yield useful
timber. The timber species include Tabebuia (the West Indian boxwood), the Catalpa of North
America, Paulownia from China, Kigelia pinnata of West tropical Africa, Stereospermum
kunthianum, and Newbouldia laevis. Many species have local medicinal uses. The unripe fruits of
Kigelia pinnata are used to treat syphilis and rheumatism, and pieces of the fruit rubbed on the
breast of mothers are used to increase the supply of milk. The pods of Stereospermum kunthianum

are chewed to relieve a cough. Markhamia acuminata is used to treat backache. The leaves of
Tecoma stans are used to treat diabetes.
Some plants of the family Bignoniaceae have been recorded as causing dermatitis. The wood
of several species contain the naphthoquinone lapachol (formerly called tecomin), which is 2-
hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone.2 Lapachol is an allergic sensitizer, and is very
much less potent than deoxylapachol, which was first isolated from Tectona grandis (Verbenaceae)
by Sandermann and Simatupang.3 It was later isolated from Tabebuia species4-6 and is present in
other Bignoniaceae (Table 20.1). While it is abundant in some species, it occurs only sparingly in
others and is absent in yet others. Its presence in other families is not proven. Cross sensitivity
occurs between lapachol and deoxylapachol.7
20.2 PARATECOMA
Paratecoma peroba Kuhlm. (syn. Tecoma peroba) is a native of Brazil. The valuable timber is
exported to Europe and elsewhere. Because the timber of Aspidosperma polyneuron is superficially
similar, the latter is known as Peroba rosa. The wood has also been misnamed Illipa or Bassia.
This wood is among the six most commonly causing dermatitis in France.8 Early accounts of
dermatitis from this species are those of Touraine et al.,9 and Touraine and Gole.10 Barnett11
described the extensive dermatitis caused by the sawdust, involving the hands, face, and neck, and
sometimes axillae and groins. Paratecoma was shown to contain lapachol, lapachone, and an
alkaloid. In patients with dermatitis, patch tests incriminated lapachone (lapachenole) as the sen-
sitizer; lapachol was present only in small amounts.12
20.3 TABEBUIA
About 100 species are distributed over an area ranging from Mexico to northern Argentina, including
the West Indies. Many species provide valuable timber, and many of them, perhaps all, can cause
dermatitis owing to the lapachol, deoxylapachol, and lapachone content of their wood.5 The woods
of these species, which were formerly often named Tecoma, can also cause conjunctivitis and
respiratory symptoms13 and constitutional symptoms.14
Table 20.1 shows the occurrence of lapachol, deoxylapachol, and lapachone derivatives in
several of these species and in some other members of the family. These compounds occur
predominantly in the wood. Some of these quinoid compounds have antitumor, antibacterial, or
antifungal properties.15-18 From the leaves and flowers of this species were reported the presence
of flavonoids19-24 and from the stem and rootbark, iridoid, phenylpropanoid, and benzenoid com-
pounds were reported.25-28
20.4 TECOMA
There are 16 species in the region between Florida and Argentina. Some produce useful timber
while others are used as a source of tecomin, a yellow dye, which turns red in alkaline solution.
Several species, for example, T. avellanedae, T. pentaphylla, and T. serratifolia were reported to
produce dermatitis, respiratory, and constitutional symptoms, and now have been transferred to the
genus Tabebuia.
20.5 JACARANDA
There are about 50 species in Central and South America and the West Indies. Many of these trees
and shrubs are highly ornamental and are cultivated where conditions are suitable. The wood of
J. chelonia is used in cabinetmaking. According to Woods and Calnan,29 the use of Jacaranda as

TABLE 20.1
Potential Dermatitis-Inducing Quinoids from the Bignoniaceae
Compound Plants Reference
Lapachol (1) Catalpa longissima 67

Catalpa ovata 68
Dolichandrone crispa 69
Haplophragma adenophyllum 70
Kigelia pinnata 18
Markhamia hildebrandtii 71
Markhamia platycalyx 72
Markhamia stipulata 73
Millingtonia hortensis 74
Newbouldia laevis 75
Paratecoma peroba 6
Radermachera sinica 76
Stereospermum kunthianum 77
Stereospermum suaveolens 78
Stereospermum tetragonum 79
Tabebuia chrysantha 6
Tabebuia chrysotricha 80
Tabebuia Donnell-Smithii 6
Tabebuia guayacan 81
Tabebuia ochracea 82
Tabebuia rosea 83
Tabebuia serratifolia 84
Tecoma stans 85
Tecomella undulata 86
Zeyheria digitalis 87
Zeyheria tuberculosa 88
Lapachol methyl ether (2) Paratecoma peroba 6
Deoxy-lapachol (3) Catalpa ovata 89
Tabebuia bahamensis 90
Tabebuia avellandae 5
Tecomella undulata 86
a-Lapachone (4) Catalpa ovata 89
Haplophragma adenophillum 70
Lundia densiflora 91
b-Lapachone (5) Catalpa longissima 67
Haplophragma adenophillum 70
Markhamia platicalyx 72
Paratecoma peroba 5
4-Hydroxy-a-lapachone (6) Catalpa ovata 92

4,9-Dihydroxy-a-lapachone (7) Catalpa ovata 92
4-Hydroxy-9-methoxya-lapachone (8) Mansoa alliacea 93
4-Oxo-a-lapachone (9) Catalpa ovata 92
6-Hydroxy-9-methoxy-a-lapachone (10) Lundia densiflora 91
6,8-Dihydroxy-7,9-dimethoxy-a-lapachone (11) Lundia densiflora 91
6-9-Dihydroxy-7-methoxy-a-lapachone (12) Lundia densiflora 91
7-Methoxy-a-lapachone (13) Lundia densiflora 91

Potential Dermatitis-Inducing Quinoids from the Bignoniaceae
Compound Plants Reference
9-Hydroxy-a-lapachone (14) Catalpa ovata 94

9-Methoxy-a-lapachone (15) Catalpa ovata 94
Mansoa alliacea 93
Dehydro-a-lapachone (16) Catalpa ovata 95
Dolichandrone crispa 69
Heterophragma adenophillum 96
Kigelia pinnata 18
Markhamia hildebrandtii 71
Paratecoma peroba 5
5-Hydroxy-dehydro-a-lapachone (17) Crescentia cujete 97
Dehydro-iso-a-lapachone (18) Catalpa ovata 95
Heterophragma adenophillum 96
Markhamia platicalyx 72
3-Hydroxy-dehydro-iso-a-lapachone (19) Catalpa ovata 95
Crescentia cujete 99
3-Hydroxy-5-methoxy-dehydro-iso-a-lapachone (20) Newbouldia laevis 98
5-Hydroxy-dehydro-iso-a-lapachone (21) Crescentia cujete 99
(2R)-5-Methoxy-dehydro-iso-a-lapachone (22) Crescentia cujete 99
3,5-Dihydroxy-6-methoxy-dehydro-iso-a-lapachone (23) Radermachera sinica 76
3,6-Dimethoxy-dehydro-iso-a-lapachone (24) Radermachera sinica 76
3,8-Dihydroxy-dehydro-iso-a-lapachone (25) Catalpa ovata 92
5,7-Dihydroxy-dehydro-iso-a-lapachone (26) Newbouldia laevis 98
6-Hydroxy-dehydro-iso-a-lapachone (27) Newbouldia laevis 98
7-Hydroxy-dehydro-iso-a-lapachone (28) Newbouldia laevis 98
(2R)-5,6-Dimethoxy-iso-a-lapachone (29) Crescentia cujete 99
8-Hydroxy-dehydro-iso-a-lapachone (30) Catalpa ovata 95
a genus name has often been confused with jacaranda, the popular common name for several species
of Dalbergia and Machaerium of the Leguminoseae family. It is therefore impossible to interpret
many case reports of dermatitis, in which the responsible species has not been botanically identified.
It is probable that in such reports species of Dalbergia were responsible because some of them are
potent sensitizers. However, some of the Jacaranda species that have been implicated include
J. braziliensis, J. acutifolia, and J. ovalifolia.30
The quinoid, jacaranone, has been isolated from the leaves of several species of Jacaranda.31-34
This compound was found to have antitumor activity.35,36 Other compounds isolated from the leaves
and stem of plants of this species were triterpenes.31,35,37–39 The flowers contained flavonoids.19,40,41

20.6 CAMPSIS
The genus Campsis comprises two species of rampant, hardy, woody vines, sometimes climbing
to 40 ft. The American trumpet vine, Campsis radicans (L.) Seemann (syn. Bignonia radicans L.;
Tecoma radicans L.) is native from Florida north to Pennsylvania where it often becomes a
troublesome weed in cultivated fields. The Chinese species is C. grandiflora (Thumb.) K. Schumann
[syn. C. chinensis (Lam.) Voss; Bignonia grandiflora Thumb; Tecoma grandiflora (Thumb) Loisel.;
Bignonia chinensis Lam]. Both are beautiful climbing plants that are extensively cultivated. C.
radicans is hardy out of doors in the milder areas of Britain and Northern Europe. The number of
cases of dermatitis reported in those handling the flowers or leaves is likely to be a measure of
their popularity rather than an indication of high sensitizing potential. All reports implicate C.
radicans, but identification may not always have been reliable because hybrids and cultivars are
numerous.42-45 A cross between C. chinensis and C. radicans, C. tagliabuana (Visiani) Rehder,
does not sprout and become a nuisance. This species with training makes an interesting “living
post.”
C. radicans—Trumpet vine or cowitch is a large woody vine climbing along fences or high in
shrubs, trees, and poles. It grows in moist or dry woods. The leaves are opposite and are pinnately
divided into 9 to 11 ovate leaflets with toothed margins. The flowers occur in clusters, tubular, 5
lobed, orange-yellow to red and 2 to 3 in. long. The fruit is an elongated slender capsule with many
winged seeds. Contact with leaves or flowers may cause inflammation of the skin with blisters
persisting for a few days. The rash is similar to that induced by poison ivy.
Not much is known about the chemistry of C. radicans. From the leaves were found some
alkanes, salicylic acid, squalene, stansioside, verbascoside, ferulic acid, trimethoxy-cinnamic
acid, and cyanidin-3b-rutinoside.19,46-48 Trumpet vine should be investigated further in connection
with dermatitis in order to determine the actual constituents inducing the observed allergic
response.
Several iridoid glycosides, phenylpropanoids, and flavonoids have been isolated from the leaves
of C. grandifolia.49-54 The flowers of this Chinese plant were found to contain essential oils.55
20.7 CATALPA
This genus contains 11 species of trees native to East Africa and to North and South America.
Several species are extensively cultivated for their horticultural value, and some yield a useful
timber. Catalpa speciosa Warder commonly known as western catalpa or catawba tree, native from
Illinois to Arkansas, a tree to 100 ft high or more, is planted in Hawaii for reforestation. The
common catalpa, Indian bean (C. bignonioides Walt.), from the southeastern United States, is a
smaller tree cultivated for the beauty of its flowers. The flowers of various species of Catalpa have
been suspected to cause dermatitis.42,56,57
Iridoids, phenylpropanoids, flavonoids, and the steroid, sitosterol have been isolated from C.
bignonioides.58-61 The leaves of C. speciosa were also found to contain iridoids.62-66
20.8 CONCLUSIONS
Plant-induced dermatitis, like an allergy, is dependent on a previous sensitivity of the individual.
The degree of poisoning may vary from minor or temporary skin irritation to very painful inflam-
mation with blisters persisting for weeks and possibly requiring hospitalization. The severity of
dermatitis produced by plants in the Bignoniaceae depends on the plant contacted, the degree of
contact, and the relative susceptibility of the individual. Although only a few species of the
Bignoniaceae have been reported to induce dermatitis, more species may be able to do so, but have
not been tested for this ability.

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antitumor activity, Hua Hsueh Hsueh Pao, 44, 61, 1986.
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21 Bromeliaceae
Félix Córdoba Alva, Eduardo Pérez-Campos, and
Patricia Magaña
CONTENTS
21.1 Introduction
21.2 Botanical Aspects
21.2.1 Classification
21.2.2 The Body
21.2.2.1 Biology
21.2.3 Distribution
21.3 Biochemistry of Bromeliaceae
21.3.1 Biochemistry of Pineapple
21.3.2 Bromelain
21.3.3 Other Proteolytic Proteinases from Pineapple
21.3.4 Proteolytic Enzymes in Other Species of Bromeliaeae
21.4 Pathology Induced by Pineapple and Bromelain
21.4.1 Allergic Reactions to Bromelain
21.4.2 Mechanisms in Allergic Skin Diseases
21.5 Clinical and Experimental Application of Bromelain
21.6 Traditional Uses of Bromeliaceae
21.8 References
21.1 INTRODUCTION
Bromeliads are members of a large family of plants (Bromeliaceae). The best known member is
the edible pineapple (Table 21.1). The Bromeliaceae family is exclusive to America where almost
2500 species are found. The only exception is Pitcairnia feliciana of Africa. Bromeliads are found
from Virginia in the United States to southern Argentina. There are certain regions of the world
with a large variety of species such as Mexico, the Antilles, Costa Rica, eastern and southern Brazil,
the Andes of Colombia, Peru, and Chile.
During the explorations of Columbus, Americo Vespucci, Oviedo, and Portuguese explorers,
the first bromeliad, Ananas (whose name come from the Brazilian Guarani Indian word “Anana”)
was taken to Europe and then carried around the world. Ananas flourished in almost every tropical
country as in India, Java, Sumatra, and the Philippines. Oviedo represented the pineapple in his
Historia General de las Indias published in 1535.1 Rumph was the first botanist to describe it
(Figure 21.1).

TABLE 21.1
The Pineapple Family: The Species of the Genera Pseudananas and Ananas
(Pineapple) are Shown in This Table Based on Smith and Downs4 and Leal90
Scientific Name Common Name
Pseudananas sagenarius Gravatá de cerca, gravatá de (Arruda da Camara) Camargo rede, y vira
Ananas ananasoides Ananas de ramosa, curibujil, (Baker) L. B Smith maya, piñon, piñuela
Ananas nanus (L. B. Smith) Ananaí L. B. Smith
Ananas parguazensis Gravatá, piña montañera. Camargo and L. B. Smith
Ananas lucidus Miller Curagua, curaná, curauá, kulaiwat
Ananas bracteatus (Lindley) Ananas bravo, ananas do mato (Schultes f.)
Ananas fritzmuelleri Camargo Ananas silvestre, gravatá de cerca
Ananas comous (L) Merril Abacaxi, ananas, piña
FIGURE 21.1 The earliest pineapple drawing from Oviedo’s Historia General y Natural de las Indias.1

It is possible that Linnaeus was the first one to be recognized for his bromeliad studies published
in the Species Plantarum in the year 1753, 12 years after the work of Rumph. The two bromeliad
genera recognized by Linnaeus, Bromelia and Tillandsia, were named after a Swedish botanist.
These genera have now been divided into several new genera, including Ananas.
In the seventeenth century, several species were introduced to Europe as ornamental plants and
many botanical gardens began to cultivate them. Their popularity grew until the nineteenth century.
Around 1833, Edouard Morren, considered the specialist of the family, prepared a good number
of high quality illustrations of bromeliads. He had a strong influence on several of his students.
Among them, Francois André, published a monograph entitled Bromeliaceae Andreanae where he
described 91 new species and 14 varieties of bromeliads collected in South America. Another of
Morren’s students, Carl Mez, carried out a prolonged and thorough study that in 1935 led to the
publication of Engle’s Das Pflanzenreich, one of the most extensive monographs on Bromeliaceae
up to that time. He was a good taxonomist and carried out a series of brilliant experiments and
demonstrations to show how bromeliad trichomes absorb salts and moisture with leaves. Mez’s
work is still part of the basis of the study of the bromeliad family.
Lyman B. Smith studied the bromeliad family around 1930 and described many new species.
Along with Robert J. Downs, Smith published several monographs for the family that separated
the family into three subfamilies based on the type of fruit and seed.2-4 Most of the papers published
during the last 30 years are based on these monographs.
The Bromeliaceae family has been studied from the taxonomic point of view by Gilmartin,5
Rauh,6 Richter,7 Gardner,8 and Utley.9,10
In 1950, the Bromeliad Society was founded and named the Bromeliad Society International.
This association publishes the journal of the Bromeliad Society that includes description of new
species, tips for cultivation, and information for amateurs.
In Mexico, Dr. Eizi Matuda was one of the main taxonomic researchers of the bromeliad family.
He has published the iconography of several species and described new taxa especially from Chiapas
and the state of Mexico.11,12
21.2 BOTANICAL ASPECTS

21.2.1 CLASSIFICATION
Bromeliaceae is a family of the order Bromeliads (Angiospermae, Monocotiledonae). The family
is subdivided into three subfamilies: Pitcairnioideae, Tillandsioideae, and Bromelioideae.
The Pitcairnioideae subfamily accounts for almost all terrestrial plants. The flowers are hypo-
genous or epigynous. The fruit is usually a dry dehiscent capsule. The seeds are never plumose
and leaf margins are often armed. Pitcairnioideae include 16 genera.
Tillandsioideae are mostly epiphytic. Flowers are usually hypogenous and the fruit a dry,
dehiscent capsule with plumose seeds. Leaf margins are never armed. Tillandsioideae include nine
genera.
Bromelioideae are terrestrial or epiphytic. Flowers are epigynous. Fruit is a berry containing
seeds without appendages. Leave margins are frequently armed. Bromelioideae include 31 genera.
21.2.2 THE BODY

In regard to size, bromeliads are found in an entire range, from tiny, moss like species to very big
forms. In general, they can live several years or be perennial. The body of all but a few bromeliads
is divided into two basic parts: a root system composed exclusively of roots and a more complex
shoot system which at maturity, includes one or more attached stems, leaves, buds in the axils of
those leaves, and one or more inflorescences.13

FIGURE 21.2 Based on A Bromeliad Glossary, from the Bromeliad Society, Inc. (With permission.)
Basic characteristics of the family are
1. Root system only as a support in epiphytic species. This can disappear in mature plants.
2. Rosette leaves, generally with reduced stems.
3. Trichomes (hairs or scales) on the surface that absorb water and nutrients.
4. Terminal inflorescence supported by a scape with coloring bracts.
5. Flowers in series of three tepals: three sepals, three petals, six stamens, and three carpels.
They are generally hermaphroditic.
6. Fruits are capsules or berries.
7. Apiculate seeds or with a coma basal or apical.
These characters have been used traditionally in the classification of the family (Figure 21.2).
Some other, like stigma form, are useful in some taxa.14

21.2.2.1 Biology
Most epiphytic bromeliads grow in median altitudes between 1500 and 2500 m. However, terrestrial
bromeliads are found as high as 4000 m. The distribution of the family north and south of the
equator indicates that plants receive rainfall at differing times of the year.
Bromeliads are generally pollinized by birds, but bats, bees, and butterflies also have been
observed visiting flowers.
In cultivation, hybrids are produced, but some studies have been made with regard to hybrid
formation in nature.
21.2.3 DISTRIBUTION
Seeds are dispersed by wind, but in bromelioideae seeds are dispersed by animals. There are a
variety of living forms associated with aquatic bromeliads that accumulate water in the base of
leaves.
Some genera are dioecious (e.g., they have male and female reproductive parts on separate
plants).
Bromeliaceae can be described in ecological terms as a group of stress-tolerant tropical herbs
with a pronounced tendency toward epiphytism and saxicoly. Whether supported by rock, soil, or
a host, a large majority of the species prefer habitats characterized by at least one major physical
restraint. Light, water, or mineral nutrients, or some combination of these commodities, is in short
supply (or much less commonly in excess) at least part of each year.13
21.3 BIOCHEMISTRY OF BROMELIACEAE

21.3.1 BIOCHEMISTRY OF PINEAPPLE
Pineapple is an important fruit in the tropical and subtropical regions of the world. The processed
pineapple products are mainly canned syrup, fruit, and juice. Pineapple is high in sugar content (12
to 18° brix).15 The fruit contains small quantities of all vitamins except vitamin D and the ashes are
rich in bases, particularly potassium.16-18 The fruit also contain the proteolytic enzyme, bromelain.19
As stated, a great deal of the chemistry and biochemistry in Bromeliaceae come from studies
of fresh pineapple that is produced in Brazil, Thailand, India, and in lesser amounts in other African
and Asian countries. It is also cultivated in Hawaii and Mexico. The pineapple variety of commercial
cultivars is the Smooth Cayenne with Pernambuco Smooth Cayenne in Brazil, Singapore Spanish
in Malaysia, and James Queen in Australia.20,21 Otha et al.22 evaluated the components of fresh and
canned pineapple. They also have studied the volatile compounds that give this fruit its characteristic
flavor. Approximately 73 low molecular weight substances in various concentrations were found
using gas chromatographic analysis. The main ones were ethanol, acetic acid, acetoin, isoamyl
alcohol, ethyl-3-acetoxyhexanoate, caprolactone, and trace amounts of other compounds. Tawata
et al.23 isolated cinnamic, p-coumaric and ferulic acids from pineapple.
Although the concentrations of these compounds are significantly minor, it is not known if they
contribute or not to the clinical manifestations and allergies described in humans (Section 21.4.2
and 21.5).
The chemical and biochemical research on Bromeliaceae has been centered on the isolation
and characterization of the proteolytic enzymes present in the plants. The best known of them is
the proteolytic family of bromelain and related enzymes from the fruit and stem of the pineapple.
These enzymes have been of medical interest in allergic disorders, pharmaceutical uses, and
industrial applications. Isolated from pineapple (Ananas comosus) were four cysteine proteinases;
bromelain from the fruit, bromelain from stem, ananain, and comosain (see Section 21.3.2).24,25

21.3.2 BROMELAIN
Bromelain (EC 3.4.22.32) is the main protease of pineapple juice. A highly purified enzyme fraction
(FA2) was isolated using ionic exchange chromatography. It shows a molecular weight value of
31 kDa and an isoelectric point of 4.6. This FA2 enzyme is not glycosylated. Amino acid compo-
sition of FA2 and stem bromelain is not identical. The catalytic mechanism of FA2 is similar to
the one described for papain, the thiol protease from papaya latex.24,26 In a more recent work,
Harrach et al.27 separated nine proteolytic active components from stem bromelain. The main
bromelain proteinase F4 and F5 and F9, which is the more active, were purified and characterized.
The molecular mass of bromelain F9 was 23,427 and 22,800 according to mass spectrometry and
SDS–PAGE. Higher molecular masses were found for F4 (24,397) and F5 (24,472). The difference
in molecular mass between F4 or F5 and F9 is owing to the glycosylation of F4 and F5: fucose,
N-acetylgucosamines, xylose, and mannose in a ratio of 1.0:2.0:1.0:2.0.
F9 was found to be unglycosylated. The sequence data gives valine or alanine as the N-terminus
for F4 and F5 with identical amino acids up to the 20th position. Ritonja et al.28 showed that F9
differs in positions 10 (tyrosine fi serine) and 20 (asparagine fi glycine). It is remarkable that in
all kinetics studies F4 and F5 were closely related to papain while F9 was quite different.
F9 has recently been shown to have immunomodulating effects, enhance antitumor activity of
human lymphocytes,29 and reduce CD44 binding to cells30 (see the following section).
The reason for the greater activity of F9 compared to crude bromelain and its main components
could be the pH of F9 compared to F4 and F5.27 The pH of F9 is close to physiological pH while
F4 and F5 are inactive at physiological pH levels.
Because the major proteases found in pineapple stem are glycoproteins,27 a study of confor-
mational analyses of the N-glycan of pineapple bromelain was undertaken31 using a powerful new
nuclear magnetic resonance (NMR) technology. This relies on nuclear overhauser enhancement
(NOE) NMR. Stem bromelain was chosen because this glycoprotein has only one glycosylation
site and no microheterogeneity present. The study was also undertaken to study the effect of the
polypeptide on the N-glycan conformation.32 The results indicate that except for the xyl b 1-2 man
linkage, the mobility around the glycosidic linkages in the glycoprotein were reduced compared
to a model compound with the same N-glycan. The findings might be the result of an interaction
of the polypeptide chain with the Fuc a-man a side of the N-glycan. The biological significance
of this fine molecular interaction in the multiple activities of bromelain in vivo and in vitro and the
participation of the N-glycan chains remain to be established.
21.3.3 OTHER PROTEOLYTIC PROTEINASES FROM PINEAPPLE

