ENDOCRI NE

Endocrine, paracrine and autocrine hormone effects

hydrophilic
lipophilic
Determinants of the Concentration of a Hormone
at Target Cells
Rate of synthesis and secretion

Proximity of target cell (dilution effect)

Dissociation constants of
hormone-transport protein

Conversion of inactive forms fully active form

Rate of clearance
Determinants of Target Cell Response
The number/relative activity/state of
occupancy of the specific receptors

Metabolism of hormone in target cell

Other factors necessary for hormone response

Up/down regulation of receptor

Postreceptor desensitization
Hormonal Regulation System
Plasma Level Dynamics
Principles of Hormone Action
I. Hormones that bind to intracellular receptors
Androgens
Calcitriol
Estrogens
Glucocorticoids
Mineralocorticoids
Progestins
Retinoic acid
Thyroid hormones (T3 and T4)
II. Hormones that bind to cell surface receptors
A. The second messenger is cAMP :
2-Adrenergic catecholamines
-Adrenergic catecholamines
Adrenocorticotropic hormones
ADH
Calcitonin
hCG
Corticotropin-releasing hormone
FSH
Glucagon
Lipotropin
LH
MSH
Parathyroid hormone
Somatostatin
TSH

B. The second messenger is cGMP :
Atrial natriuretic factor
Nitric oxide

C. The second messenger is calcium or phosphatidyl-
inositols (or both) :

Acetylcholine (muscarinic)
1-Adrenergic catecholamines
Angiotensin II
ADH (vasopressin)
Cholecystokinin
Gastrin
Gonadotropin-releasing hormone
Oxytocin
Platelet-derived growth factor
Substance P
Thyrotropin-releasing hormone
D. The second messenger is a kinase or phosphatase
cascade :

Chorionic somatomammotropin
Epidermal growth factor
Erythropoietin
Fibroblast growth factor
GH
Inslin
Insulin-like growth factor I and II
Nerve growth factor
Platelet-derived growth factor
Prolactin
General Features of Hormone Classes
Group I Group II
Types Steroid, iodothyronines,
calcitriols, retinoids
Polypeptides, proteins,
glycoproteins, catechol-
amines
Solubility Lipophilic Hydrophilic
Transport
proteins
Yes No
Plasma halflife Long (hours to days) Short (minutes)
Receptor Intracellular Plasma membrane
Mediator Receptor-hormone
complex
cAMP, cGMP, Ca
2+
,
Metabolites of complex
phosphoinositols,
kinase cascades
Hormone hierarchy
Hypothalamus
Hypophysis
Peripheral gland
Target cell
HYPOPHYSIS
LOBUS ANTERIOR :
1. GH
2. TROPINS
2.1 LTH (prolactin)
2.2 GONADOTROPIN :
2.2.1 FSH
2.2.2 LH
2.3 TSH
2.4 ACTH
LOBUS INTERMEDIUS :
1. MSH
LOBUS POSTERIOR
1. VASOPRESSIN (pitressin)
2. OXYTOCIN
ADENOHYPOPHYSIS
NEUROHYPOPHYSIS
Targets : bones / soft tissues

Accelerates body growth by:

cells amino acids uptake

protein synthesis

Deficiency : dwarfism / pygmis

Excess : since childhood gigantism

adult acromegali
GH (Growth Hormone)
Prolactin Pregnancy : regulate placental hormones

Mammary glands / milk production
FSH Ovaries : Growth of ovarian follicles

Testes : Spermatogenesis
LH Ovaries : Follicles maturation / ovulation
Stimulates corpus luteum to secrete
estrogens and progesterone
Testes : Interstitial cells secrete testosterone
TROPINS
Gonadoptropins
TSH Thyroid gland : synthesis / release

thyroid hormones
ACTH Adrenal cortex : secretion of
glucocorticoids
MSH Melanocytes : Melanine
TROPINS .. con
LOBUS INTERMEDIUS
ADH Kidney tubules : water reabsorption
Peripheral vasoconstriction
Stimulated by : dehydration / plasma osmlarity
stress (psycho- / physical)
morphine / nicotine
Deficiency : Diabetes Insipidus
OXYTOSIN Uterus : contraction
Mammary glands : secretion of milk
LOBUS POSTERIOR
triodothyronine (T3) and
tetraiodothyronine (T4 or thyroxine)

metabolic rate
glucose absorption
body temperature
affect growth and development
(mRNA & protein synthesis )

Excess : Toxic goiter
Deficiency : Endemic goiter
Cretinism
Myxedema
THYROID GLAND
Parathyroid hormone (PTH)

plasma calcium level

by : 1. formation / activity of osteoclasts

2. kidney tubules calcium reabsorption

3. synthesis 1,25-dihydroxycholecalciferol
PARATHYROID GLANDS
Calsitonin

(parathyroid / thyroid / thymus)

effect ??
Adrenal cortex
Glucocorticoids (corticosterone, cortisol)
1. Regulate carbohydrate and lipid metabolism,
protein catabolism
2. Large dose inhibit inflammatory response
3. Promote vasoconstriction
4. Resist body stress

