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METABOLISM / BIOTRANSFORMATION of TOXICANTS

METABOLISM / BIOTRANSFORMATION of TOXICANTS. Wongwiwat Tassaneeyakul Department of Toxicology Khon Kaen University. A D M E. สารเคมี (Xenobiotics). Highly lipophillic compounds. Lipophillic compounds. สะสมในเซลล์ไขมัน. Phase I biotransformation (oxidation, reduction, hydrolysis ).

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METABOLISM / BIOTRANSFORMATION of TOXICANTS

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  1. METABOLISM / BIOTRANSFORMATION of TOXICANTS Wongwiwat Tassaneeyakul Department of Toxicology Khon Kaen University W. Tassaneeyakul

  2. A D M E W. Tassaneeyakul

  3. สารเคมี(Xenobiotics) Highly lipophillic compounds Lipophillic compounds สะสมในเซลล์ไขมัน Phase I biotransformation (oxidation, reduction, hydrolysis) Polar compounds Phase IIbiotransformation (conjugation) ถูกขับออกจากร่างกาย (Renal excretion, Biliary excretion) Hydrophillic cpds W. Tassaneeyakul

  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 W. Tassaneeyakul

  5. 2 1 3 (Parkinson 2001) W. Tassaneeyakul

  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 W. Tassaneeyakul

  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 W. Tassaneeyakul

  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 W. Tassaneeyakul

  9. Lipophilic toxicant Biotransformation Hydrophilic metabolite Metabolite excreted W. Tassaneeyakul

  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 W. Tassaneeyakul

  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) W. Tassaneeyakul

  12. Relative abundant of human XMEs Phase II Phase I W. Tassaneeyakul

  13. PHASE 1 reactions Hydroxylation -CH2CH3 -CH2CH2OH Oxidation-CH2OH -CHO -COOH N-dealkylation -N(CH3)2 - NHCH3 + CH3OH Oxidative deamination-CH2CHCH3 -CHCOCH3 + NH3 | NH2 W. Tassaneeyakul

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

  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 W. Tassaneeyakul

  16. CYP 102 (Graham & Peterson 1999) W. Tassaneeyakul

  17. Reduced carbonmonoxide difference spectrum of cytochrome P450 W. Tassaneeyakul

  18. Inducibility of CYP W. Tassaneeyakul

  19. W. Tassaneeyakul

  20. (Parkinson 2001) W. Tassaneeyakul

  21. Content of CYP in human liver CYP2D6 CYP2A6 & 2B6 CYP1A2 CYP3A CYP2E1 CYP2C W. Tassaneeyakul

  22. Phase I in Action Imipramine N 4-hydroxy imipramine (cardiotoxic) CH2 CH2 N CH3 CH3 desmethyl imipramine (antidepressant) W. Tassaneeyakul

  23. Cytochrome P450 dependent Mixed Function Oxidases DRUG METABOLITE =DRUG+O O2 Liver microsomes NADP+ NADPH WATER H+ W. Tassaneeyakul

  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-decarboxylaseetc.) W. Tassaneeyakul

  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) W. Tassaneeyakul

  26. Cofactors for Phase II W. Tassaneeyakul (Source: Parkinson 2001)

  27. BIOACTIVATIONS W. Tassaneeyakul (Source: Parkinson 2001)

  28. W. Tassaneeyakul (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 physiologicalconditions W. Tassaneeyakul

  30. CP UDPGT Conjugated-CP Excretion GREY BABY SYNDROME (toxicity of chloramphenicol in newborn baby) Volmiting irregular & rapid respiration Cyanosis AGE • Fetus & Neonate : • Lower drug metabolizing capacity compare to adult • Sensitive to drug, • Long duration of action • Glucoronosyltransferase (UDPGT) % Enzyme activity Birth Adult

  31. Rate of Hexobarbital metabolism SPECIES 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. Variation in toxicant metabolism Variation of toxicant level in the body Variation of toxicant response/toxicity 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. Nutrients Protein Cabohydrate Fat Vitamins Non-nutrients Pyrolysis products some chemical in plants : Indole compounds (Cabbage/ Brussel sprout) FOOD 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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