Ananain is a cysteine proteinase (EC 3.4.22.31) isolated from pineapple stem using cationic
chromatography. The Mr value of ananain is around 25 kDa. This enzyme is inhibited by cystatin.
It shows immunological differences with bromelain. The kinetics and general structure is similar
to bromelain and comosain (another protease from pineapple), but the amino acid composition is
different; amino acids 170 to 174 and the hydrophobic residues around His-157 gives ground to a
chemical differentiation. Ananain presents five isoforms of the enzyme with different specific
activities.33
A second cysteine protease has been isolated from pineapple stem and named comosain. It is
a different enzyme than bromelain and ananain.24
Bromelain has been shown to be a member of the papain superfamily.28 However, bromelain
is atypical, whereas ananain comprises only a few percent of the total protein. It is most probably
ananain that corresponds to crystalline bromelain as found by Gounaris et al.34 to be inhibited by
kininogen. The discovery of a new proteolytic enzyme in bromelain preparations may cause the
revaluation of previous work.
Ananain probably contributes to the proteolytic activity of crude bromelain that has been used
for many years in food and other industries and in clinical trials.33

21.3.4 PROTEOLYTIC ENZYMES IN OTHER SPECIES OF BROMELIACEA
The juice of several not cultivated Bromeliaceae growing wild in semiarid regions of the tropics
(Mexico, Puerto Rico, and Cuba) contains powerful cysteine proteinases. The research on these
enzymes started with the work by Asenjo and del Capella de Fernández35 with the discovery of
pinguinain (EC 3.4.99.18) from Bromelia pinguin. In Puerto Rico, this plant is known as maya and
has a pleasantly acid taste, causes a burning sensation in hands and lips, and peeling of the skin
after a few hours.35 Toro Goyco et al.36-39 have purified, crystallized, and characterized the enzyme
Similar enzymes from Bromelia hemisphaerica, B. plumieri, B. silvestris, and B. palmieri were
isolated and studied by Castañeda et al. (1974) in México.40
Also, Córdoba’s group studied enzymes from B. hemisphaerica and B. plumieri (formerly
karatas).41-43 They confirmed that these enzymes are true cysteine proteinases and can be purified
using a mercurial-sephadex adsorbent.41 They assessed the potential immunological cross-reactions
with bromelain. Using calibrated dialysis membranes, they have shown that the enzymes can be
dissociated to low molecular weight active enzymes (8 kDa) named H-D and K-D, respectively.
Also that fruit juice of B. hemisphaerica and B. plumieri appears to contain a mixture of high and
low molecular weight proteases in what seems to be stable equilibrium. The sequence of karatasin
up to amino acid 15th showed partial homologies with papain and with stem bromelain.42,43
21.4 PATHOLOGY INDUCED BY PINEAPPLE AND BROMELAIN

Although pineapple was administered orally as a medical remedy in pre-Hispanic times,21 there is
no doubt that pineapple is a prominent fruit food allergen. Pineapple, similar to other common
fruits among which are kiwi, papaya, tomato, maya (another Bromeliaceae), are good examples of
potential allergens.44 The main dermatologic symptoms after pineapple ingestion were intense
itching, urticarial rashes and flushed face. In a recent study, 68 percent of the patients became
symptomatic within 1/2 h of eating pineapple, but the patients recovered uneventfully after receiving
antihistamine and intravenous fluids.45
In contrast, in atopic dermatitis patients, common foods such as pineapple precipitates wide
symptomatology.46 Atopic dermatitis (AD) is a chronic disabling condition with no cure yet avail-
able.47 The evidence that the diet plays a role in children with atopic dermatitis seems irrefutable.48,49
Pineapple along with tomatoes, oranges, and soft drinks preserved with sulfur dioxide are the most
common triggers of cutaneous symptoms. These types of foods produced symptoms in greater
numbers of AD children in contrast with the children sensitized to the traditional IgE reaction type
of foods, namely, fish, eggs, milk, and peanuts.
Other atopic manifestations frequently develop after the onset of AD in about 80 percent of
the children studied. AD is characterized by an erythematous papulovesicular, intensely pruritic
rash. Many factors including irritant (e.g., soap), infections, heat humidity, and stress may result
in exacerbation of AD. Further evidence of an association with food came from open food challenges
that caused exacerbation of eczema in up to 80 percent of patients. The cutaneous areas affected
by AD in children are the face, arms, and legs and, to a smaller degree, the trunk and scalp. A
reaction to pineapple occured in 36 percent of them, oranges affected about 46 percent, and banana
affected only 13 percent. The typical IgE foods (e.g., milk and fish) caused abdominal symptoms
in addition to cutaneous alterations.47
The association of pineapple and other plant food is especially prominent with the kiwi fruit
allergy. This last allergy, because of increased kiwi consumption in recent years, is noteworthy. In
a well documented study, the authors state that immediate type hypersensitivity reactions after the
ingestion of kiwi fruit have been published with greater frequency during the past 10 years.50 The
authors employed skin tests, determination of specific IgE, and RAST. It was found that all of the
patients with kiwi allergy also presented birch pollen allergy and, thus, kiwi allergy represents a
new manifestation of birch pollen-associated food allergy. Furthermore, kiwi allergy is not only

associated closely with birch allergy, but to other food allergies like pineapple, apple, hazelnut,
and papaya.50 They stated that patients with severe clinical symptoms showed stronger reactions
to food antigens than those with mild localized symptoms. All 22 patients showed positive prick
reaction to the fruit foods.
Because the nature of the kiwi allergen has not been identified, they included fruits containing
thiol proteinases owing to the fact that kiwi fruit contains actinidin, a protease as well. They found
reactions to pineapple and papaya and to bromelain and papain. These enzymes are thiol proteases,
but actinidin from kiwi fruit appears to be a smaller protein with only close to 12.8 kDa molecular
weight. The isoelectric point is different also but, nevertheless, shows cross reactivity (RAST) with
bromelain and papain.50
The authors explain the results stating that birch pollen contains large quantities of cross-
reacting antigens whereas other food allergens, among them pineapple, contain lesser amounts.
Because kiwi fruit allergy most likely is owing to cross-reacting birch pollen IgE antibodies,
increasing numbers of allergies reactive to kiwi fruit and other high consumption tropical fruits
like pineapple are expected in the future.
Natural rubber latex allergy is responsible for a wide spectrum of clinical symptoms, ranging
from rhinoconjuntivitis to severe anaphylaxis. Workers in the rubber and latex industries, health
care workers and surgeons, and patients with spina bifida are more at risk for this kind of sensiti-
zation.51 In a recent study of latex allergy, the authors analyzed 453 children in an allergy clinic
and found a total of 326 atopic children because they presented positive SPT to common inhalants
and/or food antigens.52 The fruits tested in this study were pineapple, orange, apricot, avocado,
banana, and apple. Positive reactions were observed in all latex symptomatic children when tested
with the fruits. The association between an allergy to latex and one to various fruits has been
suggested as owing to the sharing of antigens.53
Nevertheless, the main problem in detecting latex allergy using SPT and RAST tests is that
the antigenic molecule profiles differ among the products used and between the raw materials. In
addition, the specificity of the antibody IgE (antilatex) has varied among sensitive patients and the
associated food skin reactions are limited by the extracts used.54,55
In another study of latex-fruit syndrome, an association between allergies to latex proteins and
to various fruits and pineapple was reported.56 Serum samples of 136 patients with well documented
clinical relevant, immediate type hypersensitivity against latex proteins were analyzed for IgE
antibodies against a panel of different fruits. These fruits included pineapple, papaya, avocado,
banana, passion fruit fig, melon, mango, kiwi, and tomato using the RAST and immunological
inhibition. Fruit specific IgE antibodies were detected in 69 percent of the serum samples and 43
percent reported allergic symptoms owing to these fruits. A total of 112 intolerance reactions were
recorded with IgE antibodies to fruits in their serum. Thus, serologic tests seem to be of limited
value for prediction of food allergy in latex allergic patients.
In summary, the consumption of pineapple as fruit food by the normal healthy population,
children and adults, can induce allergic symptoms with intense itching and urticarial rashes almost
immediately after eating the fruit.57 In most of these cases, treatment with antihistamine and fluids
allows recovery in a short time. On other hand, pineapple and other fruit ingestion in an atopic
population is a serious medical complication triggering cutaneous symptoms in about 50 percent
of children with AD and characterized by intense pruritic rash, erythema papulovesicular, and
eczema.
In recent years, kiwi fruit allergy has become noticeable owing to the fact that this fruit is
becoming a popular fruit food in many countries. Kiwi allergy and various other fruits like pineapple
and birch allergy seem to be strongly associated. Although the relationship of kiwi antigens are
focused on a molecular relationship between proteolytic enzyme (actinidin) and well-known pro-
teases, bromelain in pineapple and papain in papaya, the mild reactivity in patients to the isolated
enzymes makes this hypothesis a feeble one. It appears that the pathogenesis of kiwi-birch pollen
allergy is of a more complex nature.50 A similar situation appears in the study of latex allergy

present in latex industry workers and people in health care activities. These patients develop
cutaneous symptoms on ingestion of various fruit foods; the water soluble protein, or glycoprotein,
present in watery rubber extracts give positive SPT, but the nature of these factors and relations
with putative fruit antigens remains unclear.51
21.4.1 ALLERGIC REACTIONS TO BROMELAIN

There seems to be a consensus that pineapple induced pathology in humans is owing to the proteolytic
enzyme(s) contained in the fruit. Nevertheless, it is not clear if the allergic reactions are owing to
protease activity or to the molecule as antigen. Some interesting data from Baur and Fruhmann58 suggest
that the latter is more probable. The reason is because specific blocking of bromelain activity (thiol
inhibitors) can lead to a preparation still capable of entire RAST response in sensitized patients.58 The
same group58 and Galleguillos59 have some pertinent studies to substantiate the idea of antigenicity of
isolated bromelain. They studied pharmaceutical workers that regularly developed rhinitis and asthma
when handling bromelain. RAST and SPT showed strong positive reactions to bromelain; even ingestion
of 190 g of pineapple resulted in allergic reactions. Also, five workers sensitized to papain showed
positive RAST and SPT test to bromelain. In addition, 8 of 60 asthmatic patients not exposed to plant
proteases, but probably present in their foods, had positive RAST results to bromelain. The data indicate
that bromelain is capable of inducing IgE allergic reactions. Also, there are clear results concerning
the antigenic cross reactions between two plant proteases, bromelain and papain, in humans. Other
tests using bromelain inhalation in two patients resulted in an immediate asthmatic reaction.
Further work by Baur60 studying the specificity of IgE antibodies to bromelain and papain
confirmed a relationship between antibody reactions to papain and bromelain and, in several cases,
between the reactions to the proteases and grass pollen and flour. RAST inhibition showed papain,
bromelain, wheat flour, rye flour, grass pollen, and birch pollen mutually inhibit an IgE antibody
to each antigen in varying degrees.
Several investigators have suggested that antigens from plants have individual antigens but share
similar epitopes as well, leading to immunological cross-reactions.45,54,60,61 They state that papaya fruit,
pineapple (stem and fruit), fig lattices, several beans, wheat seed, white gourd, melon fruit, pollen
grains, and maya fruit all contain proteases as constituents. The RAST inhibition of bromelain conju-
gated disks are especially interesting: high values of RAST inhibition (from 20 to 86 RAST units) are
present with mixed grass pollen (negative values equal to 1 unit). Also, an inhibition occurs with birch
pollen, wheat flour, and rye flour, but does not to house dust mite antigens. Several researchers have
found similar homology in amino acid sequences between bromelain, papain, and ficin.60,62-64 On the
other hand, Montes et al.43 indicated a partial homology between bromelain and the protease found in
Bromelia plumieri (karatas), a different bromeliacea that is consumed in tropical areas in México.
The consideration that RAST inhibition could be owing to the proteolytic activity of the
proteases bromelain and papain (e.g., through digestion of antibodies or antigens) is unlikely
because blocking the enzymatic activity of the proteases did not result in significant change of the
RAST values nor prevent the inhibition to develop.60
Galleguillos and Rodriguez59 found that 100 asthma cases in a clinical service showed negative
results in the SPT test to bromelain, but several workers in the pharmaceutical industry where
bromelain is handled became sensitized by inhalation of bromelain dust. The cases displayed
immediate positive SPT. Accordingly, they state that antigen sensitization is determined by
1. The immunological reactivity of the individual increased markedly in atopic dermatitis

2. The antigen as a molecule
3. The characteristics of the antigen exposure
Pike et al.65 did experimental work using rabbits and found antibody to rye grass (Lolium
perennis) cross-reacted with bromelain and vice versa. Deglycosylation of the proteases showed
that cross-reactions were based on recognition of the carbohydrate moiety of the allergen indicating

that sugar residues in antisera to glycoproteins constitute the most probable structural feature for
the wide cross-reactions encountered with plant antigens.65
21.4.2 MECHANISMS IN ALLERGIC SKIN DISEASES

Pineapple contact in food industrial workers,66 ingestion of the fruit, and sensitization with brome-
lain present in pharmaceutical factories and numerous therapeutic preparations,67 that can include
digestive aids,68 topical anti-inflammatory agents, arthritis medication, and others,69 are capable of
inducing allergic pathology with prominent cutaneous response such as urticaria, itching, and
eczema with or without concomitant systemic symptomatology.
In the last decade, several research groups have started to investigate the cellular and molecular
mechanisms underlying the dermatologic pathology. Several interesting mechanisms are presently
being actively studied. Fuhlbrigge et al.70 have discovered that in atopic and contact dermatitis
memory T cells infiltrating the skin express a unique homing receptor called cutaneous lymphocyte-
associated antigen (CLA). CLA’s carbohydrate epitope facilitates targeting of T cells to the skin.
This receptor appears to be an enzymatic modification of a known membrane glycoprotein (PSGL-1)
that regulates homing of T cells.
On the other hand, Cox and associates71 described a major pathogenic feature of AD and IgE
allergies that involves binding of IgE to the receptor (FC epsilon RI) on the surface of mast cells
and basophiles triggering the release of mediators. A subunit of the receptor is controlled by human
chromosome 11g 12-13 and the atopic dermatitis family display polymorphism with this receptor.
Valenta et al.72 have demonstrated that IgE recognizes exogenous allergens and related human
proteins leading to autoreactivity in atopic diseases. Sera from 12 out of 20 atopic patients contained
Western-blot detectable IgE antibodies. The results suggest that IgE auto-immunity occurs fre-
quently in atopic dermatitis patients with pathogenic significance in the chronicity of the disease.
Beyer et al.73 tested peripheral blood mononuclear cells in vitro from AD children for suspected
food allergens. After 14 days in culture, quantitative and qualitative distribution of T-cell receptors
were examined by flow cytometry. Allergen stimulation induced significant decrease of CD4-L-
selectin expression. The data indicate that a shift in lymphocyte functions are present in severe
allergic reactions in food sensitized AD children.
Miles et al.74 cultured peripheral blood mononuclear cells from infants of atopic and nonatopic
parents and a range of food antigens was tested. Proliferation responses to seasonal allergens
increased over the first year of life while those to perennial allergens fell in babies who developed
allergies. The induction of systemic immune tolerance by perennial exposure to antigens or a
movement of sensitized cell to target organs where allergen exposure occurs is suggested.
The T-cell response seems to be polarized between CD4+T helper (Th) and the CD8+T cytotoxic
(Tc). Th1 may be involved in pathogenesis of organ specific auto-immunity and contact dermatitis
and the Th2 cells (Tc) in atopic disorders. Thus, both sets of the polarized T-cell population seem
to participate in allergic responses.75
Earlier studies by Agata et al.76 have demonstrated that the activity of interleukin-2 (IL-2) in
supernatants of food antigen stimulated T-cell cultures could be detected in patients with atopic
dermatitis but not in healthy children. These results suggest that the increased IL-2 production, after
food antigen stimulation, is owing to increased T-cell activity in food sensitive atopic dermatitis patients.
Sampson and his group did important research on the pathology of AD and food hypersensi-
tivity.77,78 They found that children with atopic dermatitis displayed clinical evidence of food
hypersensitivity with pruritus and erythematous macular and macropapula rash. This type of skin
lesions lead to scratching and subsequent eczematous lesions. In a different study, they encountered
that basophiles in vitro from AD patients showed high rates of histamine release similar to patients
displaying food hypersensitivity. Additionally, mononuclear cells from persons with food allergies
spontaneously produced a histamine releasing factor in vitro that provoked release of histamine
from basophiles of other food sensitive persons and this did not occur in the controls.78

21.5 CLINICAL AND EXPERIMENTAL APPLICATION OF
BROMELAIN
Although the precise molecular organization of proteolytic enzyme complexes from pineapple (i.e.,
Bromelain) is not fully determined,24 these enzymatic substances (i.e., bromelain, ananain, or
comosain) have shown distinct pharmacological promise. Their properties include
1. Interference with growth malignant cells.79

2. Inhibition of platelet aggregation.80
3. Skin debridement properties.81
4. Depletetion of high molecular weight kininogen.82
5. Fibrinolytic activity.83
6. Anti-inflammatory action.84-86
7. Prevention of intestinal fluid secretion medicated by secretagogues such as 3¢:5¢-cyclic
monophosphate.87
These biological functions of bromelain, a nontoxic compound, have therapeutic values in

modulating tumor growth, blood coagulation, inflammatory changes, debridement of third-degree
burns, and enhancement of absorption of drugs.
Munzig et al.30 have shown that highly purified bromelain preparations can be employed for
basic research at the cellular level to clarify interactions essential for understanding bromelain
pathology including induced allergy and pineapple sensitization; both of them with prominent
dermatologic manifestations as previously explained in this chapter.
These researchers employed very pure bromelain to enzymatically remove the CD44 receptor
from human blood lymphocytes. The CD44 molecule has been of interest because of its multiple
pro-inflammatory functions and regulation of other adhesion molecules. The bromelain effect is
associated with enhanced CD2 mediated T-cell activation and T-cell binding to monocytes and to
interleukin-2 release.30
Elucidation of a cellular mechanism as described previously, exhibited by the careful use of
bromelain in vitro, could have significance at the clinical level and remains to be explored in the
future.
21.6 TRADITIONAL USES OF BROMELIACEAE

Since pre-Hispanic times, American societies have employed plants of the Bromeliaceae family
for different uses, among them medicinal remedies. Brief examples of traditional uses of pineapple
and other bromeliad with respect to skin and dermatologic pathology (from the work of Rios and
Khan88 follows.
Bromelia crysantha—Jackin Terrestrial; in Venezuela, local name maya4; small scales are used
to disinfect wounds; local name Chiguichigue; Venezuela; the Antilles. When the fruit is eaten raw,
it causes dysentery owing to irritation of the mucous membranes of the mouth.
Bromelia pinguin—Linnaeus Terrestrial; in Honduras, Garifuna people make a decoction or
poultice from the leaves that is administered orally or topically for insect, snake, and scorpion bites
or stings; local name Tidibu yeiawa.89
Tillandsia aeranthos—(Loiseur) L. B. Smith Epiphytic and Tillandsia recurvata—(Linnaeus)
Linnaeus Epiphytic; in Uruguay, aerial plants are used as an antispasmodic and for eye infections;
local name Clavel del Aire.90
Tillandsia usneoides—(Linnaeus) Linnaeus Epiphytic; in the United States, American Indians
and soldiers in the American Civil War used it as bandaging material; bromelain, a proteolytic
enzyme, is thought to break down dead tissue and fibrin to enhance the rate of healing; extracts
have been found to have significant analgesic effects.

A description of further ethnobotanical applications of Bromeliaceae has been published
recently by Rios Khan.88
We would like to thank Freddy Leal, Shinkichi Tawata, and A. E. Duane Bartholomew for their
valuable information. We thank Miss Odeth Santos Brown and Miss Oralia Aragón Miranda for
their skillful help with the manuscript.
This manuscript was prepared with the support of CONACyT (México) No. 2307P-N9508 and
PAPPIT University of México No. IN201095.
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22 Lichens
Marius Rademaker
CONTENTS
22.1 Introduction
22.1.1 History
22.1.2 Lichens
22.1.3 Medicinal Use
22.1.4 Economic Uses of Lichens
22.2 Chemistry
22.2.1 Atranorin
22.2.2 Usnic Acid
22.2.3 Evernic Acid
22.2.4 Other Lichen Acids
22.3 Clinical Effect
22.3.1 Contact Dermatitis
22.3.2 Immediate Hypersensitivity Reactions
22.3.3 Photosensitising Ability
22.3.4 Cross Reactions
22.3.5 Individual Case Reports
22.4 References
22.1 INTRODUCTION
22.1.1 HISTORY
Theophrastus used the term lichen (derived from the Greek leprous) to describe a superficial growth
on the bark of olive trees. Initially, lichens also included the liverworts (Hepaticae), but Diocorides
ascribed the term to true lichens on account of their resemblance to the cutaneous disease (pre-
sumably lichen planus) for which they were supposed to be specific.
Lichens were first formally segregated botanically in 1694 by Tourneforte although it was in
1868 when the concept of a compound organism living in symbiosis was advanced by Schwendener.
Lichens are now classified in the phylum Mycophycophyta in the kingdom Fungi.
22.1.2 LICHENS
Lichens are dual organisms composed of a symbiotic relationship between an alga and a fungus.
The fungus, usually an Ascomycete, provides the plant its shape, and the alga provides the ability
to photosynthesis. This successful combination is able to produce a more elaborate and durable

organism than either partner alone. Lichens are able to colonize inhospitable areas such as bare
rock. As pioneer plants, lichens break down the rock surface and, together with decaying material
from the lichen, eventually form soil conditions suitable for other plants. Many lichens are epiphytic
(able to grow on trees), gaining nutrition from rain running down tree trunks. Only a few species
tolerate air polluted with sulphur dioxide so few survive in cities.1
Lichens are variable in shape, either tubular, upright and branching, or flat and leaf-like or
forming an amorphous greyish crust. See Ainsworth2 for a detailed classification of the fungi and
Ahmadjian3 for the algae. There are over 15,000 lichen species, comprising 60 families with over
400 genera. Lichens are widely distributed from the tropics to the high arctic and from the seashore
to high altitudes.
22.1.3 MEDICINAL USE

The medicinal use of lichens can be traced back to the eighteenth dynasty (1700–1800 B.C.) when
Evernia furfuracea was first used as a drug. Herbal lore often used plants that looked like a disease
to treat that disorder. Xanthoria parietine, being yellow, was supposed to cure jaundice, while
Peltigera aphthosa, the thallus of which is dotted with small wart-like tubercles, was recommended
for children who suffered from thrush. The long filaments ofUsnea barbata were used to strengthen
the hair, although Hippocrates prescribed it for uterine ailments. Boerhaven used Lobaria pulmo-
naria for hemorrhage and asthma. Other species of Evernia, Peltigera, Parmelia, Cladonia, Roccella,
and Pertusaria were used to control fevers, diarrhea, infections, skin diseases, epilepsy, convulsions,
and as purgatives.
The Maori of New Zealand dried and then reduced lichens or kohukohu to powders for
application onto cutaneous eruptions. The active ingredient, similar to the Chinese drug shi-hoa
and the Japanese seki-ka, is usnic acid which is known to be antibacterial.4-6
Lichens, with few exceptions are nonpoisonous, though their acid substance has proven
extremely irritating when taken internally. The main poisonous lichens appear to be Evernia vulpina
and Cetraria pinastria, although a number of other lichens have been found to contain toxic levels
of selenium (Parmelia molliuscula), beryllium (P. saxatilis), and chlorine (Evernia furfuracea).
22.1.4 ECONOMIC USES OF LICHENS