Mineralocorticoids (deoxycorticosterone, aldosterone)
Regulate extracellular electrolites ( Na
+
, K
+
)

Sex hormone : DHEA (dehydroepiandrosterone)
ADRENAL GLANDS
Adrenal medulla
Amines hormones (dopamine, epinephrine and
norepinephrine)
Sympathetic responses

Adrenergic receptors :

1 2
glycogenolysis lypolysis
smooth muscle contraction vascular beds smooth muscle contr.
(blood vessels, UG tract) GI tract smooth muscle relaxation


1 2
lypolysis liver : gluconeogenesis
heart muscle contraction glycogenolysis
heart beat muscle : glycogenolysis
force secretion of insulin / glucagon /
renin
smooth muscle relaxation

SEX HORMONES
TESTIS : Testosterone
DHEA
Effect : androgenic
metabolic : protein synthesis
glycolysis

OVARY : 1. Estrogenic (follicle)
Estradiol / Estrol / Estrone
Effect : second. Sex
uterus prep.

2. Progestational (corp. luteum)
Progesterone
Effect : uterus prep.
Glucagon ( cells) :
Stimulate glycogenolysis

Insulin ( cells) :
Stimulate glucose transport, glycolysis
(lowers blood glucose level)

Somatostatin ( cells) :
Stimulate incorporation of sulfur into cartilage
and collagen formation
PANCREAS (islets of Langerhans)
Hormonal Regulation of Glucose Metabolism in the Liver
Hormones : overview
Regulatory Circuit
Lipophilic Hormones
Lipophilic Hormones
Lipophilic Hormones
Biosynthesis of Steroid Hormones
Inactivation of Steroid Hormones
Mechanism of Action of Lipophilic Hormones
Receptors of Lipophilic Hormones
Signaling Substances Derived from Amino Acids
Examples of Peptide Hormones and Proteohormones
Metabolism of Peptide Hormones
Biosynthesis
Degradation and Inactivation
Mechanisms of Action
Second Messengers
Signal Cascades
Eicosanoids
Cytokines
Signal Transduction in the Cytokines
XENOBIOTICS
XENOBIOTICS
foreign substances: pharmaceuticals

food additives

cosmetics

anutrients

pestisites

port dentree: food
lungs

skin

BIOTRANSFORMATIONS
inactivating & excreting

(similar with endogenous substances)

mainly in the liver

metabolism: 1. phase I reactions (interconversion)

2. phase II reactions (conjugations)
Phase I

X2 Oxidation

X3 Reduction

X4 Hydrolysis
Phase II
Conjugation






X1
Excretion







INTERCONVERSION REACTIONS
not always a detoxification process
Toxicity/ Toxicity/
LD
50
(g/kg rat) Xenobiotic Metabolite LD
50
(g/kg rat)

2.0 benzoic acid hipuric acid 4.15
2.85 p-amino benzoic acid p-amino benzoic acid 4.93
1.8 sulfadiazine acetylsulfadiazine 0.6
1.2 piridine methylpiridine chloride 0.22
Cytochrome P450 systems
Hydroxylation is the chief reaction involved
The reaction catalyzed
by a monooxygenase (cytochrome P450)
Isoforms of Cytochrome P450 Make Up a Superfamily of
Heme-Containing Enzymes
about 150 isoforms
have a systematic nomenclature for isoforms of P450
and for their genes
CYP1A1 CYP1A1
gene encoding (italic) cytochrome P450
family
subfamily
individual P450s
are hemoproteins
highest amount in liver
Mainly in the membranes of the smooth endoplasmic
reticulum
NADPH, not NADH, is involved in the reaction
mechanism
Most isoforms are inducible
Lipids are also components of the CYP. The preferred lipid is
phosphatidylcholine
Certain CYPs exist in polymorphic forms (genetic isoforms)
CYP
Induction of CYP has Important Clinical Implications
a biochemical mechanism of drug interaction
warfarin (anticoagulant)
metabolized by CYP2C9
epilepsy phenobarbital CYP2C9
(inducer of CYP)
warfarin
components found in tobacco smoke
induction CYP2E1
carcinogens
ethanol
REDUCTION and HYDROLYSIS
Reduction of carbonyl, azo-, or nitro- compounds,
dehalogenation

R-NO
2
R-NO
-
R-NHOH R-NH
2
Hydrlysis of ether, ester, peptide bonds
PHASE II CONJUGATIONS
GLUCURONIDATION
2 ways:

1. X activation Xactive + CM X-CM

2. CM activation CMactive + X X-CM
the most frequent conjugation reaction
PHASE II CONJUGATIONS
Methylations
PHASE II CONJUGATIONS
OTHERS CONJUGATE MOLECULES:

Glucoside

Glycine

Glutamine

Glutathione

Asetil

Sulfat
RESUME
XENOBIOTICS

ENDOGENOUS
SUBSTANCES
BIOTRANSFORMATION
CONJUGATION
(DETOXICATION)
WATER SOLUBLE,
INACTIVE,
NON-TOXIC