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METABOLISM /

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XENOBIOTIC METABOLISM ... Most importance enzyme in xenobiotic metabolism ... Activity of xenobiotic metabolizing enzymes can be vary between individual ... – PowerPoint PPT presentation

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Title: METABOLISM /


1
METABOLISM / BIOTRANSFORMATION of TOXICANTS
Wongwiwat Tassaneeyakul Department of
Toxicology Khon Kaen University
2
A D M E
3
Hydrophillic cpds
4
XENOBIOTIC METABOLISM
  • Toxicants (xenobiotics) catalyze by enzymes to
    form metabolite (s) with modified structure
  • Several routes of metabolism found in vivo
  • May inactivate or bioactivate action
  • Liver is the major site of metabolism
  • Genetically variation with some enzymes
  • Not constant - can be changed by other chemicals
    basic of many interactions

5
2
1
3
(Parkinson 2001)
6
XENOBIOTIC METABOLISM
metabolism is what the body does to the
toxicants ..
  • Toxicants may converted to
  • Less toxic chemicals (metabolite) , or
  • More toxic chemicals (metabolite) , or
  • Chemicals with different type of effect or
    toxicity

7
Sites of Metabolism
  • where ever appropriate enzymes occur
  • plasma,
  • kidney,
  • lung,
  • gut wall and LIVER
  • the liver is ideally placed to intercept natural
    ingested toxins (bypassed by injections etc) and
    has a major role in biotransformation

8
The Liver
Hepatocytes (liver cells)
smooth endoplasmic reticulum
bile
portal venous blood
Feces
microsomes
contain cytochrome P450 (CYP)
systemic arterial blood
venous blood
Urine, Expiration
9
Lipophilic toxicant
Biotransformation
Hydrophilic metabolite
Metabolite excreted
10
Types of Biotransformation Reaction
Any structural change in a molecule Phase I -
creates site for phase II oxidation (adds O)
e.g. microsomes reduction hydrolysis (e.g.
by plasma esterases) others Phase II - couples
group to existing (or phase I formed)
conjugation site glucuronide (with glucuronic
acid) sulphate others
11
Xenobiotic-Metabolizing Enzymes (XME)
Phase 1 P450s Flavin-containing monoxygenases
(FMO) Epoxide hydrolases Phase 2
Transferases Sulfotransferases
(ST) UDP-glucuronosyltransferases
(UGT) Gluthione S-transferases (GST)
12
Relative abundant of human XMEs
Phase II
Phase I
13
PHASE 1 reactions
Hydroxylation -CH2CH3 -CH2CH2OH
Oxidation -CH2OH -CHO -COOH
N-dealkylation -N(CH3)2 - NHCH3
CH3OH
Oxidative deamination -CH2CHCH3
-CHCOCH3 NH3


NH2
14
Phase I Enzymes
  • Cytochromes P450
  • Flavin Containing Monooxygenase
  • Epoxide Hydrolase
  • Alcohol /Aldehyde Dehydrogenases
  • Monoamine Oxidases
  • Xanthine oxidase

15
Cytochromes P450 (CYP)
  • Most importance enzyme in xenobiotic metabolism
  • Membrane bound enzyme locate in smooth
    endoplasmic reticulum membrane
  • All require NADPH and O2
  • Divided to Family Subfamily Isoform
  • CYP1, CYP2, CYP3 involved in the metabolism of
    xenobiotic

16
CYP 102 (Graham Peterson 1999)
17
Reduced carbon monoxide difference spectrum of
cytochrome P450
18
Inducibility of CYP
19
(No Transcript)
20
(Parkinson 2001)
21
Content of CYP in human liver
CYP2D6
CYP2A6 2B6
CYP1A2
CYP3A
CYP2E1
CYP2C
22
Phase I in Action
Imipramine
N
4-hydroxy imipramine (cardiotoxic)
CH2 CH2 N CH3 CH3
desmethyl imipramine (antidepressant)
23
Cytochrome P450 dependent Mixed Function Oxidases
DRUG
METABOLITE
DRUGO
O2
Liver microsomes
NADP
NADPH
WATER
H
24
Other (non-microsomal) Phase I reactions
  • Hydrolysis in plasma by esterases (suxamethonium
    by cholinesterase)
  • Alcohol and aldehyde dehydrogenase in liver
    cytosolic (ethanol)
  • Monoamine oxidase in mitochondria (tyramine,
    noradrenaline, dopamine, amines)
  • Xanthine oxidase (6-mercaptopurine, uric acid
    production)
  • Enzymes for particular substrates (tyrosine
    hydroxylase, dopa-decarboxylase etc.)

25
PHASE 2 Reactions
  • CONJUGATIONS
  • -OH, -SH, -COOH, -CONH with glucuronic acid to
    give glucuronides
  • -OH with sulphate to give sulphates
  • -NH2, -CONH2, amino acids, sulpha drugs with
    acetyl- to give acetylated derivatives
  • -halo, -nitrate, epoxide, sulphate with
    glutathione to give glutathione conjugates
  • all tend to be less lipid soluble and therefore
    better excreted (less well reabsorbed)

26
Cofactors for Phase II
(Source Parkinson 2001)
27
BIOACTIVATIONS
(Source Parkinson 2001)
28
(Source Parkinson 2001)
29
Factors Affecting Metabolism
  • Age (reduced in aged children)
  • Sex (women more sensitive to ethanol)
  • Species (phenylbutazone 3h rabbit, 6h horse, 8h
    monkey, 18h mouse, 36h man)
  • Race (fast and slow isoniazid acetylators, fast
    95 Eskimo, 50 Brits, 13 Finns 13 Egyptians)
  • Clinical or physiological conditions

30
AGE
  • Fetus Neonate
  • Lower drug metabolizing capacity compare to adult
  • Sensitive to drug,
  • Long duration of action
  • Glucoronosyltransferase (UDPGT)

Enzyme activity
Birth
Adult
31
SPECIES
  • Rate of Hexobarbital metabolism

Coumarin 7-Hydroxylation found in only human,
rabbit, cat but not in rat, mice Therefore
animal used for toxicity test must has the drug
metabolism process similar to human
32
GENETICS
  • Activity of xenobiotic metabolizing enzymes can
    be vary between individual
  • Population can be divided to RAPID METABOLIZER
    and SLOW METABOLIZERS

33
DISEASES
  • Liver diseases reduced drug metabolism
  • cirrhosis
  • Acute alcohol exposure chronic ethanol exposure
    alcoholic cirrhosis
  • Endrocrine disorders diabetes

Hormones
Thyroid hormone Insulin Pituitary hormone Sex
hormones
34
FOOD
  • Nutrients
  • Protein
  • Cabohydrate
  • Fat
  • Vitamins
  • Non-nutrients
  • Pyrolysis products
  • some chemical in plants Indole compounds
    (Cabbage/ Brussel sprout)

PYROLYSIS PRODUCTS Break down products of amino
acid after over cook meat at high temp
(fried/charcoal -broiled) Induce drug
metabolizing enzymes P450s and
UDPGT Mutagenecity/ Carcinogenicity
35
Chemicals/ Drugs
  • INHIBITORS cimetidine
  • prolongs action of toxicants or inhibits action
    of those biotransformed to active agents
    (pro-drugs)
  • INDUCERS barbiturates, carbamazepine
  • shorten action of toxicants or increase effects
    of those biotransformed to active agents
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