Lichens7 are used as fodder, particularly the Reindeer lichens: Cladonia raniferina, C. alperstris,
and C. sylvatica. Other fodder species include Cetraria, Stereocaulon, and Alectoria.
Cetraria islandica has been made into bread, porridge, or gruel for human consumption. Lichens
have been used instead of hops for brewing beer and were the basis of a large Swedish brandy
industry in the nineteenth century; 10 kg of lichen yielding 5 l of 50 percent alcohol.
Lichen dyes were renown for their high quality and colour but have largely been replaced by
synthetic aniline dyes. Litmus paper was originally manufactured by the Dutch from lichens. Since
the sixteenth century, members of the families Cladoniaceae, Stictaceae, Parmeliaceae, and
Usneaceae have been used as raw materials in the perfume and cosmetic industries. As manufac-
turing techniques improved, lichen extracts have been combined into toilet powders and scented
sachets. Today, the principal species still used in perfumery are Evernia prunastri (Oak moss), E.
furfuracea, and several Ramalinae spp.8
22.2 CHEMISTRY
Compared with common sensitizers of occupational and environmental importance, lichens are of
minor significance only. The sensitizing genera of lichens include Parmelia, Evernia, Cladonia, and
Usnea although Alectoria, Cetraria, Lecanora, and Xanthoria species have also been reported to be
allergenic (see Table 22.1). The allergens are largely the so-called lichen acids that include atranorin,

TABLE 22.1
Specific Lichens of Dermatological Significance9,76
Botanical Name Specific Species Typical Habitat Comments
Cladoniaceae23,35,86 Cladonia fimbriata71 Abundant in arctic/subarctic “Reindeer moss”; much-

Cladonia furcata84 regions; heather and moors branched, bluish gray;
Cladonia ochrochlora84 about 8 cm in height
Cladonia poldactyla84
Cladonia portentosa27
Cladonia rangiferina9
Cladonia stellaris17,22,33,37
Hypogymnia13,35 Hypogymnia physodes23,21,71,77 Common on tree bark; Pale gray; upper surface
Hypogymia tubulosa32 tolerates pollution smooth
Lecanora spp. Lecanora conizaeoides57,84 Walls, tombstones; tolerates Gray granular crusts; often
Lecanora expallens84 pollution; common in towns white at the edge
Lecanora varia84
Parmeliaceae23,35,57,86 Cetraria glauca (syn. Cetraria spp.—mostly Gray or gray-green,
Platismatia glauca)21,27,49,71 heather and mountains forming large rosettes;
Cetraria islandica14,21,30,37,71,85 Parmelia spp.—common on C. islandica is brown;
Parmelia caperata18,21,26,45,71,82 trees C. nivalis is cream
Parmelia exasperatula23 Platismatia spp.—common Platismatia spp.—upper
Parmelia furfuracea (syn. on fences, walls, trees, rocks surface gray, under
Pseudoevernia Pseudoevernia spp.—rock, surface brown; broad
furfuracea)18,20-22,32,71,72,78,81,82,86 stone walls, fences, trees lobes
Parmelia perlata78 Pseudoevernia spp.—“Oak
Parmelia quercina78 moss”; much forked
Parmelia reticulata18,26,58 branches; upper surface
Parmelia sulcata23,32,78 dark gray, under surface
Parmelia verru-culifera78 black or gray-black
Physciaceae23,35,37 Physconia distorta71 Chiefly rocks and walls Small rosettes; many
Physcia tenella23,32 covered with a white
powder
Umbilicariaceae13,35,37 Lasallia pustulata71 Rocks, especially in mountain Brownish gray; some
areas species hairy at margin
Usneaceae18,86 Bryoria fuscescens49 Usnea spp.—trees, often in “Old man’s beard”; long
Alectoria jubata49 dense shade hanging stems attached to
Alectoria sarmentosa49 Evernia spp.—common on trees; gray green,
Evernia prunastri18,20-22,38,74,79,86 trees/fences occassional red
Letharia vulpina27
Ramalina farinacea25
Ramalina fastigiata71
Ramalina lusitanica18,26,58
Usnea barbata49,80
Usnea rubiginea25
usnic acid, evernic acid, petaloric acid, and fumarprotocetraric acid.9-14 Lichens acids are generally
produced by the fungal component of the lichen.15,16
22.2.1 ATRANORIN
Atranorin was first extracted in 1877 from Lecanora atra, which gave it its name. A number of
studies11,14-30 have demonstrated the allergenic potential of atranorin. Using the guinea pig

FIGURE 22.1 Structures of sensitizers.
maximisation test, Sandberg and Thune28 were able to sensitize 30 percent of test animals, which
corresponds to a moderate allergenic capacity (grade III). It is unclear whether atranorin is also
a photosensitizer receiving negative results from phototesting by Sandberg and Thune28 but
positive results by others.12,13,31,34
22.2.2 USNIC ACID

Usnic acid (Arabic and Persian, ushnah equals moss) is a weak sensitizer.10,14,18,19,22,23,25,27,29,30,33–35
It comes in two enantiomeric forms, namely (–) and (+) usnic acid (Figure 22.1). In nature, they
are likely to exist in a racemic mixture. In experimental sensitization, (–) usnic acid gives a much
stronger response than (+) usnic acid.33 Patch tests studies, however, suggest a higher prevalence
of reactions to the (+) usnic acid form. In patients patch tested,10,34,36,37 22 out of 27 reacted to

the (+) form and only 8 to the (–) form.10,34,36,37 While usnic acid is only a weak sensitizer, it
makes up 5 percent of the dry weight of the lichen plant, so this is probably the most important
lichen allergen.
22.2.3 EVERNIC ACID

Evernic acid11,13,14,17-20,22,27,29 and perlatolic acid11,27,29 are weak sensitizers. It is unclear whether or
not stictic, fumaroprotocetraric, and protocetraric acids are immunologically active, with some
reports suggest that they are13,17-19,22,33,38 and others suggest that they are not.11,14
22.2.4 OTHER LICHEN ACIDS

Other lichen compounds with reported immunologic activity include barbatic acid,13 diffractaic
acid,14 divaricatic acid,11 gyrophoric acid, lecanoric acid, lobaric acid,13,30 physdic acid,28 psoromic
acid and salazinic acid,13,30 thamnolic acid, and vulpinic acid.
22.3 CLINICAL EFFECT

22.3.1 CONTACT DERMATITIS
In 1907, Horand39 described a patient with crocodile hands (mains de crocodile) from contact with
the bark of chestnut trees. He postulated that the lower order plants (i.e., lichens) growing on the
trees might have been responsible for the dermatitis. Spillmann40 reported a case of a man who
developed dermatitis on the side of his neck and ear after carrying freshly cut oak logs on his
shoulder. He suggested that fungi on the bark might be responsible. A similar case was reported
from Italy where it was observed that the rash recurred each time upon returning to work with
wood.41 Dubreuilh, in 1931, described six cases of woodcutter’s eczema that he thought secondary
to bark.42 Spillman and Weis reported similar observations when nearly the whole population of a
small village in France suffered dermatitis of the hands, face, and genitalia after contact with the
bark of oak trees.43 By 1933, Senear reports dermatitis from contact with the bark of oak (Quercus),
beech (Fagus), chestnut (Castanea), poplar (Populus), acacia (Robinia), plane (Platanus), elm
(Ulmus), and conifers.44
In 1948, Tenchio reported positive patch tests to the lichen Parmelia caperata found growing
on the bark of firs (Abies), larches (Larix), and chestnuts (Castanea).45 Further reports published
confirmed the role of lichens in inducing allergic contact dermatitis.46-49
Work by LeCoulant and Lopes50 and subsequently by Mitchell et al.,51-53 however, demonstrated
that many cases of suspected contact dermatitis to lichens, were owing to liverworts which are
commonly found growing together with lichens. In a study by LeCoulant,54 more reactions were
noted to Frullania and other liverworts than to lichens. Further work confirmed that in France, at
least, the main cause of woodcutter’s eczema was allergy to liverworts.50 Mitchell subsequently
demonstrated that many cases of cedar poisoning in Canada were also owing to exposure to
liverworts, predominantly Frullania.55 The allergen(s) in Frullania are sesquiterpene lactones that
are not present in lichens.56
There is no doubt, however, that lichens do cause contact dermatitis. Mitchell,49 investigating
cedar poisoning in British Columbian lumbermen, obtained positive patch tests with bark lichens
and usnic acid. Patch tests to the wood itself were negative.47 Champion46 found similar positive
reactions to usnic acid in an English woodcutter’s wife who had indirect contact with ash bark
through her husband’s work clothes. He also described three patients whose atopic eczema deteri-
orated following contact with lichens (mainly Lecanora spp.).57
Most occupational contact dermatitis to lichens occurs in forestry workers who have contact
with lichens growing on the bark of trees.58 The rash is usually confined to exposed skin surfaces
but less obvious patterns can occur when lichens get inside an open shirt and lodge at the waistline

or when the clothes are saturated with rain. Usnic acid is insoluble in water but is carried down
tree trunks by rainwater and is present in soil until degradation occurs.
Lichen sensitivity may also develop from nonoccupational contact with wood, for example,
from carrying firewood or from contact with wood ash. Wood and Rademaker59 report an 8 year
old girl with allergic contact dermatitis from contact with lichens while climbing a tree.
Some ground lichens can also sensitize. A third of lichen pickers who harvest Cladonia stellaris,
used in Christmas decorations, flower arrangements, toy trees in model railway layouts, and so on,
suffer from allergic contact sensitization.33,37 Dalhquist and Fregert38 report a patient with face and
hand eczema who reacted to reindeer moss after arranging it as a Christmas decoration. Brasch
and Jacobsen60 described hand eczema in a churchyard gardener who had arranged reindeer moss
as a grave decoration.
Today, the main cause of contact dermatitis to lichens is through exposure to perfumes con-
taining oak moss, predominantly from Evernia prunastri and Pseudevernia furfuracea.61,62 Aromatic
lipids in the lichen are extracted with a volatile hydrocarbon organic solvent that is then evaporated.
In several European countries, including Denmark,63 Italy,64,65 Portugal,19 and the Netherlands,66,67
oak moss is the main allergen of fragrance mix.
22.3.2 IMMEDIATE HYPERSENSITIVITY REACTIONS

Lichenized fungal spores and portions of the lichen body (thallus) can become airborne.49,68,69
Immediate hypersensitivity to lichens has been reported by Philippe et al.70 Champion57 reported
positive skin prick reactions to the algal component (patch test negative) in an atopic individual
whose eczema rapidly deteriorated following contact with lichens.
22.3.3 PHOTOSENSITISING ABILITY

Thune and Solberg13 report a photodermatitis-like airborne contact dermatitis from lichens. It is
unclear, however, whether or not lichens are true photosenisitizers.12-14,20,28,30,32,35,71-73
22.3.4 CROSS REACTIONS

A number of patients are allergic to both lichens and liverworts. This probably represents multiple
sensitization, rather than cross-sensitization, because both lichens and liverworts (Frullania) coexist
on trees.18,51,53,55 The allergens in Frullania are sesquiterpene lactones that are probably not present
in lichens.33
22.3.5 INDIVIDUAL CASE REPORTS

Hahn23 reported about a 65 year old man with a rash on his neck and hands. The man was cutting
wood in an orchard. Patch tests results were positive to lichens (as is), usnic acid, atranorin, cinnamic
alcohol, oak moss, and isoeugenol. The lichens included Hypogymnia physodes, Parmelia sulcata,
P. exasperatula, Physcia tenella, and Candelariella cf. reflexa.
Quirino25 reported about a 57 year old man with a rash on his face, neck, forearms, and hands.
This man cuts trees to build vineyard poles. Patch tests results were positive to usnic acid, atranorin,
lichen mix, Usnea rubiginea, and Ramalina farinaceae. The man was also sensitive to Frullania
dilatata and sesquiterpene lactone mix.
Wood59 reported about an eight year old girl with a recurrent dermatitis, predominantly of the
face and hands, after climbing the garden tree. Patch tests results were positive to lichen acid mix
and D-usnic acid. Lichens on the tree were identified as the Parmelia species. When the girl avoided
climbing the tree, clinical improvement resulted.
Held74 reported about an allergic contact dermatitis in a woman that was found to be owing to
oak moss in her husband’s after-shave lotion.
Rafanelli75 reported a contact dermatitis from usnic acid in vaginal ovules.

Allergens and concentrations used for patch testing:
Lichen (specific plant) as is.

D-usnic acid 1 percent.
Evernic acid 1 percent.
Atranorin 0.5 percent.
Oak moss 2 percent.
Further allergens and concentrations used for patch testing:
Stitic acid 1 percent.

Fumarprotocetraric acid 1 percent.
22.4 REFERENCES
1. Gilbert, O. L., Lichens as indicators of air pollution in the Tyne Valley, in Ecology and the Industrial
Society, Goodman, G. T., et al., Eds., Blackwell, Oxford, 1965, 35.
2. Ainsworth, G. C., Ainsworth and Bisby’s Dictionary of the Fungi, 6th ed, Kew, Commonwealth
Mycological Institute, 1971.
3. Ahmadjian, V., A guide to the algae occurring as lichen symbionts: isolation, culture, cultural phys-
iology and identification, Phycologia, 6, 127, 1967.
4. Bylicka, H., Antibiotics of lichens, Acta Microbiol. Polon., 1, 185, 1952.
5. Kerry-Nicholls, J. H., The origin, physical characteristics, and manners and customs of the Maori
race, from data derived during a recent exploration of the King Country, New Zealand, J. R. Anthrop.
Inst., 15, 187, 1886.
6. Shibata, S., Relation between chemical constitution and antibacterial effects, of usnic acid and its
derivatives, J. Pharm. Soc. Jpn., 68, 298, 1948.
7. Perez-Llano, G. A., Lichens. Their biological and economic significance, Bot. Rev., 10, 1, 1944.
8. Arctander, S., Perfume and Flavor Materials of Natural Origin, Published by the author, Elizabeth,
NJ, 1960.
9. Lovell, C. R., Plants and the Skin, Blackwell Scientific Publications, Oxford, 1993.
10. Mitchell, J. C. and Maibach, H. I., Sensitizing capacity of usnic acid derived from lichenized fungi,
Acta Derm. Venereol., 49, 498, 1969.
11. Mitchell, J. C. and Shibata, S., Immunologic activity of some substances derived from lichenized
fungi, J. Invest. Dermatol., 52, 517, 1969.
12. Thune, P., Allergy to lichens with photosensitivity, Contact Derm., 3, 213, 1977.
14. Thune, P., Solberg, Y., McFadden, N., Staerfelt, F., and Sandberg, M., Perfume allergy due to oak
moss and other lichens, Contact Derm., 8, 396, 1982.
15. Asahina, Y. and Shibata, S., Chemistry of Lichen Substances, Japanese Society Promotion of Science,
Tokyo, 1954.
16. Culberson, C. F., Chemical and Botanical Guide to Lichen Products, Chapel Hill, University of North
Carolina Press, 1969.
17. Dahlquist, I. and Fregert, S., Atranorin and oak moss contact allergy, Contact Derm., 7, 168, 1981.
18. Gonçalo, S., Contact sensitivity to lichens and Compositae in Frullania dermatitis, Contact Derm.,
16, 84, 1987.
19. Gonçalo, S., Cabral, F., and Gonçalo, M., Contact sensitivity to oak moss, Contact Derm., 19, 355, 1988.
20. Fernandez de Corres, L., Photosensitivity to oak moss, Contact Derm., 15, 118, 1986.
21. Fernandez de Corres, L., Leaniz Barrutia, I., Munoz, D., Bernaola, G., Fernandez, E., and Audicana,
M. T., Multiple sensitizations to plants in a farmer, Contact Derm., 17, 315, 1987.
22. Fregert, S. and Dahlquist, I., Patch testing with oak moss extract, Contact Derm., 9, 227, 1983.

23. Hahn, M., Lischka, G., Pfeifle, J., and Wirth, V., A case of contact dermatitis from lichens in southern
Germany, Contact Derm., 32, 55, 1995.
24. Lorenzi, S., Guerra, L., Vezzani, C., and Vincenzi, C., Airborne contact dermatitis from atranorin,
Contact Derm., 32, 315, 1995.
25. Quirino, A. P. and Barros, M. A., Occupational contact dermatitis from lichens and Frullania, Contact
Derm., 33, 68, 1995.
26. Pecegueiro, M. and Menezes-Brandao, F., Airborne contact dermatitis to plants, Contact Derm., 13,
277, 1985.
27. Robertson, W. D. and Mitchell, J. C., Allergic contact and photodermatitis, Can. Med. Assoc. J., 97,
380, 1967.
28. Sandberg, M. and Thune P., The sensitizing capacity of atranorin, Contact Derm., 11, 168, 1984.
29. Tan, K. S. and Mitchell, J. C., Patch and photopatch tests in contact dermatitis and photodermatitis,
a preliminary report of investigation of 150 patients, with special reference to “cedar-poisoning,” Can.
Med. Assoc. J., 98, 252, 1968.
30. Thune, P. and Eeg-Larsen, T., Contact and photocontact allergy in persistent light reactivity, Contact
Derm., 11, 98, 1984.
31. Wennersten, G., Photodynamic reactions induced by compounds derived from lichens, Acta Derm.
Venereol., 59, 197, 1979.
32. Thune, P., Contact allergy due to lichens in patients with a history of photosensitivity, Contact Derm.,
3, 267, 1977.
33. Hausen, B. M., Emde, L., and Marks, V., An investigation of the allergenic constituents of Cladonia
stellaris (Opiz) Pous & Vezda (“silver moss,” “reindeer moss” or “reindeer lichen”), Contact Derm.,
28, 70, 1993.
34. Mitchell, J. C., Stereoisomeric specificity of usnic acid in delayed hypersensitivity, J. Invest. Dermatol.,
47, 167, 1966.
36. Heine, A. and Tarnick M., Allergic contact eczema caused by usnic acid in deoderant sprays, Dermatol.
Monatsschr., 173, 221, 1987.
37. Salo, H., Hannuksela, M., and Hausen, B., Lichen picker’s dermatitis (Cladonia alpestris (L.) Rab.),
38. Dahlquist, I. and Fregert, S., Contact allergy to atranorin in lichens and perfumes, Contact Derm., 6,
111, 1980.
39. Horand, R., Mains de crocodule, dermatose professionelle produite par le bois de chataignier, Gaz.
Hop., 80, 255, 1907.
40. Spillmann, L., Dermite artificielle due à l’action du chêne, Bull. Soc. Fr. Derm. Syph., 6, 33, 1921.
41. Tommasi, L., Dermite dei boscaiuoli de ipersensibilita, G. Ital. Dermatol., 70, 1223, 1929.
42. Dubreuilh, W., L’eczéma des bûcherons, Ann. Derm. Syph ., 7(S.2), 199, 1931.
43. Spillmann, L. and Weis, N., Deux cas de dermite artificielles dues veraisemblablement à l’action de
substances végétales chez le bûcherons, Bull. Soc. Fr. Derm. Syph., 38, 339, 1931.
44. Senear, F. E., Dermatitis due to woods, J. Am. Med. Assoc., 101, 1527, 1933.
45. Tenchio, F., Etiologie de l’ eczèma des bucherons, Dermatologica, 97, 72, 1948.
46. Champion, R. H., Wood-cutter’s disease, contact sensitivity to lichen, Br. J. Dermatol., 77, 285, 1965.
47. Mitchell, J. C. and Armitage, J. S., Dermatitis venenata from lichens, biology of lichens related to
criteria for diagnosis of occupational dermatitis and to industrial exposure risk, Arch. Environ. Health,
11, 701, 1965.
48. Mitchell, J. C., “Cedar poisoning” and lichen allergy, Br. Columb. Med. J., 7, 489, 1965.
49. Mitchell, J. C., Allergy to lichens. Allergic contact dermatitis from usnic acid produced by lichenized
fungi, Arch. Dermatol., 92, 142, 1965.
50. LeCoulant, P. and Lopes, G., Wood dermatitis. Experimental research on the allergy due to mosses,
J. Med. Bordeaux, 133, 245, 1956.
51. Mitchell, J. C., Schofield, W. B., Singh, B., and Towers, G. H., Allergy to Frullania. Allergic contact
dermatitis occurring in forest workers caused by exposure to Frullania nisquallensis, Arch. Dermatol.,
100, 46, 1969.

52. Mitchell, J. C., Fritig, B., Singh, B., and Towers, G. H., Allergic contact dermatitis from Frullania
53. Mitchell, J. C., Dupuis, G., and Geissman, T. A., Allergic contact dermatitis from sesquiterpenoids
of plants. Additional allergenic sesquiterpene lactones and immunological specificity of compositae,
liverworts and lichens, Br. J. Dermatol., 87, 235, 1972.
54. LeCoulant, M. P., L’allergie au Frullania, son role dans la “Dermite du Bois de Chêne,” Bull. Soc.
Fr. Derm. Syph., 73, 440, 1966.
55. Mitchell, J. C., Industrial aspects of 112 cases of allergic contact dermatitis from Frullania in British
Columbia during a 10-year period, Contact Derm., 7, 268, 1981.
56. Knoche, H., Ourisson, G., Perold, G. W., Foussereau, J., and Maleville, J., Allergenic component of
a liverwort, a sesquiterpene lactone, Science, 166, 239, 1969.
57. Champion, R. H., Atopic sensitivity to algae and lichens, Br. J. Dermatol., 85, 551, 1971.
58. Gonçalo, S., Born, M., and Pereira dos-Santos, A. P., Contact dermatitis due to lichens, Contact Derm.,
7, 118, 1981.
59. Wood, B. and Rademaker, M., Allergic contact dermatitis from lichen acids, Contact Derm., 34, 370,
1996.
60. Brasch, J. and Jacobsen, P., Flechten und ihre Allergene, Allergologie, 14, 99, 1991.
61. Frosch, P. J., Pilz, B., and Andersen, K. E., et al., Patch testing with fragrances, results of a multicenter
study of the European Environmental and Contact Dermatitis Research Group with 48 frequently used
constituents of perfumes, Contact Derm., 33, 333, 1995.
62. Frosch, P. J., Pilz, B., and Burrows, D., et al., Testing with fragrance mix. Is the addition of sorbitan
sesquioleate to the constituents useful?, Contact Derm., 32, 266, 1995.
63. Johansen, J. D. and Menne, T., The fragrance mix and its constituents; a 14-year material, Contact
Derm., 32, 18, 1995.
64. Angelini, G., Vena, G. A., and Giglio, G., et al., Contact dermatitis due to cosmetics, J. Appl. Cosmetol.,
3, 223, 1985.
65. Santucci, B., Cristaudo, A., and Cannistraci, C., et al., Contact dermatitis to fragrances, Contact Derm.,
16, 93, 1987.
66. de Groot, A. C., Liem, D. H., Nater, J. P., and van Ketel, W. G., Patch tests with fragrance materials
and preservatives, Contact Derm., 12, 87, 1985.
67. de Groot, A. C., van der Kley, A. M., and Bruynzeel, D. P., et al, Frequency of false negative reactions
to fragrance mix, Contact Derm., 28, 139, 1993.
68. Garrett, R. M., Studies on some aspects of ascospore liberation and dispersal in lichens, Lichenologist,
5, 33, 1971.
69. Petterrson, B., Experimentelle Untersuchungen über die evenemochore Verbreitung der, Sporenflanzen
Acta Bot. Fenn., 25, 1, 1940.
70. Philippe, J., Guibert, L., and Combes, R., Considérations sur les allergies sylvaines, Rev. Fr. Allergol.,
5, 95, 1965.
71. Fernandez de Corres, L., Munoz, D., Leaniz Barrutia, I., and Corrales, J. L., Photo contact dermatitis
from oak moss, Contact Derm., 9, 528, 1983.
72. Mitchell, J. C., Absence of psoralen-type phototoxicity from usnic acid, some lichens, and lichen
substances, J. Invest. Dermatol., 47, 61, 1966.
73. Thune, P., Lichens, compositae and photosensitivity, Photodermatology, 4, 1, 1987.
74. Held, J. L., Ruszkowski, A. M., and Deleo, V. A., Consort contact dermatitis due to oak moss, Arch.
Dermatol., 124, 261, 1988.
75. Rafanelli, S., Bacchilega, R., Stanganelli, I., and Rafanelli, A.. Contact dermatitis from usnic acid in
vaginal ovules, Contact Derm., 33, 271, 1995.
76. Schmidt, R. J., Allergic contact dermatitis to liverworts, lichens, and mosses, Semin. Dermatol., 15,
95, 1996.
77. Krauskopf, J., Contact hypersensitivity to Hypogymnia physodes, Cesk. Dermatol., 51, 217, 1976.
78. Bhalme, A. Y. and Pasricha, J. S., Irritant and sensitizing potential of some common Indian cacti,
succulents, lichens and aquatic plants, Indian J. Dermatol. Venereol. Leprol., 52, 89, 1986.
79. Guin, J. D. and Jackson, D. B., Oakmoss photosensitivity in a ragweed-allergic patient, Contact Derm.,
18, 240, 1988.

