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Introduction

Foreign and potentially toxic compounds absorbed into


biological systems are generally lipophilic substances. They
are therefore not ideally suited for excretion.
In the biotransformation of foreign compounds, the body
attempts to convert such lipophilic substances into more polar,
and consequently, more readily excreted metabolites.
The conversion to water-soluble chemicals through
biotransformation is catalyzed by multiple enzymes primarily
in the liver with contributions from other tissues.

Highly lipophilic substances such as polybrominated


biphenyls and DDT are poorly excreted and therefore may
remain in the animals body for years.
The enzymes involved in biotransformation also have a
particular subcellular localization: many are found in the
smooth endoplasmic reticulum (SER).
Metabolism can be simply and conveniently divided into two
phases: phase 1 and phase 2.

Example of Phase 1 and Phase 2 Biotransformation


The foreign molecule benzene is a highly lipophilic molecule,
which is not readily excreted from the animal except in the
expired air, as it is volatile.
The Phase 1 metabolism converts benzene into a variety of
metabolites, but the major one is phenol. The insertion of a
hydroxyl group allows a phase 2 conjugation reaction to take
place with the polar sulfate group being added.
Phenyl sulfate, the final metabolite is very water soluble and
is readily excreted in the urine.

(Principles of Biochemical Toxicology, John A. Timbrell)

(Principles of Biochemical Toxicology, John A. Timbrell)

http://goo.gl/MQPXUz phase 1 and phase 2 metabolism

Phase 1 metabolism
The major phase 1 reactions are oxidation, reduction, and
hydrolysis, exposing or introducing a functional group (-OH)
to increase reactivity and slightly increase hydrophilicity.

Cytochrome P450:
Cytochrome P450 (CYP) enzymes are the most important in
biotransformation in terms of the catalytic versatility and
number of xenobiotics that it metabolizes: 400 isozymes and
36 families.

Cytochrome P450 isozymes are localized in the smooth


endoplasmic reticulum of the cell.
P450s have an absolute requirement for molecular oxygen.
Oxidations include hydroxylations and dealkylations.
Has multiple CYP Families.
Example of CYP 450 families are 1A2, 2C9, 2D6, 3A4.
CYPs are heme-containing proteins.

Oxidation
The majority of these reactions are catalyzed by one enzyme
system, the cytochrome P450 mono-oxygenase.
The liver has the highest concentration of this enzyme although
it can be found in most, if not all tissues.
The reactions catalyzed also require NADPH, molecular oxygen
and magnesium,

(Introduction to toxicology, John Timbrell)

Reduction
Reductases in the microflora present in the gastrointestinal
tract has an important role in the reduction of xenobiotics.
There are a number of different reductases, which can catalyze
the reduction of azo and nitro compounds.
Reduction of the azo dye prontosil to produce the antibacterial
drug sulfanilamide is a well-known example of azo reduction.

(Principles of Biochemical Toxicology, John A. Timbrell)

Phase 2 Metabolism

Phase 2 reactions include glucuronidation, sulfation,


acetylation, methylation, conjugation with glutathione, and
conjugation with amino acids (glycine, taurine and glutamic
acid) that strongly increase hydrophilicity.

Sulfation
The addition of the sulphate moiety to a hydroxyl group is a
major route of conjugation for foreign compounds.
It is catalyzed by a cytosolic sulphotransferase enzyme and
utilizes the coenzyme phosphoadenosine phosphosulphate.
The product is an ester which is very polar and water soluble.

(Introduction to toxicology, John Timbrell)

Glucuronidation
Glucuronic acid is a polar and water soluble carbohydrate
molecule which may be added to hydroxyl groups, carboxylic
acid groups, amino groups and thiols.
This process is a major route of phase 2 metabolism and utilizes
glucuronosyl transferases, which are microsomal enzymes, with
uridine diphosphate glucuronic acid as the cofactor.

(Introduction to toxicology, John Timbrell)

References
Timbrell, J. A. 2009. Principles of Biochemical Toxicology.
Informa Healthcare(USA).
Timbrell, J. 2002. Introduction to Toxicology. Taylor &
Francis Inc, London.
www.xenotechllc.com/chapter-6
nature.berkeley.edu/~dnomura/pdf/Lecture4MetabolismPhaseI
v2.pdf
nature.berkeley.edu/~dnomura/pdf/Lecture5Meta
bolismPhaseII.pdf