10-minggu xiii dan xiv - biokimia

8/11/2019 10-Minggu XIII Dan XIV - Biokimia

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ENDOCRINE


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Endocrine, paracrine and autocrine hormone effects


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hydrophilic

lipophilic


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Determinants of the Concentration of a Hormone

at Target Cells

Rate of synthesis and secretion

Proximity of target cell (dilution effect)

Dissociation constants ofhormone-transport protein

Conversion of inactive forms fully active form

Rate of clearance


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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


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Hormonal Regulation System


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Plasma Level Dynamics


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Principles of Hormone Action


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I. Hormones that bind to intracellular receptors

Androgens

Calcitriol

Estrogens

Glucocorticoids

Mineralocorticoids

Progestins

Retinoic acid

Thyroid hormones (T3 and T4)

II H h bi d ll f


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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

FSHGlucagon

Lipotropin

LH

MSH

Parathyroid hormoneSomatostatin

TSH

B. The second messenger is cGMP :

Atrial natriuretic factor

Nitric oxide


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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


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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

G l F t f H Cl


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General Features of Hormone Classes

Group I Group II

Types Steroid, iodothyronines,

calcitriols, retinoids

Polypeptides, proteins,

glycoproteins, catechol-

amines

Solubility Lipophilic Hydrophilic

Transportproteins

Yes No

Plasma halflife Long (hours to days) Short (minutes)

Receptor Intracellular Plasma membrane

Mediator Receptor-hormone

complex

cAMP, cGMP, Ca2+,

Metabolites of complex

phosphoinositols,

kinase cascades


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H hi h


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Hormone hierarchy

Hypothalamus

Hypophysis

Peripheral gland

Target cell


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HYPOPHYSIS


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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

GH (G th H )


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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)

TROPINS


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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

TROPINS con


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TSH Thyroid gland : synthesis / release

thyroid hormones

ACTH Adrenal cortex : secretion of

glucocorticoids

MSH Melanocytes : Melanine

TROPINS .. con

LOBUS INTERMEDIUS

LOBUS POSTERIOR


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ADH Kidney tubules : water reabsorption

Peripheral vasoconstrictionStimulated by : dehydration / plasma osmlarity

stress (psycho- / physical)

morphine / nicotine

Deficiency : Diabetes Insipidus

OXYTOSIN Uterus : contractionMammary glands : secretion of milk

LOBUS POSTERIOR

THYROID GLAND


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triodothyronine (T3)and

tetraiodothyronine (T4 or thyroxine)

metabolic rate

glucose absorption

body temperatureaffect growth and development

(mRNA & protein synthesis )

Excess : Toxic goiterDeficiency : Endemic goiter

Cretinism

Myxedema

THYROID GLAND

PARATHYROID GLANDS


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Parathyroid hormone (PTH)

plasma calcium levelby : 1. formation / activity of osteoclasts

2. kidney tubules calcium reabsorption

3. synthesis 1,25-dihydroxycholecalciferol

PARATHYROID GLANDS

Calsitonin

(parathyroid / thyroid / thymus)

effect ??


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SEX HORMONES


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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.

PANCREAS (i l t f L h )


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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


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Hormonal Regulation of Glucose Metabolism in the Liver

Hormones : overview


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Hormones : overview

Regulatory Circui t


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Regulatory Circui t

Lipophilic Hormones


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p p

Lipophilic Hormones


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p p

Lipophilic Hormones


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Lipophilic Hormones

Biosynthesis of Steroid Hormones


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Inactivation of Steroid Hormones


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Mechanism of Action of Lipophilic Hormones


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Receptors of Lipophilic Hormones


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p p p

Signaling Substances Derived from Amino Acids


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Signaling Substances Derived from Amino Acids

Examples of Peptide Hormones and Proteohormones


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Metabolism of Peptide Hormones


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Biosynthesis

Degradation and Inactivation


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g

Mechanisms of Action


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Second Messengers


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Signal Cascades


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Eicosanoids


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Cytokines


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XENOBIOTICS

XENOBIOTICS


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XENOBIOTICS

foreign substances: pharmaceuticalsfood additives

cosmetics

anutrients

pestisites

port dentree: food

lungsskin

BIOTRANSFORMATIONS


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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

ConjugationX1Excretion

INTERCONVERSION REACTIONS


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not always a detoxification process

Toxicity/ Toxicity/

LD50(g/kg rat) Xenobiotic Metabolite LD50(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 0.61.2 piridine methylpiridine chloride 0.22

Cytochrome P450 systems


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Hydroxylation is the chief reaction involved

The reaction catalyzed

by a monooxygenase (cytochrome P450)


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Isoforms of Cytochrome P450 Make Up a Superfamily ofHeme Containing Enzymes


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Heme-Containing Enzymes

about 150 isoforms

have a systematic nomenclaturefor isoforms of P450

and for their genes

CYP1A1 CYP1A1

gene encoding (i tal ic)cytochrome P450

family

subfamily

individual P450s

CYP


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arehemoproteins

highest amount inliver

Mainly in the membranes of the smooth endoplasmic

reticulum

NADPH, not NADH, is involved in the reactionmechanism

Most isoforms are inducible

Lipids are also components of the CYP. The preferred lipid is

phosphatidylcholine

Certain CYPs exist in polymorphic forms(genetic isoforms)

Induction of CYP has Important Clinical Implications


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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


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Reduction of carbonyl, azo-, or nitro- compounds,

dehalogenation

R-NO2 R-NO- R-NHOH R-NH2

Hydrlysis of ether, ester, peptide bonds

PHASE II CONJUGATIONS

2


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GLUCURONIDATION

2 ways:

1. X activation Xactive + CM X-CM

2. CM activation CMactive+ X X-CM

the most frequent conjugation reaction



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Methylations



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OTHERS CONJUGATE MOLECULES:

Glucoside

Glycine

Glutamine

Glutathione

Asetil

Sulfat

RESUME


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XENOBIOTICS

ENDOGENOUS

SUBSTANCES

BIOTRANSFORMATION

CONJUGATION

(DETOXICATION)

WATER SOLUBLE,

INACTIVE,

NON-TOXIC

10-minggu xiii dan xiv - biokimia

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