80. Novak, M., Contact sensitisation to constituents of perfume composition in antiphlogistic ointment,
Cs. Derm., 49, 375, 1974.
81. Favennec, F., Sensibilisation su lichen, à la Candidine et a Frullania, L’Ouest Médical, 27, 1647, 1974.
82. Favennec, M. J. and Favennec, F., Les maladies cutanes en agriculture, L’Ouest Médical, 29, 395, 1976.
83. Leonardi, G., Spore di lichens boschivo (Palmeria caperata) causa di al ergosi cutanea, Folia Allergy,
1, 219, 1954.
84. Champion, R. H., Dermatitis from pollens and lichens, Br. J. Dermatol., 81, 869, 1969.
85. Thune, P., Sandberg, M., Allergy to lichen and compositae compounds in perfumes. Investigations on
the sensitizing, toxic and mutagenic potential, Acta Derm. Venereol. Suppl. (Stockholm), 134, 87, 1987.
86. Rycroft, R. J. G, Menne, T., Frosch, P. J., and Benezra, C., Textbook of Contact Dermatitis, Springer-
Verlag, Berlin, 1992.

23 Verbenaceae
Evy Paulsen and Klaus E. Andersen
CONTENTS
23.1 Introduction
23.1.1 Plant Family
23.1.1.1 Geographical Location
23.1.1.1.1 Subfamilies, Genera, and Species
23.2 Chemistry
23.2.1 General Chemistry of the Verbenaceae
23.2.1.1 Chemistry of Selected Species
23.3 Clinical Efffects
23.4 References
23.1 INTRODUCTION
23.1.1 PLANT FAMILY
The Verbena family is large, comprising more than 3000 species in 75 to 100 genera.1,2 It includes
herbs, shrubs, trees, lianas, and several thorny xerophytes, accounting for the distribution of the
family in dry regions.
Botanically, the Verbena family is characterized by usually opposite, rarely whorled or alternate,
leaves, entire or divided, that lack stipules. The flowers are bisexual and arranged in a cyme or a
raceme. The calyx is four- or five-lobed or toothed. The tubular corolla likewise is four- or five-
lobed. The fruit is either a drupe or, less commonly, a capsule, or dividing into two or four one-
seeded nutlets.1,3 The Verbenaceae are often hairy and characteristicallly the hairs are incrusted with
calcium carbonate and/or silicic acid.2 Glandular hairs, secreting essential oils, are also common.2
23.1.1.1 Geographical Location
Though the distribution is worldwide, the majority of species is found in tropical, subtropical, and
also temperate regions in the southern hemisphere.2 The family belongs to the order Lamiales along
with Labiatae and others and though the Verbenaceae is largely woody, it is considered to be closely
related to the herbaceous Labiatae.1
23.1.1.1.1 Subfamilies, Genera, and Species
According to Hegnauer,2 the family is divided into eight subfamilies:
1. Viticoideae that includes the genera Callicarpa, Clerodendron (equivalent to Cleroden-

drum), Premna, Vitex, Tectona, and others.
2. Verbenoideae that includes the genera Lantana, Lippia, and Verbena, among others.

3. Chloanthoideae that includes, for example, Chloanthes and Dicrastylis.
4. Caryopteroideae that includes, for example, Caryopteris and Teysmanniodendron.
5. Avicennioideae that only includes Avicennia.*
6. Nyctanthoideae that includes Nyctanthes.
7. Symphorematoideae.
8. Stilboideae.
However, Hegnauer states that another source only includes the Viticoideae, Verbenoideae,
Caryopteroideae, and Nyctanthoideae in the Verbena family.
Important economic uses include among others timbers, essential oils, teas, herbal remedies,
and ornamentals.1 Timber-producing genera are Tectona (teak) from Southeast Asia, Citharexylum
(zither wood) from Mexico and South America used for musical instruments, Vitex celebica from
Southeast Asia, Petitia domingensis Jacq. (fiddle wood) from the West Indies, and Premna from
Malaya used by the Japanese for knife handles.1 Valuable oils are obtained from Vitex agnus-castus
(chaste tree) and Lippia citriodora (verveine odorante, lemon-scented Verbena). The latter yields
Verbena oil.5 The leaves of this and other Lippia species as well as some Lantana species are used
for tea in South America and West and South Africa. The most widely used herbal remedy of the
Verbenaceae is probably Verbena officinalis L. (vervain, wild verbena). Other important species in
that respect are Lippia dulcis (Yerba dulce) of Mexico and L. scaberrima of South Africa and L.
citriodora.6,7 Many genera are cultivated for ornamental purposes in tropical and subtropical
gardens, and in gardens of temperate regions species of Callicarpa, Caryopteris, Clerodendron
(equivalent to Clerodendrum), Vitex, and Verbena are found. Species of Clerodendron, Lippia, and
Lantana are also used as indoor plants.
Relatively few species of this large family have been reported to cause dermatitis of allergic,
irritant, or urticarial nature or other skin symptoms (Table 23.1). Some of the more important are
presented in the following.
Lantana camara L.—A woody, half-climbing, up to 6 ft high shrub with a variety of flower
colors and a strong unpleasant smell. Stems and leaves are covered with short hairs and are rough
to the touch.8 Some races of this plant are prickly.8 It is native to the tropical regions of America,
but is now found in tropical, subtropical, and warm-temperate parts of the world, cultivated as a
hedge or ornamental plant, including house plants or naturalized (Figure 23.1).3 It is the prinicipal
weed in 12 countries and a serious weed in 10.9 As indicated by some of its common names (Table
23.1), it is considered a serious pest, not only because of its rapid spread as a weed, but more so
because it is reported to be one of the 10 most toxic weeds in the world.9 The toxicosis caused by
livestock’s (cattle, buffalo, sheep, and goats) ingestion of lantana plants, the allelopathic effect of
the plant on neighboring vegetation including grasses, and the infestation thus diminishing the
potential pastures available are sources of economic losses.9
Lantana toxicity runs a three-phased course: the first is release and absorption of the toxins in
the gastrointestinal tract, followed by interaction between toxins and hepatocytes, closure of bile
canaliculi, and gall bladder paralysis resulting in cholestasis and hepatic injury. This leads to
hyperbilirubinemia and hyperphylloerythrinemia, phylloerythrin being a breakdown product of
chlorophyll.5 The third phase is the manifestation of the tissue damage caused by excessive amounts
of bilirubin and phylloerythrin and includes renal damage and inflammation, photochemical reac-
tions, and photosensitization of skin.9,10 Acute poisoning in animals leads to constipation, followed
by sedation and photosensitization in the next 24 to 48 h, reddening of the muzzle that together
with other hairless parts become swollen, conjunctivitis, and later severe, bloody gastroenteritis
and possibly death in 3 to 5 days.5,8-10 In chronic poisoning, photosensitization is a prominent
feature. Nonpigmented skin without hair is first affected, whereas black, hairy skin may never
become involved.8 The affected skin becomes yellow, swollen, and hard with painful cracking and
* This subfamily has been reclassified and now belongs to the family Avicenniaceae.4

TABLE 23.1
List of Plant Species of the Verbena Family Reported to Cause Dermatitis
and Other Skin Symptoms
Species (Common Name)
Clerodendron aculeatum Griseb. (crab prickle)

Gmelina elliptica = Gmelina villosa (common bulang)
Lantana camara L. (lantana, common lantana, yellow sage, shrub verbena,
bunchberry, the curse of India, the curse of Barbados,
tick-berry)
Lippia scaberrima Sonder (Beukessboss of South Africa, Beukesbos, Beukesbossie,
Benkess Boas)
Tectona grandis L.f. (teak, teck, djati, true teak)
Teysmanniodendron pteropodum = (tikiko)
Teijsmanniodendron pteropodum
Verbena elegans
Verbena hastata L. (blue vervain, wild hyssop, simpler’s joy)
Verbena x hybrida Voss. (Garten-Verbenen)
Verbena officinalis L. (vervain, wild verbena, herb of grace, herbe sacreé, herba
veneris)
Verbena venosa Gillies & Hooker = (veined vervein, stiff Verbena)
Verbena rigida Sprengel
Vitex littoralis A.Cunn. = Vitex lucens (puriri, New Zealand teak)
T. Kirk
FIGURE 23.1 Lantana camara L. hybrid.
peeling, leaving raw areas. The inflammation involves adjacent mucous membranes of mouth, nose,
and eye as well as eyeballs.8 The chronic poisoning in sheep results in significant reduction in both
cellular and humoral immunity and the nonspecific phagocytic activity of splenic reticulo-endot-
helial cells.11

Potential beneficial effects—In West Africa, the leaf is used for coughs and colds and likewise
it is used to cause sweat in fevers in El Salvador.12,13 A mild decoction of the leaves is also a tropical
remedy for rheumatism and indigestion, a stronger decoction is used for snakebites.14 In South
America, lantana leaves are used for tea and the plant is considered to have insect repellant
properties. This is supported by Dua et al.’s study where Lantana flower extract in coconut oil
shows repellant properties against Aedes mosquitoes with a more than 50 percent protection rate
up to 4 h after one application. No adverse effects were observed in the human volunteers after a
three-month period.15 The rootbark of lantana shows antimalarial activity in vitro, and lantadenes
and related triterpenoids seem to inhibit activation of Epstein-Barr virus.16,17
Lippia scaberrima Sonder—The genus Lippia is generally found in tropical America and
Africa.5 The dried leaves are used as a hemostatic herbal remedy in South Africa and among Dutch
people in the same region, brandy in which the leaf has been soaked is used as a stomachic and
tonic. Likewise, an infusion of the leaf is taken as a tonic by the Zulu people. Finally, a decoction
of the plant is also applied externally as a counterirritant for backache.12
Tectona grandis L.f.—Teak comes from Southeast Asia, including India to which it is native,
Burma, Thailand, Indo-China, and Java, and is also cultivated in Africa and the West Indies.1,18,19
Teak is an example of a timber with different trade names depending on the place of growth, harbor,
and shipment.20 The names Siam teak, Bangkok teak, Burma teak (which is further subdivided into
Rangoon and Moulmain teak), and Java teak are all synonymous with true teak.20,21 T. tenuifolia
from Burma and T. philippinensis from the northern Philippine Islands, two lesser species, are also
named teak.5 On the other hand, so-called teaks from Africa, Australia, and South America are not
botanically related.20 Teak is one of the oldest trade timbers in the world, being in use 4000 years
ago, and it is highly valued because the hard, beautiful wood is extremely resistant to water,
alternations between humidity and drought, termites, wood rot, fungi, and chemicals.19-22 The
durability is among other things attributed to an essential oil that does not damage metal and the
timber is, therefore, used especially in ship building where metal–wood contact is frequently
present.5,21 The durability is proven by the fact that the wood has been found well preserved in
more than 2000 year old Indian temples.5 Teak is the economically most important species of the
Verbenaceae and it is also used for furniture, flooring, veneer, and framing.1,22
Verbena elegans is a perennial, native to Texas and the southern part of Mexico, that is cultivated
as an annual in colder climates. According to Siri von Reis Altschul, a decoction of the plant is
used for stomach troubles.13
Verbena hastata L.—Native to the United States, fluid extract made from the dried, aerial parts
is used as a tonic, emetic, expectorant, and so on.23
Verbena x hybrida Voss. Hybrids of many different species with flowers of many colors (Figure
23.2). As indicated by the German colloquial name, these popular garden plants also are grown in
temperate regions of the northern hemisphere.
Verbena officinalis L. is a perennial with many small, pale lilac flowers found in Europe,
northwards to 54° N and naturalized or casual further north.3 It also is found in Barbary, China,
and Japan.23 The name Verbena was the Roman name for altar plants in general, and this species
in particular, and it was used by priests for sacrifices and later widely used in magic rites.23 Also,
it was considered from ancient times to be an all-round herbal remedy or as stated by Hippocrates
“one of the few all-curing herbs.” Accordingly, the list of diseases for which verbena is recom-
mended is long. Herba Verbenae, dried flowering shoots, is used in medical wine for migraine
and fatigue and for indigestion, including diseases of the liver and gallbladder, as well as diseases
of the kidney and irregular menstruation. It is also applied externally, for example, as a poultice,
or the fresh sap is used in baths for slowly healing wounds. The poultice acts as a rubefacient
and is good in, for example, headache, earneuralgia, and rheumatism.23 It is still used today
although in the form of an omelette made from egg white and verbena flowers as described by
del Pozo et al.24

FIGURE 23.2 Verbena hybrid.
Verbena venosa Gillies & Hooker, equivalent to Verbena rigida Sprengel—The Sotho use a
root decoction of the plants for heartburn and colic.12
Vitex littoralis A. Cunn., equivalent to Vitex lucens T. Kirk is native to New Zealand.18
23.2 CHEMISTRY
23.2.1 GENERAL CHEMISTRY OF THE VERBENACEAE
The most common compounds within the family are flavone glycosides, such as vitexin and
orientin.25 Other important compounds are iridoid glycosides, such as verbenalin, phenols and
phenolic acids, methylated 6- or 8-hydroxy flavonols, quinones, diterpenoids, and essential oils.2
23.2.1.1 Chemistry of Selected Species
Clerodendron aculeatum Griseb—This species contains verbascoside and cistanoside-D.26

Lantana camara L.—Lantana camara taxa contain both toxic and nontoxic triterpenes, but in
the more than 50 years of research on the chemistry of lantana toxins, there have been many
contradictory reports as to the exact chemical identity of the toxins.9,10 Louw in 1943 and 1948
stated that the pentacyclic triterpenes lantadene A (22-b-angeloyloxy-3-oxoolean-12-en-28-oic
acid) and lantadene B (22-b- dimethylacryloyloxy-3-oxoolean-12-en-28-oic acid) were major com-
ponents of lantana leaves and that only lantadene A was toxic.9 In 1963, Brown et al. showed that
chromatographically pure lantadene A had no toxic/icterogenic activity, whereas reduced lantadene
A was icterogenic.9 The latter observation was confirmed by Pass et al. and Seawright and Hrdlicka,
even if the last-mentioned also showed toxicity of both lantadene A and B.9,27 Because of the low
toxicity of lantadene B and low concentration of reduced lantadene A (5 percent of lantadene A)
in the leaves, they were considered unlikely to be of much importance in the poisoning of
ruminants.27 In accordance with this, reduced lantadene A and B were nontoxic when given to
sheep in amounts equivalent to the estimated content of these in a toxic amount of dried plant
material.9 Sharma stated that pure crystallized lantadene A was nontoxic, but that an impure fraction

containing, among other things, lantadene A was toxic and that the toxins seemed to resemble
lantadene A and B closely. In 1991 Sharma et al.28 reported that lantadene A was obtained in two
polymorphic forms, I and II, and whereas form I seemed to be nontoxic to guinea pigs, form II
produced symptoms similar to those of lantana poisoning. Later, Sharma et al.29 reported on a new
hepatotoxicant, lantadene C, from Lantana camara var. aculeata. Lantadene C was found to be
identical with dihydrolantadene A and was obtained in two forms that both were hepatotoxic.
Another poisonous constituent of lantana is lancamarone, toxic to fish, but its potential role in
lantana poisoning has not been clarified.9 Barre et al.30 recently reported on a new triterpene from
Lantana camara, 22-b-acetoxylantic acid, with antimicrobial and antimutagenic activity.
In addition to lantadene A, B, and C, the leaves of Lantana camara contain oleanonic acid,
lantanilic acid, icterogenin, and camaroside.31 Verbascoside (acteoside), a phenolic compound, has
also been isolated from Lantana camara. It has, for example, hypertensive, antitumor, and anti-
hepatotoxic activity and is an inhibitor of both protein kinase C and lens aldose reductase.32,33 The
roots of the plant contain triterpenoid constituents as, for example, lantanolic acid, oleanolic acid,
and lantaiursolic acid as well as oligosaccharides and iridoid glycosides.34,35 Essential oils from
Lantana camara L. of Indian origin contain caryophyllene, a-phellandrene, and geraniol and,
depending upon the source, may contain citral, a-pinene, and dipentene among other compounds.2
Saleh36 found significant quantitative and qualitative differences in the essential oils of five varieties
of lantana and attributed this to taxonomic position rather than ecological factors. The main
compound in all of them was citral, whereas geraniol represented the major oxygenated terpene.36
In addition, D-a-pinene, DL-camphene, b-pinene, D-limonine, 1,8-cineol, b-phellandrene, dipen-
tene, g-terpinene, P-cymene, a-caryophellene, b-caryophellene, D-citronellol, and a-cadinol were
isolated from all five varieties.36 The flowers contain an anthocyanin and carotene.12
Lippia scaberrima Sonder—According to Hegnauer an unknown, possibly iridoid, glycoside
was described by Power and Tutin in 1907.2 In addition, they isolated tannin from dried leaf and
stem, a crystalline alcohol called lippianol and a volatile oil with a camphoraceous odor.12
Tectona grandis L.f.—The content of chemical compounds, including allergens, varies widely
depending on origin, age, and possibly also the subspecies of teak.2 The first chemical investigation
was made by Matthes and Schreiber in 1914, followed by patch testing in one person. They found
that chloroform and alcoholic extracts, but not splinters or sawdust, elicited positive reactions.19,21
Patch testing with different extracts and shavings or teak tree sawdust in patients and controls led
some researchers such as Hoffmann in 1926 and Carrié and Stelzer in 1955 to believe that the
reactions observed were of an allergic nature.19,21 A few years later, Sandermann and Dietrichs
isolated the known sensitizer lapachol (Figure 23.3), and this was thought to be the primary allergen
of teak.2,4,19 In accordance with this, in 1962, Schulz showed that teak-sensitive persons were patch
test positive to lapachol, but not tectoquinone.4 However, he suspected another sensitizer which
was isolated shortly after by Sandermann and Simatupang37 and named deoxylapachol (Figure
23.3). This was found to be the primary, very strong sensitizer, whereas lapachol in experimental
studies could not sensitize, but only elicit true cross-reactions once sensitization to deoxylapachol
was present.38 The patch test reactions to the latter was 100 to 200 · stronger than those to lapachol.19
Both lapachol and deoxylapachol are found in other tree species and there is an especially close
relationship between the quinones of the Bignoniaceae and teak.2,5 However, experimental studies
have shown cross-reactions between, for example, dalbergiones and deoxylapachol and the findings
of Krogh (1964) where 7 of 13 teak-sensitive workers were positive to Jacaranda dust (probably
Brazilian rosewood) could be owing to true cross-reactions between closely related quinones.19,39
As mentioned previously, the content of lapachol and deoxylapachol varies considerably in local
races of teak and even individual trees.2,4 In plantation experiments in Germany, it was possible to
grow teak containing little or no deoxylapachol and likewise cultivation of teak in South Africa
has produced trees with a lower deoxylapachol content.19,22 On the other hand, the allergen content
may be high enough to cause irritant reactions, and therefore patch testing with the pure allergen,
deoxylapachol, in a concentration not exceeding 0.01 percent in petrolatum or alcohol is

FIGURE 23.3 Lapachol (left) and deoxylapachol (right).
recommended.22 Krogh20 showed that moistened teak dust was toxic when patch testing both patients
and controls, whereas native teak dust only elicited allergic reactions. However, patch testing with
teak wood dust or shavings generally should be avoided because the combined possible irritant and
allergic properties may make interpretation difficult.4,22
The termite and insect repellant activity is owing to tectoquinone (2-methy lanthraquinone)
and related anthraquinones and deoxylapachol.2,33 Probably lapachol, deoxylapachol, and other
naphthoquinones as well as dehydrotectol and other naphthol derivatives are also responsible for
the antifungal activity. Additionally, teak may contain 2-methoxytoluene, 2-iodobenzoic acid, n-
heptylamine, butyric acid, a cis 1-4 polyisophrene, tectol, and often has a high rubber content.2,20
Verbena hastata L.—The plant contains the iridoid glycosides verbenalin and hastatoside.2
Verbena officinalis L.—The first iridoid glycoside isolated was verbenalin in 1908, and in 1935
it was recognized as identical with the well-known cornin.2 Another iridoid glycoside, hastatoside,
was isolated in 1970 and aucubin in the 1980s.2 The major flavonoid compound is luteolin 7-
diglucuronide and other flavonoids are the 6-O-substituted aglycones sorbifolin (trihydroxy-5,6,4´-
methoxy-7 flavone), pedalitin (tetrahydroxy-5,6,3´,4´-methoxy-7-flavone), and nepetin (equivalent
to eupafolin) (tetrahydroxy-5,7,3´,4´-methoxy-6-flavone).40,41 Tomás-Barberán et al.25 detected the
6-hydroxyflavone glycosides 6-hydroxy luteolin and 6-hydroxyapigenin (scutellarein), and Reynaud
et al.42 isolated four O-glycosylflavonoids, namely luteolin 7-glucoside, apigenin 7-glucuronide,
pedalitin 6-glucoside, and apigenin 7-galactoside. In addition, verbascoside (acteoside), a phenolic
compound isolated from more species of the Verbenaceae, has been found in Verbena officinalis.43
The dried leaves contain caffeic acid.2 The allergen(s) are unknown, but potential candidates include
flavonoids and phenols.44
Verbena venosa Gillies & Hooker, equivalent to Verbena rigida Sprengel—The leaves contain
urease.12
Vitex littoralis A. Cunn., equivalent to Vitex lucens T. Kirk—The iridoid glucoside5 aucubin
and agnuside (equivalent to agnoside) have been isolated from the wood as well as the flavone-C-
glycosides vitexin (apigenin 8-C-glucoside), isovitexin (equivalent to saponaretin equivalent to
homovitexin equivalent to apigenin 6-C-glucoside), orientin (luteolin 8-C-glucoside), isoorientin
(luteolin 6-C-glucoside), and vicenin-2. The leaves contain p-hydroxybenzoic acid and stearic acid
and the bark contains wax alcohols such as ceryl alcohol and the phytosterol b-sitosterin.2

Clerodendron aculeatum Griseb—This species is included in the list of plants of the U.S. Virgin
Islands that cause mechanical injury. The local common name, crab prickle, indicates the reason
for this.8
Gmelina elliptica (equivalent to Gmelina villosa)—According to Mitchell and Rook,5 this plant
causes mechanical injury by its thorns.
Lantana camara L.—Contact with the hairy rough leaves may cause skin irritation and, likewise,
the prickly plant may cause dermatitis.9,14 The strong offensive smell of the leaves may cause
headache and giddiness in persons working in the vicinity of the plants.9 Leaves and stem may be
potentially toxic to humans like they are to animals, but their rough texture prevents ingestion of
larger amounts, and cases of jaudice and photosensitization have not been reported in humans.10
On the other hand, ingestion of the unripe berries have been reported to cause severe and, in one

case, fatal poisoning in children.10 The symptoms are weakness, ataxia, lethargy, vomiting, diarrhea,
cyanosis, deep and labored breathing, depressed tendon reflexes, dilated or, in one case, pinpoint
pupils, photophobia, and coma. Gastric lavage as quickly as possible after exposure seems to be
the cornerstone of treatment.10 Ripe berries are reported to be nontoxic to children.9
Lippia scaberrima Sonder—A cloth dipped in this decoction is applied to the back to relieve
pain and produces a severe and painful dermatitis of unknown nature.12
Tectona grandis L.f.—Teak constituents may cause mechanical, irritant, and allergic skin
symptoms as well as urticaria and asthma. The first report on teak as a cause of dermatitis was a
Letter to the Editor in the Lancet in 1896 (Anonymous), followed almost 10 years later by a report
by Evans (1905) on a carpenter with weeping dermatitis.4,5,19 Since then, numerous cases and larger
reviews have been published.4,5,19-22,39
Allergenic compounds are often found in the heartwood and, therefore, persons at risk include
joiners, carpenters, wood machinists, cabinetmakers, and others exposed to the fine wood dust.4 In
agreement with this, the allergic contact dermatitis from teak takes the form of an airborne contact
dermatitis affecting exposed skin on the face, especially the eyelids, neck, scalp (in bald men),
forearms, and the dorsa of hands. Manual allergen transfer leads to rapid involvement of the genitals
and if the clothes are not tight-fitting, wood dust may enter at the collar, sleeves, and trouser legs
causing eczema of the moist skin of the axillae, groins, and waistband as well as the ankles and
dorsa of the feet.4,22 In case of involvement of flexures, the clinical picture may resemble atopic
dermatitis and likewise involvement of the sweaty areas of chest, groins, axillae, and elbow flexures
may mimic seborrhoic dermatitis.4 More rarely, the dermatitis may be localized to, for example,
the hands or eyelids only.4
Clinically, the eczema is characterized by erythema, swelling and possibly papules, followed
by desquamation.20,21 However, in highly sensitive individuals, the teak dermatitis may be vesicular
and weeping. In such patients, there is often a gradually worsening course for each flare-up that
may make complete avoidance of teak necessary.20 Krogh,20,39 in his extensive epidemiological
study on occupational teak contact eczema in a furniture factory, found 18.7 percent of the 112
exposed workers allergic to native teak dust; 12.5 percent had an allergic contact dermatitis while
6.2 percent were considered to have a latent allergy. The symptoms of the last-mentioned were
either severe itching or no symptoms. In four workers with negative patch tests who previously
had experienced flare-ups on exposure to teak, the symptoms had gradually diminished, indicating
development of hardening. Out of 60 workers occupied with particle-producing dusty work such
as sandpapering or sawing, 31 workers had skin symptoms owing to teak. This shows that other
mechanisms than allergic contact dermatitis were involved. Of the workers with positive toxic
reactions to the irritant moistened teak dust, four had had acute, transient eczemas during the hot
part of the summer, and they were considered to have irritant contact dermatitis owing to primary
irritant(s) in teak. The mechanical effect of the dust was also considered a contributing factor to
the high prevalence of occupational skin symptoms. In contrast, the teak wood as is and the
manufactured products such as furniture do not sensitize.20,39
Based on these results, specific recommendations concerning the exhaust ventilation system,
protective clothing, and general and personal hygiene were proposed and in a subsequent study
were found to have reduced considerably the prevalence of occupational skin symptoms.39
According to Carrié and Stelzer,21 Hoffmann saw one patient with urticaria owing to teak dust.
He considered inhalation and resorption of the irritant dust a possible explanation. Likewise,
urticaria with systemic effects was reported by Schmidt. A 38 year old carpenter, with a previous
history of dermatitis and discomfort when working with diluents, palisander, and bubinga woods,
changed his job to a cabinetmaker and developed itching and diarrhea when exposed to exotic
woods.
Patch testing with teak resulted in systemic symptoms in the form of flushing of the face, neck
and elbows, a periocular edema, and gastrointestinal upset 3 h after application of the tests. Despite
immediate removal of these, a 2+ reaction to teak was present after 72 h. Retesting with teak 1

week later produced flushing urticaria and gastrointestinal symptoms after 3 h and a fine universal
urticaria after 5 h. Apparently this is a very rare manifestation of immediate hypersensitivity to
teak resulting in a contact urticaria syndrome.45
Finally, although rarely, teak sawdust may cause asthma.4,46 Inhalation tests are reported to be
more reliable than scratch and intradermal tests owing to the risk of both false positive and false
negative reactions.4
Teysmanniodendron pteropodum—Siri von Reis Altschul in her herbarium report on drugs and
foods from little-known plants states that the ashes of this wood is very itchy when it comes in
contact with the skin.13
Verbena elegans—A case of concomitant immediate and delayed hypersensitivity to Verbena
elegans, ‘Cleopatra,’ was reported in 1995 in a 16 year old Danish female gardener apprentice.47
She had a previous history of cold and pressure urticaria and after a few months of almost daily
handling of Verbena plants in the nursery, she developed an urticaria-like rash with swelling of
hands, forearms, and other exposed sites on contact with the plants. The dermatitis did not disappear
completely within 24 h and gradually could be elicited by even slight contact. At the same time,
she developed vesicular eczema of the lateral aspects of fingers and interdigital spaces. After one
year, she gradually developed rhinitis, followed by itchy conjunctivitis and periorbital edema, and
finally asthma. After three years of full-time and two years of part-time employment, she discon-
tinued her work, causing her dermatitis to improve considerably and her rhinitis to disappear
whereas her asthma persisted. She was examined more than one year later, and skin prick testing
showed small positive reactions to birch and timothy pollen and dog and large positive reactions
to Verbena leaf as is, as well as positive scratch patch tests to the top and underside of the leaf.
Even if histamine release tests with a plant specimen from the hospital ground were negative, the
patient’s history and the results of the skin prick and scratch patch tests were considered suggestive
of an immediate hypersensitivity.
Patch tests with Verbena leaf and stalk moistened with ethanol were positive (1+) on days 4
and 6. Control patch tests with the same kind of Verbena plant in 27 consecutive eczema patients
indicated irritant properties of the test material with doubtful positive (?+) reactions in 8 patients
and a follicular 1+ reaction to the stalk in 1 patient. Positive reactions to all plant parts in another
patient were considered weakly allergic and possibly owing to true cross-reactions because the
patient was sensitized to thyme. Contrary to the gardener, none of the controls had positive reactions
at both readings. The allergen(s) are unknown.
Verbena hastata L.—According to Mitchell and Rook, this species may cause dermatitis which
they seem to relate to the irritant properties reported by Pammel.5,18
Verbena x hybrida Voss.—The first case of immunologic contact urticaria and other symptoms
from Verbena hybrids was reported in 1992 and in more detail in 1995.47,48 A 14 year old boy from
South Africa with a longstanding history of allergic rhinitis and occasional attacks of wheezy
bronchitis induced by respiratory infections, developed a generalized urticarial rash, palpitations,
dizziness, and a tight chest with wheeze after retrieving a cricket ball from a garden flower bed.
After intravenous administration of promethazine at the hospital, the symptoms rapidly cleared. A
similar, but less serious, attack six months previously had responded to oral promethazine. Appli-
cation of crushed Verbena hybrida leaves on the boy’s forearm induced a rapidly spreading urticarial
reaction within a minute. The subsequent laboratory investigations, including autoradiography of
the Western blots of Verbena hybrida leaf and flower extract, showed that the IgE of the patient
bound to the Verbena leaf extract, with maximal intensity in the 62,000 Da region. There was no
specific IgE binding to the Verbena flower extract, and it was concluded that the specific 62,000
Da allergen was present in the leaves only. The potential life-threatening symptoms and the risk
of inadvertent exposure to these commonly occurring plants necessitated future ready access to an
adrenaline inhaler or injection and rapidly acting antihistamines for the patient.
Other Verbena hybrids—In a questionnaire-based study of occupational dermatitis in Danish
gardeners and greenhouse workers, 253 selected persons were clinically examined and 250 of these

patch tested.49,50 At the time of examination, 239 were employed and 5 worked with Verbena plants.
Symptoms of skin and mucous membranes were reported by two of the five, and the same was
reported by a sixth patient who had previously worked with Verbena elegans. Out of the three
patients, two had positive patch tests to Verbena.50 The first was the female gardener apprentice
who reacted to Verbena elegans as described earlier. The second was a 27 year old male gardener
with a family history of atopy who from the very beginning of his employment developed an
urticaria-like, later vesicular, rash on the volar aspect of his forearms when packing full-grown
Verbena hybrids for sale. The rash disappeared slowly in one to two weeks when the work was
discontinued, but reappeared every year when he was packing. Patch tests showed 1+ reactions to
leaf (underside) and flower, and doubtful positive reactions to stalk and top side of leaf on day 3.
All reactions were negative on day 7. He had no symptoms of mucous membranes and, in accordance
with this, skin prick and scratch patch tests with Verbena were negative. He was classified as having
an allergic contact dermatitis. The allergen(s) are unknown.
The third patient with symptoms from Verbena was a 20 year old female gardener apprentice
with an atopic disposition (positive skin prick tests to house dust mites and grass) who from the
beginning of her employment developed rhinitis, sneezing, itching eyes, and an itching rash on the
dorsal aspect of forearms and hands when handling one Verbena hybrid with red flowers. The rash
always disappeared within 24 h and medication with antihistamine completely obliterated the
mucosal symptoms and the itching of the skin, but did not prevent reddening of the skin on plant
contact. Patch testing with leaves from three Verbena hybrids showed doubtful (?+) reactions to
the underside of the leaf of all three hybrids on day 4 and day 7. Retesting showed doubtful positive
reactions to all leaves on day 2, and they were all disappearing on day 3. Skin prick and scratch
patch tests with all three hybrids, likewise, were negative. The reactions were considered to be of
irritant or possibly urticarial nature (unpublished data).
It is remarkable that the three Danish patients and the South African patient reported on by
Potter et al. had a family history of or personal atopy.47,48,50 It is in accordance, however, with the
clinical symptoms that were suggestive of type I hypersensitivity in at least three of the patients,
even if it was only proved beyond doubt in one of them. The fact that two of the Danish patients
had symptoms from the beginning and that three of the six exposed reported symptoms suggests
irritant properties, and it thus seems that the Verbena hybrids are capable of producing both irritant
and allergic type I and IV reactions.
Verbena officinalis L.—The rubefacient effect could be owing to irritant properties as stated
by Pammel,18 even if questioned by Watt and Breyer-Brandwijk.12 Shelmire, in his extensive study
on contact dermatitis from vegetation, included wild verbena in the group of infrequent sensitizers
as opposed to the groups of strongly and moderately sensitizing plants because it caused 1 positive
reaction in 50 patients with weed dermatitis.5,51 This is in accordance with the report of del Pozo
et al.24 who, in spite of the frequent use of wild verbena as a herbal remedy in their area (Spain),
never saw a case of sensitization until the one reported in 1994. A 60 year old housewife with a
history of contact dermatitis to parabens and wool alcohols had repeatedly applied a plaster of wild
verbena omelette (made from egg white and flowers of the plant) directly on her chest for bronchitis.
Eventually, she developed an exudative dermatitis in the plaster area, but subsequently was able to
handle the plant without reaction. Patch testing with fresh plant as well as aqueous and ether whole
plant extracts showed 2+ reactions on day 4 to flower and leaf as is and the ether extract. The
allergens are unknown. The fact that the patient could handle the plant indicates weak sensitizing
properties and, as pointed out by the authors, the prolonged, close contact with the plaster and the
oily vehicle of the omelette may be important factors in the development of sensitization.24
Verbena venosa Gillies & Hooker—According to Mitchell and Rook, this species may cause
dermatitis which they seem to relate to the irritant propertites reported by Pammel.5,18
Vitex littoralis A. Cunn. (equivalent to Vitex lucens T. Kirk)—According to Mitchell and Rook5
splinters of this tree penetrating the hands and feet may cause severe inflammation.

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Section V
Special Topics
24 Allergenic Hardwoods
Bjoern M. Hausen
CONTENTS
24.1 Introduction
24.2 Cupressaceae
24.2.1 Calocedrus
24.2.2. Thuja
24.3 Boraginaceae
24.3.1. Cordia
24.4 Ebenaceae
24.4.1 Diospyros
24.5 Leguminosae
24.5.1 Leguminosae-Caesalpinioideae
24.5.2 Leguminosae-Mimosoideae
24.5.2.1. Acacia
24.5.3 Leguminoase-Papilionoideae
24.5.3.1 Brya
24.5.3.2 Bowdichia
24.5.3.3 Dalbergia
24.5.3.4 Machaerium
24.6 Malvaceae
24.6.1 Thespesia
24.7 Meliaceae
24.8 Moraceae
24.9 Proteaceae
24.10 Sterculiaceae
24.10.1 Mansonia
24.10.2 Tectona
24.11 References
24.1 INTRODUCTION
The action of woods to the human being might be as follows
• Mechanically • By bristles and splinters.

• Toxic • By shavings and dust particles causing general symptoms.
• Irritation • By dust particles affecting the skin and mucous membranes.

• Sensitizing • By fine wood dust particles that produce
— Allergic rhinitis, bronchial asthma (type I).
— Extrinsic allergic alveolitis (type III).
— Allergic contact dermatitis (type IV), (occasionally also by contact
with finished articles).
• Carcinogenic • Fine as well as coarse wood dust may produce adenocarcinoma of the
nasopharynx (the average latency period is 40 years).
According to the four types of allergic diseases, sensitizing species are found among commercial
timbers in the following order
• Type IV—approximately 120 species.

• Type I—approximately 60 species.
• Type III—approximately 10 species.
• Type II—none.
Irritation and allergic hypersensitivity of the immediate type is caused by several species listed
in Table 24.1. Only in one species the responsible sensitizer, that in contrast to the other unknown
allergens is a low molecular substance, has been identified (see Thuja plicata).
Allergic contact dermatitis (type IV hypersensitivity) generally comes from the heartwood. The
sapwood seldom contains sensitizing compounds. The constituents responsible for allergic reactions
occur in about 20 different plant families (e.g., Leguminosae, Bignoniaceae, Anacardiaceae, Lau-
raceae, Ebenaceae, Moraceae, Pinaceae, and others) and comprise such different chemical groups
as benzo-, naphtho-, furano- and phenanthrene quinones, stilbenes, flavones, coumarins (oxidation
products of resin acids), terpenes, steroids, phorbols, tropolones, and other phenolic substances. In
nearly half of the species suspected to cause allergic contact dermatitis the sensitizing constituents
are still unknown, for example, in American mahogany, Afzelia, Padouk, Sapeli, Wengé, Panga-
panga, Imbuya, and East Indian Satinwood.
The following description concerns those wood species that cause allergic contact dermatitis
and contain sensitizing constituents that have been isolated and structurally identified up to date.
24.2 CUPRESSACEAE
The Cupressaceae family comprises 125 species in 20 genera.
24.2.1 CALOCEDRUS
Three species native to Siam, Burma, China, Formosa, and the Pacific coast of North America are
known in this genus.
Calocedrus decurrens (TORR.) FLORIN is commonly known as Incense cedar. This tree, native
to California and Oregon, is used for pencil manufacture, fence posts, boarding, venetian blinds,
chests, and toys. Two cases of contact dermatitis have been described by Calnan.22 In the first case,
a female clerk developed dermatitis of the right hand, middle and ring finger, later spreading to
the arm, chest, face, and thighs. It was caused by her pencil manufactured of cedar wood that she
was handling at work. In the second case, a carpenter showed a widespread dermatitis of the
buttocks, groins, thighs, legs, and feet owing to a pencil that he used to keep behind his ear.
Positive reactions were obtained with thymoquinone, b-thuyaplicin remained negative. Incense
cedar contains up to 4 percent of thymoquinone (structure, see Thuja plicata).

TABLE 24.1
Rhinitis, Conjunctivitis, Allergic Asthma, and Other Respiratory Reactions
Owing to Wood Dust
Botanical Name Family Trade Names Reference
Abies alba Mill. Pinaceae White wood 93

Acacia melanoxylon R. Br Leg.-Mim. Australian blackwood 33, 34, 142,
Aucoumea klaineana Pierre Burseraceae Okoumé, Gabun, Gaboon 14, 93
Chlorophora excelsa (Welw.) Benth. Moraceae Iroko, Kambala 4, 54
Dalbergia retusa Hemsl. Leg.-Pap. Cocobolo 47, 57, 109
Dumoria africana A. Chev. Sapotaceae Oukola, Douka 170
Entandophragma cylindricum Sprague Meliaceae Sapelli, Sapeli 2, 134
Euonymus europaea L. Celastraceae Spindle tree 77
Fagus sylvatica L. Fagaceae Beech 93, 98, 133, 157
Fraxinus excelsior L. Oleaceae Ash 93, 98
Gonystylus bancanus Baill. Thymelaeaceae Ramin 88, 127
Juglans regia L. Juglandaceae Walnut 98
Khaya anthotheca (Welw.) C. DC. Meliaceae Acajou blanc, Krala 64, 135, 168
Lovoa trichilioides Harms Meliaceae African walnut, Dibetou, Kongo 2, 166
hardwood
Mansonia altissima Pierre ex A.Chev. Sterculiaceae Mansonia, Bété 51, 125, 126, 138,
140, 151
Microberlinia brazzavillensis A.Chev. Leg.-Caes. African zebrawood 21
Myrocarpus fastigiatus FR. ALL. Leg.-Pap. Cabreuva, Oleo de macareo 91
Picea abies Karsten Pinaceae Fir, Norway spruce 5, 35, 58, 98
Pinus sylvestris L. Pinaceae Scots pine 5, 93
Piptadeniastrum africanum Leg.-Mim. Dabema 2, 3, 107
(Hooker) Brenan
Populus tremula L. Salicaceae Poplar 125
Prunus avium L. Rosaceae Sweet cherry, wild cherry 93
Prunus cerasus L. Rosaceae Sour cherry, Dwarf cherry 93
Quercus robur L. Fagaceae French oak 58, 59, 98, 132,
157
Sequioa sempervirens Endl. Taxodiaceae Californian redwood, Sequioa 25, 46
Shorea wiesneri Schiffn. Dipterocarpacea Phillipine red mahagony, Meranti, 93
e Lauan, Seraya
Swietenia macrophylla King Meliaceae Mahogany 62, 93, 132, 133
Tarrietia utilis Spreng. Sterculiaceae Niangon 58, 60, 93, 151
Tectona grandis L. Verbenaceae Teak 54, 58, 62, 132,
138
Terminalia ivorensis A. Chev. Combretaceae Framiré 31
Terminalia superba Eng. et Diels Combretaceae Limba 62, 64, 93, 98,
133, 134
Tieghemella heckelii Pierre ex A. Chev. Sapotaceae Makoré, Baku 93, 98, 134
Triplochiton scleroxylon K. Schum. Sterculiaceae Obeche, Samba, Wawa, Abachi 12, 16, 23, 51, 59,
81–83, 89, 90,
125–127, 134,
164, 175
Turrraeanthus africanus Pellegr. Meliaceae Avodiré 31

FIGURE 24.1 Plicatic acid and thymoquinone are the main sensitizers in Cupressaceae.
24.2.2 THUJA
Five Thuja species are known, native to China, Japan, Korea, and North America. Thuja occi-
dentalis L. (Northern white cedar) and T. orientalis L. are cultivated in most countries of the
temperate zone.
Thuja plicata DONN ex D. DON is commonly known as Western red cedar. Western red cedar
is native to the west coast of the United States and British Columbia and exported all over the
world, especially to Europe, Australia, and Japan.
Allergic rhinitis and asthma has been described by Maiden in 1904.108 After the earthquake of
1923 in Tokyo, Western red cedar was exported to Japan for reconstruction of the buildings. Beisugi
asthma, as the allergic symptoms were called in Japan, did not occur only in joiners and carpenters
after sawing and sanding, but also in those individuals living in the houses built from Western red
cedar wood.105,110,156
Occupational asthma owing to the wood was observed as well in other countries, for example,
in South Africa,43,135 Australia,53,115 and especially in its native California and British Colum-
bia.24,168 In the large timber industry of this region, Western red cedar asthma is a common
disease among cedar mill workers. Hundreds of cases have been described because plicatic acid
is abundantly present in Western red cedar.172 Plicatic acid (Figure 24.1) is the responsible
sensitizer.27,29,30,137
Up to 5 percent of the exposed workers developed red cedar asthma.26 About 1 percent developed
an immediate, 44 percent a late, and 48 percent a dual reaction.28 Specific IgE was found in 26
percent with immediate, 21 percent with late, and 26 percent with dual reactions.137
Western red cedar is a timber of good stability useful for construction, venetian blinds, boat-
building, planking, paneling, and framing. Many cases of bronchial asthma observations of occu-
pational allergic contact dermatitis have been reported as well.10,19,136 Suskind succeeded in sensi-
tizing guinea pigs with different extracts of the wood.171 Thymoquinone (see Figure 24.1) must be
considered as the main contact sensitizer, showing a high sensitizing capacity in guinea pig
experiments.65 The safe patch test concentration is 0.1 percent in petrolatum.

FIGURE 24.2 Main sensitizers found in Cordia: Cordiachromes A, B, C, D, E, F, and G.
24.3 BORAGINACEAE
The Boraginaceae is a family with more than 2300 species in 130 genera growing in tropical and
temperate regions, especially in the Mediterranean area. The chemistry is recorded by Hegnauer.76
24.3.1 CORDIA
The Cordia include Cordia millenii BAKER known as Cordia, Cordia gerascanthus R. BR. known
as Canalete, and Cordia goeldiana HUBER, known as Freijo.
Cordia goeldiana from Brazil, also often called Brazilian walnut, and Cordia gerascanthus
derived from Venezuela together with Cordai millenii and Cordia platythyrsa BAKER from tropical
Africa form a group of valuable timbers with moderate durability. Owing to their light weight,
softness, and low strength, they are used mainly for interior work, furniture, and joinery. Only the
Brazilian species are also suitable for boatbuilding and exterior constructions.
Although used abundantly, only two reports on occupational contact dermatitis are known from
the literature.143,165 However, the author also has seen four cases that remain unpublished. In these
cases, a typical airborne contact dermatitis developed in workers, owing to bad exhaustion condi-
tions, who manufactured balcony breastwork and mouldings.
Moir and Thomson isolated and identified seven quinones from the ethanol extract that was
kindly supplied for patch tests.118,119 The cordiachromes A, B, E, and I (Figure 24.2) gave strong
reactions and, thus, must be regarded as the main sensitizers.
24.4 EBENACEAE
In only 2 genera, 485 species are found occurring in the tropical zone. Most of them are native to
Indonesia and Malaysia. The chemistry is recorded by Thomson.173
24.4.1 DIOSPYROS
Ebony is the name for 475 tropical wood species belonging to the genus Diospyros. Most prized
are those with a deep black heartwood, extreme hardness, and durability. Ebony species are used
for cabinet and inlay work, piano and organ keys, organ stops, violin fingerboards and pegs, parts
of string bows (frogs), and bag pipes.

FIGURE 24.3 Structure of Macassar quinone: a moderate sensitizer found in Diospyros celebica.
Diospyros crassifolia HIERN known as African ebony is native to Nigeria, Cameroon, and
Gaboon. African ebony is highly resistant to termites and very hard to work with.
Contact dermatitis has been described by Legge,103 Herxheimer,78 and Lewin.104 Nicholas
reported a case of contact hypersensitivity with reactions on the forearm following the wearing of
an ebony bracelet.130 More recent cases have not been described in the literature.
Diospyros ebenum KOENIG is known as Ceylon ebony. This strong, hard, heavy black wood
is imported in small boles from India, Sri Lanka, Celebes, and the Andaman Islands. Eczematous
reactions of the skin after contact with the sawdust were described by Rasch.144
Diospyros celebica BAKH. is known as Macassar. As the name indicates, the tree comes from
Celebes.
Macassar has been long in use for expensive rulers. Occupational dermatitis may occur but
reports are found rarely in the literature. Buschke and Joseph20 observed hand eczema in a cabi-
netmaker owing to Macassar ebony, while Bleumink and Nater11 obtained positive patch tests to
an ethanol extract of Dalbergia melanoxylon in 4 out of 20 patients suffering from airborne contact
dermatitis owing to tropical woods.
In Macassar, a precursor (Macassar II) of a sensitizing naphtho-ortho-quinone named Macassar
quinone (Figure 24.3) is found as the main constituent. Besides that, more than 17 different naph-
thoquinone derivatives (diospyrin derivatives) have been isolated that possess possibly allergy-
inducing properties.181,182
In 1997, Rackett and Zug observed a 54 year old woodworker business owner who had worked
as a wood turner manufacturing different billiard cues for 26 years.143 The patient suffered from a
pruritic eczematous eruption with scaling of the upper eyelids and forehead. A paddy erythema
and scaling was also seen on the upper abdomen and around the axillae. In the patch test, he reacted
to diluted sawdust (mixed with petrolatum) of the six exotic wood species and, especially, reacted
with a +++-response to Macassar quinone (1 percent petrolatum) from Diospyros celebica. Macassar
quinone is a moderate sensitizer.64
Diospyros melanoxylon ROXB. is known as Coromandel. This ebony species is suspected to
cause allergic contact dermatitis but cases have not been described. Bleumink saw four positive
patch test reactions with Coromandel sawdust in 60 woodworkers handling tropical woods.11 Of
the naphthoquinones, one isolated from Diospyros melanoxylon48 gave a weak sensitizing capacity
in guinea pig experiments.64
24.5 LEGUMINOSAE
The Leguminosae is a cosmopolitan plant family with about 18,000 species in 642 genera. The
family, also called Fabaceae, is divided into different subfamilies with species occurring in the
tropical and temperate zones.
The chemistry is recorded by Dey and Harborne,42 Harborne and Baxter,61 and Thomson.173
24.5.1 LEGUMINOSAE-CAESALPINIOIDEAE
Distemonanthus benthamianus BAILL. is also known as Ayan. Movingui or Ayan is used for
domestic flooring, frames, windows, and cabinetmaking. It is imported from West Africa to England,
where it is mainly used for coffins.

FIGURE 24.4 Sensitizers found in Ayan (Distemonanthus benthamianus BAILL.).
Morgan and Thomson reported a case of severe dermatitis recurring for four years in a carpenter
engaged in making coffins.123 Patch tests were positive with the sawdust and two of the four isolated
flavonoids.96,97 Allergic reactions were observed with oxyayanin A (++++) and oxyayanin B (+++)
(see structures in Figure 24.4).
Woods and Calnan180 described 13 cases of Ayan dermatitis. A case was observed by Orsler in
1969.136
24.5.2 LEGUMINOSAE-MIMOSOIDEAE
24.5.2.1 Acacia
Acacia melanoxylon R. Br. is known as Australian Blackwood and comprises 1200 species in
tropical and subtropical regions.
Australian blackwood (Acacia melanoxylon) is the most important timber for almost every
purpose in Australia. Even fences and musical instruments are manufactured from it. Although
mainly used in its native country, small quantities are occasionally exported to Europe.37
Nott suffered from a rash of his hands and forearms after handling this wood himself.131 Nose-
bleeding and bronchial asthma were recognized by Pulleine in 1925.142 Cleland observed several
cases of weeping dermatitis in joiners and boatbuilders (face, neck, and forearms) connected with
severe itching and conjunctivitis.33,34 Robertson reported one case of asthma and nine cases of
contact dermatitis.148 Though his patch tests remained negative, he suggested that sensitization must
have played a role.
Further observations with positive patch test results have been contributed by Behl in 19669
and Burry in 1969 and 1973.18,19
In a more recent case the wife of a joiner, who was making cabinets in his house, suffered
from allergic contact dermatitis although the working room was in the basement.174 Beside acamelin
and 2,6-dimethoxy-1,4-benzoquinone, the main sensitizer was identified as a hexahydroxyflavan
named melacacidin (Figure 24.5).71 This substance is abundantly found in Acacia species,100 so that
allergic contact dermatitis to related timbers are not uncommon.99
24.5.3 LEGUMINOSAE-PAPILIONOIDEAE
24.5.3.1 Brya
The genus Brya comprises 12 species native to Central America and the West Indies.
Brya ebenus BENTH. (Leg.-Papilionaceae) is known as Cocus. Cocus is a small tree from the
West Indies used for musical instruments, particularly for flutes, recorders, and clarinets. It also
serves for interior turnery, cutlery, and door handles, fancy articles, sawed veneers, and wooden
breakfast platters.
Although of low diameter, it has been imported from Jamaica and Cuba for more than a century
as one of the most valuable woods.

FIGURE 24.5 The three sensitizers found in Acacia: 2,6-dimethoxy-1,4-benzoquinone, acamelin, and
melacacidin.
FIGURE 24.6 Cocus I and Cocus II are two sensitizers identified in Bryaebenus (Cocus).
Occupational contact dermatitis has been observed not only in flute-makers sawing and sand-
papering the wood, but also in players of flutes manufactured of this wood. Typically, the allergic
lesions of the latter are swollen lips and mouths.38,113,179
Experimental sensitization of guinea pigs with an ethanol extract was successful.64 A reinves-
tigation of the wood was prompted by the recurrent lesions (swollen lips) developing in a young
girl studying flute. Two hydroxyisoflavans (Figure 24.6) were identified eliciting ++- to +++-
reactions at a 1 percent test concentration.72 A new case was observed recently in a female flute
player of a symphony orchestra (Hausen, B. M., occupational allergic contact dermatitis due to
cocus wood, Akt. Dermatol., 25, 312-314, 1999.)

FIGURE 24.7 Structure of one of the quinonoid constituents from Bowdichia that gave positive allergic
reactions.
FIGURE 24.8 Sensitizers found in Dalbergia.
24.5.3.2 Bowdichia
Four tropical species in South America. Bowdichia nitida BENTH. is known as Sucupira. Sucupira
from Brazil is best suited for structural purposes and mostly used in Europe for flooring. It gains
some interest for turned articles and as a veneer for inlays in high-class furniture. Cases of
occupational contact dermatitis have been described by Freise,50 Dantin-Galego,41 Heyl,79 and
Gonçalo55 in joiners and flooring manufacturers.
Chemical investigation revealed the occurrence of three quinones in the heartwood that were
isolated, purified, and patch-tested in Heyl´s patient. All three quinone fractions produced positive
reactions. The first quinone was identified as 2,6-dimethoxy-1,4-benzoquinone.63 The second
quinone was found to be the first naturally occurring iso-flavone quinone.17 It was named bowdi-
chione (Figure 24.7). The third quinone is still unknown but may be related to the dalbergiones,
as the patient developed cross-reactions to (R)-3,4-dimethoxydalbergion and (S)-4¢-hydroxy-4-
methoxydalbergion. Sensitizing experiments in guinea pigs using the open epicutaneous method
were successful. A reinvestigation of Sucupira wood revealed the occurrence of at least five
quinonoid constituents, all of which gave positive reactions in the sensitized animals (unpublished).
24.5.3.3 Dalbergia
About 100 species growing in the tropical and subtropical regions around the world are known,
some also occur in South Africa. They provide most valuable woods used for high-class furniture,
cabinetwork, inlay work, knife handles, chess pieces, rosaries, and parts of musical instruments.
The chemistry is recorded by Thomson173 and Donnelly.44,45

FIGURE 24.9 (R)-3,4-Dimethoxydalbergion was identified as the sensitizer in Machaerium scleroxylon TUL.
This sensitizer does not occur in the related Dalbergia species.
Dalbergia retusa HEMSL. (D. obtusa LEC.) is known as Cocobolo. Cocobolo derives from
Central America. It is strong, hard, compact, fairly heavy, easy to work, and of extreme durability.
It holds a supreme position in the cutlery trade, especially knife handles, but also serves for brush
backs, chessmen, scientific instruments, bulks of billiard cues, wooden bracelets, wooden jewelry,
and interior turnery. Cocobolo is specially used for musical instruments. Of all recorders manufac-
tured before World War II, 90 percent were made from Cocobolo. Descriptions of occupational
dermatitis occurring in workers manufacturing hairbrushes, knife handles, and recorders have been
published just as often as allergic reactions of the lips and fingertips in those playing the instru-
ments.67,106,117,128,143,160,169 The responsible allergens belong to the class of neo-flavonoids, named
dalbergiones (Figure 24.8). In Cocobolo, obtusaquinone and (R)-4-methoxydalbergion play a major
role while (S)-4¢-hydroxy-4-methoxydalbergion plays a minor role.73 Their sensitizing capacity has
been examined by Schulz et al. in animal experiments.163 Obtusaquinone, chemically near related
to (R)-4-methoxydalbergion and a sensitizer, too, disclosed a similar sensitizing power in the animal
experiments.64
Dalbergia melanoxylon GUILL. & PERR. is known as Grenadill. As a hard and heavy blue-
black colored wood, Grenadill or African blackwood is mainly imported from Mozambique,
Zimbabwe, Togo, and Senegal. Its use comprises knife handles, brush backs, chessmen, truncheons,
flutes, clarinets, oboes, chanters of bagpipes, and some types of recorders.
Cases of allergic contact dermatitis as well as conjunctivitis have been described since 1934
and were seen in clarinetmakers and in knife handle turners.69,113,180 The responsible allergens are
(S)-4-methoxydalbergion, (S)-4¢-hydroxy-4-methoxydalbergion, and (S)-3¢-hydroxy-4,4¢-dimethoxy-
dalbergione (Figure 24.8). Their sensitizing capacity was determined in animal experiments.163
Dalbergia nigra ALL. is known as Brazilian rosewood and Dalbergia latifolia ROXB. is known
as East Indian rosewood. Although of different origins, both rosewoods are used for similar purposes
and contain the same main sensitizers. While Dalbergia nigra is native to Brazil, East Indian
rosewood originally is from India and Malaysia.
The timbers are of attractive appearance when cut from old stems. Imports are low but steady.
Used for high-class furniture and cabinetwork, handles, decorative veneers, wooden jewelry (brace-
lets, necklaces), inlay work, and especially musical instruments, such as flutes, recorders, piano
cases, pegs, bridges of violins, and chin rests. Occupational contact dermatitis has been observed
in cabinetmakers, knife grinders, as well as knife users (e.g., in butchers) and chin rests by
professional violinists.39,49,52,56,70,75,86,111,141,180 Contact allergy owing to a wooden necklace was
reported recently.73
The responsible sensitizers (R)- and (S)-4-methoxydalbergion, (S)-4,4¢-dimethoxydalbergion
and (S)-4¢-hydroxy-4-methoxdalbergion do not only occur in the two species named previously,
but also in Dalbergia stevensonii Standley (Honduras rosewood) that has been found to produce
occupational contact dermatitis as well.13,180 In animal experiments, the dalbergiones showed a
moderate to strong sensitizing activity.163

FIGURE 24.10 Sensitizer isolated from Thespesia populnea.
24.5.3.4 Machaerium
Machaerium scleroxylon TUL. is also known as Pao ferro or “Santos”-Palisander and Caviuna
vermelha. The wood of Pao ferro closely resembles true Brazilian rosewood in appearance and
physical properties and, thus, is frequently used as a substitute or often simply mistaken for real
rosewood. In Europe, Pao ferro is used for furniture, veneers, television sets, knife handles, record-
ers, and multiple other purposes. Outbreaks of occupational contact dermatitis have been reported
not only from its native country Brazil but also from Denmark, Great Britain, Germany, Italy, and
Spain. Altogether more than 100 cases have been described in the literature.7,36,66,116,124,143,149,150
Active sensitization occurred in two nurses who had been used as controls and patch tested with
the pure wood dust. The responsible contact allergen is (R)-3,4-dimethoxydalbergion (Figure 24.9).
This constituent is the strongest sensitizer within the group of dalbergiones.163 Its safe patch test
concentration is 0.01 percent!
In some Pao ferro samples collected from different woodworking factories, up to 4.9 percent
were detected in the heartwood.68 Thus, a patch test with the sawdust itself should strictly be
avoided. Pao ferro is the most hazardous commercial timber in the woodworking industry. (R)-3,4-
dimethoxydalbergion does not occur in the related Dalbergia species.
24.6 MALVACEAE
This family contains about 1800 species in 111 genera growing in tropical and subtropical regions.
24.6.1 THESPESIA
The genus Thespesia comprises 17 tropical species including woods and herbaceous plants. The
chemistry is recorded by Hegnauer.76
Thespesia populnea (L.) SOL. is known as Milowood. Milowood is a small tropical tree
distributed widely throughout the tropics and in many areas of the United States including Cali-
fornia, Florida, and Hawaii. Primarily, it is used for making bowls, bracelets, carved tikis, and
furniture. Among the different mansonones that are known sensitizers from Mansononia altissima,
Milowood contains a new sesquiterpenoidal quinone, named mansonone X (Figure 24.10).114
A 42 year old Hawaiian bowl turner was afflicted for more than 10 years with a purific
eczematous dermatitis, affecting the antecubital fossae, forearms, neck, and lower faces. Patch test
with extracts and isolated fractions were positive. The responsible contact allergen was isolated
and identified as the new mansonone X. In guinea pig experiments, this compound showed a
moderate sensitizing capacity.74
24.7 MELIACEAE
In this family, 565 species in 51 genera are found in warm regions. The chemistry is recorded by
Hegnauer76 and Banerjii.6

FIGURE 24.11 One of the sensitizers found in Khaya.
Khaya also known as African mahogany comprises seven species in the tropical regions of
Africa including Madagascar. The four species Khaya grandiflora C. DC, Khaya ivorensis A.
CHEV., Khaya anthotheca C. DC, and Khaya senegalensis A. JUSS are timbers of West Africa.
They serve as a substitute for South American mahogany, especially for cabinets, furniture,
boatbuilding, moulding, and other purposes where a good quality wood is required.
Khaya anthotheca C. DC is known as Krala. Outbreaks of contact dermatitis owing to this
species have been described by Morgan and Wilkinson,120,121 Morgan and Orsler,122 Wilkinson,176,177
Morgan et al.,124 Wilkinson et al.,178 Shevljakov,167 Orsler,136 and Hjorth.84 The author, too, observed
two cases in which airborne contact dermatitis had developed to the sawdust of African mahogany.
A patch test with a 10 percent ethanol extract was positive.
The responsible sensitizers are not yet known. One of the allergenic constituents seems to be
anthothecol (Figure 24.11), found in K. anthotheca up to 0.03 percent.122 Besides that, K. anthotheca
and K. ivorensis contain the weak sensitizer 2,6-dimethoxy-1,4-benzoquinone (see Acacia melan-
oxylon). Its sensitizing capacity has been determined experimentally in guinea pigs.64
24.8 MORACEAE
This family comprises about 1100 species in 38 genera. Most of them are trees and shrubs. Only
four species grow in the temperate zone. Some species produce a latex that irritates the skin (e.g.,
Ficus sp.).
Chlorophora excelsa (WELW.) BENTH. (syn. Milicia excelsa (WELW.) C. BERG) is known
as Iroko, Kambala. This West African timber is used frequently as a substitute for Teak because it
possesses many of the desirable features of Tectona grandis. It has been in demand for decades
owing to its strength and durability for construction work, especially windows, door frames, and
shipbuilding.
Occupational contact dermatitis with eruptions of the skin of the forearms, face, neck, and feet
has been described in woodworkers since 1910.8,40,80,92,139,159,161,162 In 1949, King and Grundon94
isolated a hydroxy stilbene, named chlorophorin, that was revealed to be a moderate sensitizer.64,158
Its structure (Figure 24.12), first elucidated by King and Grundon in 1950,95 was corroborated in
1986 by Krohn et al.101
24.9 PROTEACEAE
Found in tropical regions around the world , in the mountains of tropical Africa, South Africa, and
Madagascar, the Proteaceae family comprises about 1600 species in 77 genera. Chemistry is
recorded by Hegnauer,76 Rasmussen,145 Ridley,146 Ritchie,147 and Cirigottis.32
Grevillea robusta A. CUNN. is known as Australian silky oak and is native to the fifth continent,
but it is also grown in Africa, Sri Lanka, India, and the United States. Flooring, furniture, and

FIGURE 24.12 Chlorophorin is a moderate sensitizer first isolated in 1949 from Chlorophora excelsa
BENTH. (WELW.).
FIGURE 24.13 Sensitizer isolated from Grevillea robusta A. CUNN. (Proteaceae).
FIGURE 24.14 Mansonone A, a strong sensitizer, is one of the sesquiterpenoid mansonone allergens found
in Massonia altissima A. CHEV.
plywood are the main uses, but the tree is also required for telegraph poles and as a shade tree.
Grevillea poisoning is a common term for occupational dermatitis that develops from the sap
contacting the skin during sawing.1,99,112 Bracelets made from Grevillea wood grown in India and
shipped to the United States and other countries were shown to be the source of allergic contact
dermatitis of the forearms, too.85,102 The responsible allergen is grevillol (Figure 24.13), a phenolic
compound with a long side chain that resembles the sensitizing urushiols from poison ivy.
24.10 STERCULIACEAE
About 1500 species in 67 genera are found in tropical areas. The chemistry is recorded by
Hegnauer.76
24.10.1 MANSONIA
Mansonia altissima A. CHEV. is known as Mansonia and Bété. The attractive durable wood of the
Mansonia tree is imported from Nigeria and the Gold Coast and used as a substitute for walnut.
Outbreaks of occupational contact dermatitis have been described in hundreds of cases since 1936,
of which only some were cited.15,60,87,126,152
The responsible allergens belong to the class of sesquiterpenoid mansonones, of which man-
sonone A, a red ortho-quinone is the main (strong) sensitizer (Figure 24.14).161,163 A review of the
chemistry of Mansonia altissima is given in the book by Neuwinger.129 Interestingly, some of these

FIGURE 24.15 Deoxylapachol, a major sensitizer found in Teak wood (Tectona grandis L.). Lapachol is only
a secondary allergen (see: text).
quinones, for example, mansonone E and F, occur in elm species (Ulmus x hollandica); making
the tree resistant against the Dutch elm disease.
24.10.2 TECTONA
Tectona grandis L. is known as Teak. Of the four species in this genus, teak wood is one of the
most valuable timbers of the world. While native to Burma, India, Thailand, and Malaysia, it also
has been planted in South Africa and the West Indies. Owing to its strong durability, it is used in
furniture, exterior joinery, flooring, fittings, door and window frames, rails, ship building, bridges,
and wharves. Teak is resistant to termites and chemicals and, therefore, can be used outdoors and
for laboratories, too. The chemistry is recorded by Sandermann and Simatupang.154
Occupational contact hypersensitivity has been observed as early as in Ancient Egypt, where
ships were built with teak from India. More recent descriptions date back to the last century and
continue up to the 1970s, when it became one of the most common sensitizers in the wood industry.180
The primary sensitizer is a simple naphthoquinone, named deoxylapachol.153-155 Compared with
other plant allergens, deoxylapachol is one of the strongest sensitizers found in nature.162 Patch
testing with sawdust may produce false-positive reactions owing to its highly irritant properties.
Deoxylapachol may actively sensitize when not patch tested in its safe concentration of 0.01 percent.
Another major constituent of teak is lapachol, equipped with a blocking hydroxy group at the
quinonoid ring that may be tested at 1 percent in petrolatum. Cross reactions between deoxylapachol
and lapachol are obligatory (Figure 24.15).
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139. Pereira Marques, M. S. J., Dermite de contacto á Cambala, Bol. Inf. GPEDC, 3, 23, 1989.
140. Peyresblanques, J., Blépharo-conjonctivite due aux poussières de bois “coloniaux”, Bull. Soc. Ophth.,
77, 77, 1977.
141. Pontes de Carvalho, L., Dos allergenos de contato nas profissões, Brasil Med., 70, 77, 1956.
142. Pulleine, R. H., Sensitiveness to proteins of wood, Med. J. Austr., 21, 25, 1925.
143. Rackett, S. C. and Zug, K. A., Contact dermatitis to multiple exotic woods, Am. J. Contact Derm.,
8, 114, 1997.
144. Rasch, H., Bois toxique, Hyg. Trav., 22, 1, 1925.
145. Rasmussen, M., Ridley, D. D., Ritchie, E., and Taylor, W. C., Chemical studies of the proteaceae. III.
The structure determination and synthesis of striatol, a wood phenol from Grevillea striata R. BR,
Austr. J. Chem., 21, 2989, 1968.
146. Ridley, D. D., Ritchie, E., and Taylor, W. C., Chemical studies of the proteaceae. II. Some further
constituents of Grevillea robusta, Austr. J. Chem., 21, 2979, 1968.
147. Ritchie, E., Taylor, W. C., and Vautin, S. T. K., Chemical studies of the proteaceae. I. Grevillea robusta
A. CUNN. and Orites excelsa R. RB, Austr. J. Chem., 18, 2015, 1965.
148. Robertson, D. G., An investigation of certain health aspects in persons engaged in the woodworking
industries, Commonwealth of Australia, Department of Health, Series Publication (Division of Indus-
trial Hygiene), No. 4, 1927, 1.
149. Roed-Petersen, J., Menné, T., Mann Nielsen, K., and Hjorth, N., Is it possible to work with Pao ferro
(Machaerium scleroxylon TUL.)?, Arch. Dermatol. Res., 279, 108, 1987.
150. Sak, M., Uhrik, J., Fabian, J., Stracenska, H., and Hermanova, E., Dermatózy vyvolané drevinon
Machaerium scleroxylon, Csl. Derm., 58, 89, 1983.
151. Salamone, L., Di Blasi, S., and Conglio, L., Rilieva sulla patologia da legno di Mansonia, Folia Med.
(Napoli), 52, 427, 1969.
152. Sandermann, W. and Dietrichs, H. H., Über die Inhaltstoffe von Mansonia altissima und ihre gesund-
heitsschädigende Wirkung, Holz. Roh-u. Wstoff., 17, 88, 1959.
153. Sandermann, W. and Simatupang, M. H., Über Inhaltstoffe aus Teak (Tectona grandis L.). I. Isolierung
und Konstitution eines toxischen Teakchinons, Chem. Ber., 96, 2182, 1963.
154. Sandermann, W. and Simatupang, M. H., Zur Chemie und Biochemie des Teakholzes Tectona grandis
L. fil.), Holz. Roh-u. Wstoff., 24, 190, 1966.
155. Sandermann, W. and Simatupang, M. H., Ein toxisches Chinon aus Teakholz, Angew. Chem., 74, 782, 1972.
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Teakholz, Berufsdermatosen, 5, 3, 1957.

160. Schulz, K. H. and Dietrichs, H. H., Chinone als sensibilisierende Bestandteile von Rio Palisander
(Dalbergia nigra) und Cocobolo (Dalbergia retusa) Holz, Allerg. Asthma, 8, 125, 1962.
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169. Steinbrink, W., Besondere Beobachtungen an allergischen Krankheiten,Z. Ges. Inn. Med., 5, 311, 1950.
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25 Toxicodendron of the
Southern Pacific
Marius Rademaker
CONTENTS
25.1 Introduction
25.1.1 Plant Family
25.1.1.1 Geographic location
25.1.2 Species
25.1.2.1 Toxicodendron succedaneum (syn. Rhus succedanea)
25.1.2.1.1 Chemistry
25.1.2.1.2 Clinical Effect
25.1.2.1.3 Treatment
25.1.2.1.4 Cross reactions
25.1.2.2 Toxicodendron vernicifluum (syns. Rhus verniciflua,
Rhus vernicifera)
25.1.2.3 Toxicodendron striatum (syns. Rhus striata, Rhus juglandifolia)
25.1.2.4 Other Toxicodendron Species
25.2 References
25.1 INTRODUCTION
25.1.1 PLANT FAMILY
25.1.1.1 Geographic Location
There are 15 species of Toxicodendron native to China, at least 8 to Malaysia/Indonesia, and 6 to

the Western hemisphere, although they have been introduced elsewhere as exotics. Most Toxico-
dendron are small trees, shrubs, or vines with compound leaves, the exception being T. borneense
that has simple leaves. The flowers are generally asexual with five sepals (or calyx lobes), five
petals, and five stamens. The ovary has one locule, with a short style, and three stigmas.1,2
25.1.2 SPECIES
The main species of Toxicodendron to cause dermatological problems are T. radicans (poison ivy)
and T. diversilobum (poison oak) that, with their various subspecies, are found predominantly in
Northern America (see Chapter 9). There are, however, up to 15 other species in the genus
Toxicodendron that may give rise to skin reactions. In the Southern Pacific, the three main allergenic

FIGURE 25.1 Toxicodendron succedaneum in autumn color.
FIGURE 25.2 Toxicodendron succedaneum outside a primary school.
Toxicodendron are T. striatum, T. succedaneum, and T. vernicifluum. T. radicans, while present in

some botanical collections and gardens in New Zealand, Australia, and South America, is relatively
rare in the Southern Pacific.3-11
25.1.2.1 Toxicodendron succedaneum (syn. Rhus succedanea)

T. succedaneum is more commonly known as the Wax Tree or the Japanese Wax Tree. Native to
China and Japan, it is a deciduous tree that grows to 12 m in height.2,12 The leaves are pinnate and
the leaflets glossy, glabrous, purplish, and entire with numerous parallel lateral veins almost at right

TABLE 25.1
Activity at Time of Contact and Main Site of Dermatitis
Activity Site of Dermatitis
Number
Age of Cases Playing Gardening Face Upper Limbs Lower Limbs Body
0–10 35 33 1 34 77 7 4
11–20 21 17 1 17 8 7 7
21–30 3 0 1 2 1 1 1
31–40 10 1 (golf) 8 3 6 5 1
41–50 13 0 6 2 11 6 1
51–60 8 0 9 1 8 6 3
Greater than 61 2 0 4 1 0 1 0
angles to the midrib. These leaves turn orange, red, or scarlet in autumn (Figures 25.1 and 25.2).
Small yellow flowers are followed by pendulous clusters of tawny fruit. The crushed fruits produce
a wax (sumach wax). In Japan, it was formerly cultivated for the fruit that supplied wax for candles,
varnishes, polishes, ointments, and plasters.13 In Indochina it was also used as a lacquer source
although T. vernicifluum is traditionally regarded as the lacquer tree. T. succedaneum has been
extensively planted as a small ornamental garden tree in Australia, New Zealand, and in some South
American countries.11 In Japan, it is also popular for bonsai.14 In the Southern Pacific, the main
contact between humans and T. succedaneum is through gardening.15,16
The leaves, fruit, and bark can all cause dermatitis.5,17 The processed wax has been reported
to cause hand dermatitis in workers handling fabrics waterproofed with the wax.18 The sap is
vesicant.
The allergen in Toxicodendron are urushiols that contain a mixture of catechols (1,2-dihydroxy-
benzenes) and resorcinols (1,3-dihydroxybenzenes).19-22 The antigenicity of these compounds is
related to the molecular length and unsaturated double-bond content of the side chains. Longer
side-chains increase irritancy and allergenicity. The allergen in T. succedaneum is 3-heptadec(en)yl
catechol. Urushiol is inactivated rapidly in water.
Urushiol is found in the resin canals that course through the leaves, bark, and roots of the plant.
The resin canals do not drain to the surface, so exposure to urushiol usually requires physical
trauma to the plant, but this may be minimal (Table 25.1). In late autumn, however, urushiol is
spontaneously released from the plant. Most cases of contact dermatitis occur after contact with
the plant, but in some sensitive individuals the eruption can develop without apparent direct contact.
As has been reported with T. radicans, we have seen patients in whom the allergen has been
transferred on the fur of a pet, by the wind, or even in smoke of burning plants. After contact with
urushiol, a sensitized individual typically develops an erythematous, pruritic eruption on the face
and arms within two days. When the plant juice contacts the skin indirectly via clothing worn on
an outing or by patting a dog that has run through the bush, the dermatitis tends to have a more
diffuse, patchy appearance.
T. succedaneum is the commonest cause of poison ivy dermatitis in Australia and New
Zealand.15,23,24 In one center in New Zealand, 92 cases of phytodermatitis to T. succedaneum were
seen over a 12-year (1982–1994) period of time.15 Of the patients, 42 were female and 50 were
male with a bimodal age distribution (5–15 years and 35–45 years). Of the younger patients (aged
0–20 years), 90 percent presented with facial dermatitis reflecting facial contact while playing under
the trees (Figure 25.3). In six instances, two or more members of the same family, usually all

FIGURE 25.3 Facial edema with vesicular dermatitis in a 9 year old boy 3 days after climbing in a
T. succedaneum tree.
children, presented simultaneously with a phytodermatitis. Of the older patients (aged 35+ years),
three fourths presented largely with a dermatitis affecting the upper limbs reflecting contact while
gardening (usually pruning). In a second study examining all cases of phytodermatitis to T. suc-
cedaneum presenting over a 12 month period of time, 75 percent presented during autumn, the
remainder during summer.24
Like allergic contact dermatitis to T. radicans (poison ivy),20,21,25,26 patients allergic to T.
succedaneum present with a vesicular phytodermatitis; namely, linear streaks of erythema and
vesicles. In addition, similar to allergy to T. striatum in South America, facial edema with marked
periorbital swelling is common, particularly in children (Figure 25.3). The severity of the reaction
often results in mistaken diagnosis. Each year a number of the cases, including the patient in
Figure 25.3, are initially treated by nondermatologists with systemic antibiotics for presumed
cellulitis. The linear pattern of vesicles can also be confused with the dermatomal eruption of
shingles (herpes zoster).
It is unclear when T. succedaneum was first introduced in Australia and New Zealand. It is
widespread through both the North and South Island of New Zealand, with at least 20 commercial
nurseries propagating the tree. Most city councils are aware of the allergenic potential of T.
succedaneum. In some Australian States, T. succedaneum has been voluntarily banned from sale
after seven workers in one nursery were affected through handling of the plant.10,27 Unfortunately,
it is still available from garden centers in New Zealand, although a warning is usually given to
potential purchasers. It has been estimated that, in New Zealand, T. succedaneum may be found in
up to 1 in 200 private gardens.

25.1.2.1.3 Treatment
Mild soaps and gentle washing remove urushiol, but it must be done immediately. If delayed for
10 min, only 50 percent of urushiol can be removed. This falls to only 10 percent after 30 min and
to none after 1 h. Super potent topical steroids are of help, but only if applied before the vesicles
appear. Oral antihistamines are of limited benefit. The majority of patients require systemic corti-
costeroids to settle the intense dermatitis.
Prevention is more effective than treatment, but this usually requires destruction of the tree.
Hyposensitisation programs have not been attempted for T. succedaneum, but those for T. radicans
have largely failed. Similarly, barrier creams have been shown to be of limited benefit in preventing
T. radicans dermatitis.
25.1.2.1.4 Cross Reactions
Other related Toxicodendron found in Australasia, such as Rhus typhina and R. copallina, do not
appear to be active sensitizers although dermatitis has been reported.28 There are, however, a number
of cross-reacting Anarcardaceae (mango, cashew, Japanese lacquer, Indian marking nut, and African
poison ivy). Interestingly, there are also several genera of unrelated families such as Ginkgo and
Grevillea that may cross-react with Toxicodendron spp.29
25.1.2.2 Toxicodendron vernicifluum (syns. Rhus verniciflua,

Rhus vernicifera)
T. vernicifluum, better known as the Japanese lacquer tree, was used in China as early as 2255 B.C.
and was a major industry in Japan in the middle ages. The lacquer is obtained by tapping the trees
through incisions in the bark. While not common in the South Pacific, a number of specimen trees
have been introduced to the region.11
Lacquer dermatitis was described in China as early as 453 B.C.30-32 T. vernicifluum and its
lacquer can give rise to dermatitis at all stages from the initial collection of the latex to the final
application of the lacquer, and even, it appears, 1000 years later. Lacquer from a Chinese jar, buried
for over a millennium caused dermatitis.31 Contact dermatitis from the lacquer has been reported
far more frequently than from the plant because the sources of contact are often exotic and
unexpected. For example, the lacquer on Japanese rifles caused dermatitis in American servicemen
sensitive to poison ivy (T. radicans);33,34 contact with a recently varnished bar in Japan caused
dermatitis in 12 American officers;35 and a number of steamship passengers developed dermatitis
after contact with Japanese damasence.36
The lacquer contains up to 70 percent of the urushiol known to induce contact dermatitis.30,32
The clinical features of contact with T. vernicifluum are variable, according to the mode and sites
of contact, and the degree of sensitivity. In the Southern Pacific, the main source of contact with
the tree, as for other Toxicodendron spp., is now from gardening. The economic importance of the
lacquer has significantly reduced so contact with lacquered products is becoming less.
25.1.2.3 Toxicodendron striatum (syns. Rhus striata, Rhus juglandifolia)

T. striatum has a number of common names including poison sumac, manzanillo de cerro, hinchador,
hinchahuevos, and palo de sarna.
It grows as a small tree (6–12 m) native to Central and northern South America and is the main
cause of poison ivy dermatitis in South America.11 A number of specimen trees are present in
botanical collections in Australasia, but the numbers appear few. The common name for T. striatum
is manzanillo de cerro, or small apple of the mountain, although it has little resemblance to an
apple tree.

The urushiol of this species contains a mixture of 3-pentadec(en)yl catechols.37 Cross reactions
have been reported to T. radicans, T. vernicifluum, Lithraea caustica, and Mauria puberula.11
While recognized for centuries to cause dermatitis, the first documented report is probably by
Londono in 1946.11 More detailed reports are provided by Hurtado.38-40 Facial edema, rather than
linear arranged vesicles and bullae, appears to be the more common clinical presentation of allergy
to T. striatum. Patients present with an intense swelling of the face, frequently having been unaware
of direct contact with the tree.
25.1.2.4 Other Toxicodendron Species
Less common species of Toxicodendron include Toxicodendron borneense (syn. Rhus borneensis)
that is native only to northern Borneo and Toxicodendron nodosum (syns. Rhus nodosa and Rhus
perakensis) that is found in the Malay archipelago.1 Both can probably induce contact dermatitis.
In the Southern Pacific, specimen trees are confined to botanical collections.
25.4 REFERENCES
1. Gillis, W. T., The systematics and ecology of poison-ivy and the poison-oaks (Toxicodendron, Anac-
ardiaceae), Rhodora, 73, 72, 161, 370, 465, 1971.
2. Beaman, J. H., Allergic Asian Anacardiaceace, Clin. Dermatol., 4, 191, 1986.
3. Cleland, J. B., Plants, including fungi, poisonous or otherwise injurious to man in Australia, Austr.
Med. Gaz., 35, 569, 1914.
4. Standley, P. C., Poisonous trees of Central America, Trop. Woods, 9, 3, 1927.
5. Burry, J. N., The value of patch testing: a review of 363 cases of allergic contact dermatitis, Med. J.
Austr., 1, 1226, 1969.
6. Nurse, D. S., Poison ivy in Melbourne, Med. J. Austr., 1, 528, 1966.
7. Turner, T., Poison ivy and poor-man’s liquid amber, Med. J. Austr., 2, 166, 1972.
8. Apted, J. H., Poison ivy dermatitis in Victoria, Austr. J. Dermatol., 19, 35, 1978.
9. Apted, J. H., American poison ivy (Rhus radicans) in Australia, Int. J. Dermatol., 19, 81, 1980.
10. Aplin, T. E., Plants that cause dermatitis, Austr. J. Dermatol., 22, 33, 1981.
11. Hurtado, I., Poisonous Anacardiaceae of South America, Clin. Dermatol., 4, 183, 1986.
12. Nakamura, T., Contact dermatitis to Rhus succedanea, Contact Derm., 12, 279, 1985.
13. Usher, G., A Dictionary of Plants Used by Man, Constable, London, 1974.
14. Murata, K., Practical Bonsai for Beginners, (transl. by Tsuzawa, M. and Mann, D. C.), Japan
Publications Trading Co., Tokyo, 1964.
15. Rademaker, M. and Duffill, M. B., Toxicodendron succedaneum (Rhus tree), New Zealand’s poison
ivy, Contact Derm., 33, 357, 1995.
16. Cook, D. K. and Freeman, S., Allergic contact dermatitis to plants: an analysis of 68 patients tested
at the Skin and Cancer Foundation, Austr. J. Dermatol., 38, 129, 1997.
17. Guimaraes, O. P., Bento, D., Pickel, J., et al., The toxico-allergic principle of the Anacardiaceae. The
problem of Rhus succedanea in the city of Sao Paulo, Rev. Bras. Med., 17, 43, 1960.
18. Schwartz, L., Tulipan, L., and Birmingham, D. J., Occupational Diseases of the Skin, 3rd ed., Lea
and Febiger, Philadelphia, 1957, 637.
19. Baer, H., Chemistry and immunochemistry of poisonous Anarcardiaceae, Clin. Dermatol., 4, 152,
1986.
20. Lovell, C. R., Plants and the Skin, Blackwell Scientific Publications, Oxford, 1993.
21. Mitchell, J. C. and Rook, A., Botanical Dermatology: Plants and Plant Products Injurious to the
Skin, Greengrass, Vancouver, BC, 1979.
22. Connor, H. E., The Poisonous Plants of New Zealand, 2nd ed., Government Printer, Wellington, 1977.

23. Czarnecki, D. B. and Apted, J. H., Multiple cases of allergic contact dermatitis occurring simulta-
neously in families, Arch. Dermatol., 118, 73, 1982.
24. Rademaker, M. and Duffill, M. B., Allergic contact dermatitis to Toxicodendron succedaneum (Rhus
trees)—an autumn epidemic, New Zealand Med. J., 108, 121, 1995.
25. Epstein, W. L., Poison oak and poison ivy dermatitis as an occupational problem, Cutis, 12, 544, 1974.
26. Epstein, W. L., Occupational poison ivy and oak dermatitis, Dermatol. Clin., 12, 511, 1994.
27. Aplin, T. E. H., Poisonous garden plants and other plants harmful to man in Australia, Western
Australian Department of Agriculture Bulletin, 3964, 1976.
28. Maibach, H. I. and Hjorth, N., Rhus typhina, a possible cause of dermatitis, Contact Derm. Newsl.,
13, 347, 1973.
29. Menz, J., Rossi, E. R., Taylor, W. C., and Wall L., Contact dermatitis from Grevillea ‘Robyn Gordon,’
Contact Derm., 15, 126, 1986.
30. Toyama, I., Further observations on lacquer dermatitis, Trop. Dis. Bull., 22, 231 (abstr.), 1925.
31. Toyama, I., Rhus dermatitis, J. Cutan. Genito-Urin. Dis., 36, 157, 1918.
32. Toyama, I., Studies on lacquer dermatitis. III. Dermatitis produced by Chinese lacquer, Bull. Hyg.
London, 2, 808 (abstr.), 1927.
33. Hinman, F., Contact dermatitis from Japanese rifles, Ann. Allerg., 4, 384, 1946.
34. Coomber, R. B., Dermatitis from contact with varnish of Japanese rifles, Arch. Derm. Syph., 55, 110,
1947.
35. Etler, R. L., Dermatitis caused by Japanese lacquer, U.S. Arm. Forces Med. J., 2, 505, 1951.
36. Ames, O., Rhus verniciflua and Japanese damascence ware, J. Arnold Arboretum, 12, 1, 1931.
37. Nakano, T., Medina, J. D., and Hurtado, I., The chemistry of Rhus striata (“Manzanillo”), Plant.
Med., 18, 260, 1970.
38. Hurtado, I., “Manzanillo.” Dermatitis venenata causada por el Rhus striata, Med. Cutan., 2, 253, 1967.
39. Hurtado, I., Contact dermatitis caused by the “Manzanillo” (Rhus striata) tree: report of three cases,
Int. Arch. Allerg. Appl. Immunol., 28, 321, 1965.
40. Hurtado, I., Studies on the biological activity of Rhus striata (“Manzanillo”). II. Skin response to
patch tests in humans, Int. Arch. Allerg. Appl. Immunol., 33, 209, 1968.

26 Spices
Matti Hannuksela and Aila Niinimäki
CONTENTS
26.1 Introduction
26.2 Origin of Spices and Herbs
26.3 Constituents of Spices and Herbs
26.4 Irritant and Allergic Reactions to Spices and Herbs
26.4.1 Immediate Nonallergic Skin Reactions
26.4.2 IgE-Mediated Allergy
26.4.2.1 Skin Testing with Spices and Herbs
26.4.2.2 RASTs with Spices
26.4.2.3 Immediate Skin Challenge Reactions
26.4.2.4 Immediate Skin Reactions to Ingested Spices .
26.4.2.5 Allergens for Skin Prick Testing and RASTs
26.5 Delayed Type Allergy
26.5.1 Proteins
26.5.2 Chemicals
26.5.3 Systemic Contact Dermatitis
26.6 References
26.1 INTRODUCTION
Aromatic seeds, fruits, roots, buds, flowers, and barks of certain plants used to flavor foods and
beverages, mostly native to the tropics, are called spices or genuine spices. Herbs are another group
of aromatic plants used in foods and beverages to enhance or replace the flavor of spices. Herbs
can be divided into nine categories, namely culinary, salad, scented, strewing, and medicinal herbs,
and into berry vegetables, tea herbs, and dye plants.1 The borderlines between the different herb
categories and between spices and culinary herbs are poorly established. In addition to spices and
herbs, natural or synthetic essential oils are often added to our daily food both at home and in the
food-processing industry. Spices and herbs cause both irritant and allergic skin reactions that may
be immediate or delayed, local or systemic. Most of the reactions are mild and harmless, but
widespread dermatitis or anaphylactic reactions may occasionally develop. Owing to the high
number of aromatic plants, only plants belonging either to genuine spices or to common culinary
herbs are discussed in this chapter.

TABLE 26.1
Most Important Genuine Spices
Family Botanical Name Common Name(s) Spice Habitat
Apiaceae Carum carvi Caraway Fruit Asia Minor

Coriandrum sativum Coriander Fruit Mediterranean region
Cuminum cyminum Cumin Fruit Mediterranean region
Pimpinella anisum Anise Fruit Asia Minor, Egypt
Cruciferae Brassica juncea Oriental mustard Seed Ethiopia, East Asia
(Brassicaceae) Brassica nigra Black mustard Seed South-West Asia
Sinapis alba White mustard Seed Europe
Lauraceae Cinnamomum Cassia, Chinese cinnamon Bark Southern China
aromaticum
Cinnamomum zeylanicum Ceylon cinnamon Bark Sri Lanka (Ceylon)
Laurus nobilis Bay, laurel Leaf Mediterranean region
Myristicaceae Myristica fragrans Nutmeg, mace Seed, seed mantle Molucca Islands
Myrtaceae Pimenta dioica Jamaica pepper, allspice Berry Central America
Syzygium aromaticum Clove Flower bud Molucca Islands
(Eugenia caryophyllata)
Orchidaceae Vanilla planifolia Vanilla Pod Mexico
Piperaceae Piper niger Black pepper* Berry Southern Asia
White pepper**
Solanaceae Capsicum annuum*** Paprika, cayenne, chile pepper Fruit Tropical Americas
Zingiberaceae Curcuma longa Turmeric Root Southeast Asia
* Unripe berry.
** Ripe berry.
*** Genus of up to 10 species.
26.2 ORIGIN OF SPICES AND HERBS

Most spices belong to the following nine families: Apiaceae (Umbelliferae), Solanaceae, Cruciferae
(Brassicaceae), Myrtaceae, Lauraceae, Orchidaceae, Myristicaceae, Zingiberaceae, or Piperaceae
(Table 26.1).2 Correspondingly, most important culinary herbs belong to the following three families:
Apiaceae (Umbelliferae), Labiatae, or Asteraceae (Compositae) (Table 26.2).3 Some plants are listed
in both tables because they can be used either as spices or as herbs. The seeds of anise and coriander,
for example, belong to the spices, while their leaves can be used as herbs. The list of herbs is far
from complete. Many other aromatic plants, such as rue, southernwood, wormwood, and angelica,
can also be added in small quantities to salads, soups, or beverages. Flowers or their parts of bergamot,
borage, calendula (marigold), and roses, can be used as edible decorations in salads and cakes.4
26.3 CONSTITUENTS OF SPICES AND HERBS

Spices and herbs are used mainly because of their essential oils, the compositions of which are
already mostly known.5 The spices and herbs also contain many other substances, for example,
flavonoids, carotenoids, sterols, vitamins, minerals, azulenes, sesquiterpenes, proteins, glycosides,
resins, and tannins.3 Among the constituents, some irritants, allergens, and photosensitizing com-
pounds have been identified (Table 26.3).
In addition to allergenic chemicals causing cell-mediated hypersensitivity, some allergenic
proteins responsible for IgE-mediated allergic reactions to spices have been identified. Distinct
allergenic proteins with a molecular weight of 14 kDa have been characterized in yellow/white and

TABLE 26.2
Common Culinary Herbs
Family Botanical Name Common Name(s) Habitat
Apiaceae Anethum graveolens Dill Mediterranean region

Angelica archangelica Angelica Europe
Anthriscus cerefolium Chervil, salad Russia, Western Asia
Coriandrum sativum Coriander, cilantro Mediterranean region
Foeniculum vulgare Fennel Mediterranean region
Levisticum officinale Lovage Southern Europe
Myrrhis odorata Sweet cicely Europe
Petroselinum crispum Parsley Europe, Western Asia
Pimpinella anisum Anise Asia Minor, Egypt
Asteraceae Artemisia dracunculus
var. Sativa French tarragon Russia, China, Mongolia, North America
var. Inodora Russian tarragon Russia, China, Mongolia, North America
Labiatae Agastache foeniculum Anise hyssop North America
(A. anethiodora)
Hyssopus officinalis Hyssop Mediterranean region
Melissa officinalis Lemon balm, bee balm Southern Europe
Mentha x piperita Peppermint Europe, North America, Australia
Mentha spicata Spearmint Europe, Australia
Monarda didyma Bergamot, bee palm, oswego tea Eastern United States
Ocimum basilicum Basil India
Origanum majorana Marjoram Asia
Origanum vulgare Oregano, organy Europe, Asia
Rosmarinus officinalis Rosemary Mediterranean region
Salvia officinalis Sage, ramona Mediterranean region
Thymus vulgaris Thyme Mediterranean region
Rutaceae Ruta graveolens Rue, Herb-of-grace Southern Europe
oriental mustards and named, respectively, as Bra j 1 and Sin a 1.6-8 Several other proteins with
molecular weights ranging from 12 to 90 kDa have been detected in anise, coriander, ginger, cumin,
and curry,9,10 but their amino acid sequences have not been identified yet. In a case of a systemic
reaction after ingestion of oregano and thyme, obvious cross allergy was found between thyme,
oregano, hyssop, peppermint, and sage but not for lavender and basil.10
In IgE-mediated cross allergy, plant profilins have been found to be responsible for most
reactions between pollens, vegetables, and spices.12-14 In birch pollen, Bet v 1 and Bet v 2 are the
most common, but not the only cross-reacting proteins.15 Untoward reactions to genuine spices by
patients with several plant cross allergies are usually mild.13 Severe reactions have occasionally
been reported from occupational exposure.13, 16-18
26.4 IRRITANT AND ALLERGIC REACTIONS TO SPICES AND HERBS

26.4.1 IMMEDIATE NONALLERGIC SKIN REACTIONS
Curry (a mixture of eight or more spices), cassia/cinnamon, ginger, and mustard are the most
common spices to cause immediate nonimmunologic contact reactions in skin tests.19 The reaction
usually comprises redness only, but edema may also be seen, especially from cinnamon. It is
sometimes difficult to say whether or not the skin prick, scratch, or scratch chamber test reactions
are irritant. In allergic reactions, edema is a real weal, usually with pseudopodies while an irritant

TABLE 26.3
Some Irritant, Allergenic, and Photosensitizing Substances
Substance Plant/Spice Source
1. Allergens
Carnosol Salvia carnosa, S. officinalis, S. canariensis,
S. calycina, S. triloba, Rosemary
Carvone Caraway, dill, spearmint
Cinnamic aldehyde Cinnamon, cassia
Dipentene Cardamom
Eugenol Jamaica pepper, clove, basil, lemon balm
Sesquiterpene lactones Laurel, Asteraceae family
2. Irritants
Capsaicin Capsicum annuum
Cinnamic aldehyde* Cassia, cinnamon
Isothiocyanates** Mustards
3. Photosensitizers
Bergapten Angelica, rue
* Causes nonimmunologic contact urticaria.

** Rarely also allergens.
reaction is merely edema restricted to the contact area of the spice or spice extract. Patients with
nonimmunologic immediate skin test reactions to spices develop no symptoms or signs from
ingested spices. However, irritant hand dermatitis may result from repeated exposures to spices in
food handlers.19
26.4.2 IGE-MEDIATED ALLERGY

IgE-mediated allergy to various plant proteins has rapidly increased in developed countries, espe-
cially since the 1960s. Several hypotheses to explain the increase have been proposed, but none of
them has, so far, been universally accepted. The interest in spice and herb allergy has been rather
sporadic.
26.4.2.1 Skin Testing with Spices and Herbs
Jamaica pepper, vanillin, clove, white pepper, ginger, cardamom, cinnamon, and paprika, and one
spice mixture, curry, scratch-tested in 779 to 1038 atopics produced positive reactions in 0.4 to
17.4 percent.12 The twelve spices of curry (nutmeg, black pepper, turmeric, clove, ginger, cinnamon,
white pepper, cardamom, mustard, cayenne, caraway, and coriander) were scratch tested separately
in 71 patients reacting to curry. Coriander was positive in 42 (59 percent), caraway in 39 (55
percent), cayenne in 32 (45 percent), and mustard in 23 (32 percent) of them, while positive
reactions to the other components of curry were seen in less than 4 percent of the patients tested.
Highly significant positive correlations were seen between reactions to curry and birch pollen,
and between curry and fruits and vegetables, especially carrot.12 In the same study, over 300
nonatopics were also scratch tested and 1.3 percent of them showed a positive result to 1 of the
9 spices. Vanillin, white pepper, ginger, cinnamon, and curry caused a positive reaction in one
patient each.

26.4.2.2 RASTs with Spices
Spices and some herbs have also been skin- or RAST-tested in fairly small selected patient groups.
Of 51 patients allergic to celery, 88 percent reacted to curry in skin prick tests, 75 percent to
paprika, 53 percent to parsley, 22 percent to mustard, 20 percent to anise, 18 percent to fennel, 16
percent to pepper, and 4 percent to caraway.20 In another study, 66 percent of 70 patients allergic
to celery and birch and/or mugwort pollen reacted to anise in skin prick tests, while 40 percent
reacted to fennel, 37 percent to coriander, 34 percent to caraway, 16 percent to chili pepper, and
less than 10 percent to peppers, ginger, cinnamon, and nutmeg.21 In RASTs, 44 percent of 27 celery-
allergic patients reacted to anise, 41 percent to curry, 33 percent to peppers, 23 percent to tarragon,
22 percent to parsley, 22 percent to cardamom, 19 percent to caraway, and less than 10 percent to
thyme, cinnamon, and oregano.22 In another RAST study of patients allergic to celery, birch and/or
mugwort, anise, and fennel were positive in 60 percent of 41 patients, coriander in 46 percent, chili
pepper in 39 percent, peppers in 37 percent, mace in 34 percent, ginger in 32 percent, caraway in
27 percent, nutmeg in 2 percent, and cinnamon in none.21
Apart from birch pollen, mugwort pollen is another major plant source of cross allergies. Out
of 170 mugwort pollen allergic patients, 19 to 81 percent were positive in skin tests or RASTs, in
a descending order, to camomile, curry, anise, dill, fennel, coriander, caraway, parsley, paprika,
peppermint, mustard, peppers, and turmeric.23
26.4.2.3 Immediate Skin Challenge Reactions

Although roughly 20 percent of atopics show positive immediate reactions to some spices in skin
prick, scratch, or scratch chamber tests, very few people complain of dermatitis or other discomfort
from handling spices.2 Allergic contact urticaria from mustard has been reported in three fish
industry workers.24 Among 72 spice factory workers, none were skin prick test positive to any of
5 spices tested (paprika, pepper, cardamom, ginger, and clove).25 Pompholyx may appear within
15 min to some hours and developing into an eczematous reaction within 1 to 4 days after an open
challenge (rub test) has been reported from tomato, carrot, and potato.19 Such reaction might also
be possible from other plants or plant products. The mechanism of the pompholyx reaction has
remained unresolved so far.
26.4.2.4 Immediate Skin Reactions to Ingested Spices

Ingesting rather than handling mustard caused pompholyx in a cook.26 Urticaria or angioedema has
been reported from ingested mustard,2, 27-31 coriander,32, 33 cinnamon,34 clove,34 and white pepper.2
Ingested spices were spontaneously reported to cause some harmful reactions by only 2 percent
of 220 atopic patients with positive results to any of the 9 spices tested in scratch tests.12 The
percentage was as high as 35 percent when the question was asked several months after the skin
test.35 Most of the reactions were mild local symptoms and signs appearing shortly after ingestion,
itching and smarting of the mouth, lips, face, eyes, or ears being the most common ones. Urticaria
and edema in the lips and around the mouth were reported only occasionally. Ingested spices may
possibly aggravate atopic dermatitis. Spiced food has been mentioned to cause itching in atopic
skin but less frequently than chocolate.36 Out of 37 patients with strongly positive skin test reaction
to spices, 4 reported ingested spices to aggravate their dermatitis.35 On the other hand, a peroral
challenge performed in a double-blind, placebo-controlled manner remained negative in all the 20
patients with atopic dermatitis and with 3+ scratch test reactions to the corresponding spices.12
26.4.2.5 Allergens for Skin Prick Testing and RASTs

In the detection of IgE-mediated allergy, skin prick testing and RAST as well as other in vitro
methods of measuring specific IgE from serum are equally expedient. Native spices and herbs have

many disadvantages in skin testing. Irritant substances are common, including sulphur compounds
in Cruciferae plants37 and capsaicin in many species of Capsicum annuum. Nonimmunologic contact
urticaria reactions are common from cinnamon/cassia and mustards.
Attempts to purify the allergenic proteins of spices have been few, and only some main allergens
of spices, such as that of Sinapis alba (Sin a 1) and Brassica juncea (Bra j 1), have been identified
so far. Dialyzing small molecular weight proteins from spice extracts decreases the number of
positive skin-prick/scratch test reactions considerably. Spice extracts of greater than 8 kDa were
only positive in half of the patients reacting to native spices in skin prick tests.35 Skin reactions to
a greater than 8 kDa extract, however, showed a better correlation with specific serum IgE than
skin tests with corresponding native spices.
Skin prick testing with native spices is currently the method of choice for screening people
with possible IgE-mediated immediate allergy to spices. The lack of standardized spice extracts is
a major disadvantage in detecting spice allergy both in vitro and in vivo. A double-blind, placebo-
controlled peroral challenge test is still the only way to diagnose clinically significant immediate
spice allergy.
26.5 DELAYED TYPE ALLERGY

26.5.1 PROTEINS
Proteins and protein-like plant materials were found to cause both immediate and delayed patch
test responses and a condition called protein contact dermatitis as early as in the 1970s,38 but the
mechanism of the reactions remained unresolved. Since then, patch test reactions to proteins have
gained more attention, and four types of reactions have been reported: immediate weal and flare
reaction (contact urticaria), immediate eczematous reactions, probably both irritant and allergic
ones, and delayed allergic and delayed irritant reactions. Carrot and potato are good examples of
plants producing both immediate and delayed allergic contact reactions.35 Recently, tropical grasses
were found to produce delayed contact allergy.39 Spices, and especially herbs, could be candidates
for plants causing both irritant and allergic protein contact dermatitis. Studies addressing this
problem are still lacking.
26.5.2 CHEMICALS
Spices and their essential oils were already known to produce contact dermatitis more than 100
years ago, vanilla and cinnamon being the causative spices (see Reference 2). Vanilla allergy was
seen in vanilla factories and bakeries, and cinnamon allergy in bakeries. In his extensive study on
balsams, Hjorth40 laid the basis for our present knowledge of the frequency and significance of
contact allergy to balsams and spices containing the same or related essential oils and other odorous
substances. Balsam of Peru contains 60 to 70 percent of benzyl benzoate, benzyl cinnamate,
cinnamic acid, benzoic acid, vanillin, farnesol and nerolidol, and 60 to 70 percent of unknown
resins of an unknown composition.40,41 The list of fragrance materials capable of causing contact
allergy comprises roughly 100 chemicals.42 Many of them are present in spices and herbs.
Among 118 dermatological patients with contact allergy to balsam of Peru, positive patch test
reactions to clove were seen in 46 percent, to Jamaica pepper in 21 percent, and to cinnamon in
15 percent, whereas ginger, curry, cardamom, white pepper, vanillin, and paprika were positive in
less than 10 percent of the cases. Only 3 positive reactions were seen in 220 other dermatitis patients
not allergic to balsam of Peru.43 Occupational exposure to spices may cause contact allergy to them
without concomitant balsam of Peru allergy.17
Essential oils of 12 spices were patch-tested on 539 dermatitis patients with a positive result
in 27 percent.44 A majority of the patients with positive responses reacted to an average of 2 of
the 12 oils. Reactions to oils of lavender and caraway were encountered especially in those who

also reacted to turpentine. Correspondingly, patients reacting to oils of clove, cinnamon, and
peppermint were mostly allergic to balsam of Peru.44 In the study of Niels Hjorth,40 vanilla patch
test was positive in 40 percent and cinnamon test in 27 percent of 58 eczema patients with positive
patch test to balsam of Peru. Apart from fragrances, colophony, and wood tars, clove, nutmeg,
ginger, and Jamaica pepper are further examples of common spices belonging to the same cross-
allergy family as balsam of Peru, vanillin, and cinnamon.43, 45, 46 In rosemary, carnosol (a diterpene)
was recently found to be the cause of occupational allergic contact dermatitis in a food factory
worker.47
Patch tests with herbs have been performed only occasionally. Sage elicited a positive patch
test reaction in 6 and oregano in 9 out of 55 patients with suspected contact dermatitis.45 The role
of these herbs as a cause of the patients’ dermatitis remained unresolved. Undoubtedly, positive
patch test reactions to herbs are to be expected especially in fragrance/balsam allergic patients.
26.5.3 SYSTEMIC CONTACT DERMATITIS

The use of spices is increasing in most western countries, not only because of the increasing
popularity of Indian, Mexican, Chinese, and other exotic cuisines. Contact allergy to fragrances
can be estimated to be as high as 3 percent in the general population. These two facts suggest that
systemic contact dermatitis might be more common than generally suspected. In open peroral
challenge tests with spices, 7 out of 71 patients with a positive patch test reaction to balsam of
Peru showed a positive response, pompholyx on the hands and reactivation of previous positive
patch test sites being the most common signs.43
In a double-blind, placebo-controlled peroral challenge test, 1 g of balsam of Peru, 400 mg of
a spice mixture containing equal parts of cinnamon, Jamaica pepper, clove and vanillin sugar, and
400 mg of glucose as placebo were given in a randomized order at 1 to 2 week intervals to 22
patients with a positive patch test reaction to balsam of Peru.47 In this test, eight patients reacted
objectively to balsam of Peru or to the spice mixture but not to the placebo. In this test, 10 patients
did not react to any of the substances, while 3 reacted both to the active substance(s) and the
placebo, and 1 only to the placebo. The only objective symptom was an increase in palmar vesicles
of at least 30 percent. Subjectively, the patients most commonly complained of itching or a sense
of swelling of the hands, itching of the patch test area, itching of the eyes, and generalized itching.
In the studies of Veien,48,49 double-blind peroral challenges with balsam of Peru produced subjective
symptoms in 16 of 43 patients with positive patch tests to balsam of Peru, fragrances, colophony,
and/or wood tars. It, thus, seems possible that spices, especially clove, Jamaica pepper, nutmeg,
and cinnamon, all containing eugenol and/or cinnamic aldehyde, may sometimes cause systemic
contact dermatitis in persons allergic to fragrances and/or balsam of Peru.

Patch tests with spices and herbs are usually performed using commercial dry materials or fresh
herbs. Test results, however, should be interpreted with care because of the numerous irritant
reactions that are often indistinguishable from allergic ones. In scratch chamber tests, irritant and
?+ reactions were seen more often than + to +++ reactions from mustard (24 vs. 1), curry (18 vs.
1), caraway (2 vs. 0), cardamom (5 vs. 1), cassia (4 vs. 1), dill (2 vs. 1), nutmeg (3 vs. 1), and
thyme (2 vs. 0) in a study of 80 hand dermatitis patients.19 In the same study, bay leaf, clove,
ginger, Jamaica pepper, and vanillin gave + to ++ reactions more often than irritant or ?+ reactions.
Addressing the claim that patch tests with native spices are unreliable and their interpretation
is difficult, Futrell and Rietschel46 made patch tests with spices mixed with petrolatum. Ginger,
nutmeg, and oregano gave concordant reactions at 10 and 25 percent, while cayenne, curry, cumin,
cinnamon, turmeric, coriander, and sage tended to be positive only at 25 percent. Hence, 25 percent
may have been a threshold for detecting contact allergy to these spices and herbs.

The active substances of various spices and herbs producing contact allergy should be identified
more properly, and standardized patch test materials should be commercially available. In the
meantime, it seems advisable to perform patch tests with spices and herbs at 25 percent (w/w) in
white soft petrolatum.
26.6 REFERENCES
1. Phillips, R. and Foy, N., Herbs, Pan Books Ltd., London, 1990.
2. Niinimäki, A., Spice allergy, Acta Univ. Ouluen., Series D, 357, 1, 82, 1995.
3. Keville, K., Herbs: An Illustrated Encyclopedia, Michael Friedman Publishing Group, Inc., New York,
1995.
4. Bremness, L., The Complete Books of Herbs, Borling Kindersley Ltd., London, 1988.
5. Reynolds, J. E. F., Ed., Martindale. The Extra Pharmacopoeia, 31st ed., Royal Pharmaceutical Society,
London, 1996.
6. Menéndez-Arias, L., Moneo, I., Domínguez, J., and Rodríguez, R., Primary structure of the major
allergen of yellow mustard (Sinapis alba L.) seed, Sin a 1, Eur. J. Biochem., 177, 159, 1988.
7. González de la Peña, M. A., Menéndez-Arias, L., Monsalve, R. I., and Rodríguez, R., Isolation and
characterization of a major allergen from oriental mustard seeds, Bra j 1, Int. Arch. Allerg. Appl.
Immunol., 96, 263, 1991.
8. Monsalve, R. I., González de la Peña, M. A. G., Menéndez-Arias, L., Lopez-Otin, C., Villalba, M.,
and Rodríguez, R., Characterization of a new oriental-mustard (Brassica juncea) allergen, Bra j IE:
detection of a new allergenic epitope, Biochem. J., 293, 625, 1993.
9. van Toorenenbergen, A. W. and Dieges, P. H., Immunoglobulin E antibodies against coriander and
other spices, J. Allerg. Clin. Immunol., 76, 477, 1985.
10. Helbling, A., Lopez, M., Schwartz, H. J., and Lehrer, S. B., Reactivity of carrot-specific IgE antibodies
with celery, apiaceous spices and birch pollen, Ann. Allerg., 70, 495, 1993.
11. Benito, M., Jorro, G., Morales, C., Pelaez, A., and Fernandez, A., Labiatae allergy: systemic reactions
due to oregano and thyme, Ann. Allerg. Asthma Immunol., 76, 416, 1996.
12. Niinimäki, A. and Hannuksela, M., Immediate skin test reactions to spices, Allergy, 36, 487, 1981.
13. Niinimäki, A., Björkstén, F., Puukka, M., Tolonen, K., and Hannuksela, M., Spice allergy: results of
skin prick tests and RAST with spice extracts, Allergy, 44, 60, 1989.
14. Jensen-Jarolim, E., Leitner, A., Hirschrwehr, R., Kraft, D., Wütrich, B., Scheiner, O., Graf, J., and
Ebner, C., Characterization of allergens in Apiaceae spices: anise, fennel, coriander and cumin, Clin.
Exp. Allerg., 27, 1299, 1997.
15. Scheiner, O., Aberer, W., Ebner, C., Ferreira, F., Hoffmann-Sommergruber, K., Hsieh, L. S., Kraft,
D., Sowka, S., Vanek-Krebitz, M., and Breiteneder, H., Cross-reacting allergens in tree pollen and
pollen-related food allergy: implication for diagnosis of specific IgE, Int. Arch. Allerg. Immunol., 113,
105, 1997.
16. Suhonen, R., Keskinen, H., Björkstén, F., Vaheri, E., and Zitting, A., Allergy to coriander, a case
report, Allergy, 34, 327, 1979.
17. Kanerva, L., Estlander, T., and Jolanki, R., Occupational allergic contact dermatitis from spices,
Contact Derm., 35, 157, 1996.
18. Sastre, J., Olmo, M., Novalvos, A., Ibañez, D., and Lahoz, C., Occupational asthma due to different
spices, Allergy, 51, 117, 1996.
19. Niinimäki, A., Scratch-chamber tests in food handler dermatitis, Contact Derm., 16, 11, 1987.
20. Wütrich, B. and Dietschi, R., Das “Sellerie-Karotten-Beifuss-Gewürz-Syndrom”. Hauttest- und RAST-
Ergebnisse. Schweiz. Med. Wochenschr., 115, 358, 1985.
21. Stäger, J., Wütrich, B., and Johansson, S. G. O., Spice allergy in celery-sensitive patients, Allergy,
46, 475, 1991.
22. Dietschi, R., Wütrich, B., and Johansson, S. G. O., So-called “celery-carrot-mugwort-spice syndrome”.
RAST results with new spice discs, Z. Hautkr., 62, 524, 1987.
23. Thiel, C., Fuchs, E., Maasch, H.-J., and Eahl, R., Allergy to spices: cross-reactivity to other allergens,
in New Trends in Allergy II, Ring, J. and Burg, G., Eds., Springer-Verlag, Berlin, 1986, 154.

24. Kavli, G. and Moseng, D., Contact urticaria from mustard in fish-stick production, Contact Derm.,
17, 153, 1987.
25. Meding, B., Skin symptoms among workers in a spice factory, Contact Derm., 29, 202, 1993.
26. Meding, B., Immediate hypersensitivity to mustard and rape, Contact Derm., 13, 121, 1985.
27. Panconesi, E., Sertoli, A., Fabbri, P., Giorgini, S., and Spallanzani, P., Anaphylactic shock from mustard
after ingestion of pizza, Contact Derm., 6, 294, 1980.
28. Widström, L. and Johansson, S. G. O., IgE-mediated anaphylaxis to mustard, Acta Derm. Venereol.,
66, 70, 1986.
29. Leanizbarrutia, I., Muñoz, D., and de Corrès, L. F., Cutaneous allergy to mustard, Contact Derm.,
17, 262, 1987.
30. Monreal, P., Botey, J., González de la Peña, M., Marin, A., and Eseverri, J. L., Mustard allergy. Two
anaphylactic reactions to ingestion of mustard sauce. Ann. Allerg., 69, 317, 1992.
31. Malet, A., Valero, A., Lluch, M., Bescos, M., Amat, P., and Serra, E., Hypersensitivity to mustard
seed, Allergy, 48, 62, 1993.
32. de Maat-Bleeker, F., Etiology of hypersensitivity reactions following Chinese or Indonesian meals.
Ned. Tijdschr. Geneesk., 136, 229, 1992.
33. Bock, S. A., Anaphylaxis to coriander: a sleuthing story. J. Allerg. Clin. Immunol. 91, 1232, 1993.
34. Hannuksela, M., Food allergy and skin diseases, Ann. Allerg., 51, 269, 1983.
35. Niinimäki, A., Hannuksela, M., and Mäkinen-Kiljunen, S., Skin prick tests and in vitro immunoassays
with active spices and spice extracts, Ann. Allerg. Asthma Immunol., 74, 280, 1995.
36. Rajka, G., Prurigo Besnier (atopic dermatitis) with special reference to the role of allergic factors. II.
The evaluation of the results of skin reactions, Acta Derm. Venereol., 41, 1, 1961.
37. Mitchell, J. C. and Rook, A., Botanical Dermatology. Plants and Plant Products Injurous to the Skin,
Greengrass, Vancouver, BC, 1979, 227.
38. Hjorth, N. and Roed-Petersen, J., Occupational protein contact dermatitis in food handlers, Contact
Derm., 2, 28, 1976.
39. Koh, D., Goh, C. L., Tan, H. T. W., Ng, S. K., and Wong, W. K., Allergic contact dermatitis from
grasses, Contact Derm., 37, 32, 1997.
40. Hjorth, N., Eczematous allergy to balsams, allied perfumes and flavouring agents with special reference
to balsam of Peru, Acta Derm. Venereol., Suppl. 46, 102, 1961.
41. Andersen, K. E., Burrows, D., and White, I. R., Allergens from standard series, in Textbook of Contact
Dermatitis, 2nd ed., Rycroft, R. J. G., Menné, T., and Frosch, P. J., Eds., Springer Verlag, Berlin,
1995, 416.
42. de Groot, A. C. and Frosch, P. J., Adverse reactions to fragrances. A clinical review, Contact Derm.,
36, 57, 1997.
43. Niinimäki, A., Delayed-type allergy to spices, Contact Derm., 11, 34, 1984.
44. Zündel, W., Erfahrungen mit Hautfunktionsprüfungen an 2000 Patienten, Archiv. für Dermatol. Syph.,
173, 435, 1936.
45. van den Akker, Th. W., Roesyanto-Mahadi, I. D., van Toorenenbergen, A. W. and van Joost, Th.,
Contact allergy to spices, Contact Derm., 22, 267, 1990.
46. Futrell, J. M. and Rietschel, R. L., Spice allergy evaluated by results of patch tests, Cutis, 52, 288, 1993.
47. Hjorther, A. B., Christophersen, C., Hausen, B. M., and Menné, T., Occupational allergic contact
dermatitis from carnosol, a naturally-occurring compound present in rosemary, Contact Derm., 37,
99, 1997.
48. Veien, N. K., Hattel, T., Justesen, O., Norholm, N., Oral challange with balsam of Peru in patients
with eczema: a preliminary study, Contact Derm., 9, 75, 1983.
49. Veien, N. K., Hattel, T., Justesen, O., Norholm, N., Oral challange with balsam of Peru, Contact
Derm., 12, 104, 1985.

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Library of Congress Cataloging-in-Publication Data

Dermatologic botany / edited by Javier Avalos and Howard I. Maibach

© 2000 by CRC Press LLC

No claim to original U.S. Government works

© 2000 by CRC Press LLC

Howard I. Maibach, M.D.

© 2000 by CRC Press LLC

© 2000 by CRC Press LLC

Howard I. Maibach, M.D., is Professor of Dermatology, School of Medicine, University of

© 2000 by CRC Press LLC

J. Del Valle Cantu, M.D.

Jose G. Camarasa, M.D., Ph.D. Bjoern M. Hausen, M.D.

© 2000 by CRC Press LLC

Patricia Magana, Ph.D. Otto Scheiner, Ph.D.

Marian Ørgaard, Ph.D. Jan West, Ph.D.

Evy Paulsen, M.D. Hongbo Zhai, M.D.

© 2000 by CRC Press LLC

SECTION II CLINICAL AND BOTANICAL INVESTIGATIONS

© 2000 by CRC Press LLC

SECTION IV OTHER PLANT FAMILIES

© 2000 by CRC Press LLC

SECTION V SPECIAL TOPICS

© 2000 by CRC Press LLC

Javier Avalos and Howard I. Maibach

1.2 BENEFICIAL USES OF PLANTS

© 2000 by CRC Press LLC

1.2.1 HERBAL REMEDIES

1.2.2 NEW PHARMACEUTICALS

1.2.3 COSMETIC PRODUCTS

© 2000 by CRC Press LLC

1.3 ADVERSE OCCURRENCES

1.3.1 CONTACT URTICARIA

1.3.3 IRRITANT CONTACT DERMATITIS

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1.3.4 ALLERGIC CONTACT DERMATITIS

1.4 IDENTIFICATION OF ACTIVE COMPONENTS

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2.2 NATURAL PRODUCTS AND ETHNOBOTANY

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2.3 LITERATURE ON BOTANICAL DERMATOLOGY

2.4 PLANTS AND THE SKIN

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2.5 EXAMPLES OF PLANTS IN DERMATOLOGIC THERAPY

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2.6 EXAMPLES OF PLANTS IN DERMATOLOGIC DIAGNOSIS

2.7 OTHER NATURAL PRODUCTS IN DERMATOLOGY

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2.8 THE FUTURE OF NATURAL PRODUCTS IN DERMATOLOGY

2.9 HERBAL MEDICINES, BOTANICEUTICALS, AND

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2.10 CONSERVATION, BIODIVERSITY, AND PRESERVATION OF

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© 2000 by CRC Press LLC

© 2000 by CRC Press LLC

© 2000 by CRC Press LLC

3.2 CLINICAL ASPECTS

3.2.1.2 Chemical Causes

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