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Biotransformation Xenobiotic metabolism

Biotransformation Xenobiotic metabolism. “Essentials of Toxicology” by Klaassen Curtis D. and Watkins John B Chapter 6. CYP2A1 6  -OH CYP3A 6  -OH. Biotransformation. Water soluble xenobiotics are easier to eliminate ( t 1/2 ) Urine, feces but not exhalation

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Biotransformation Xenobiotic metabolism

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  1. BiotransformationXenobiotic metabolism “Essentials of Toxicology” by Klaassen Curtis D. and Watkins John B Chapter 6

  2. CYP2A1 6-OH CYP3A 6-OH Biotransformation • Water soluble xenobiotics are easier to eliminate ( t1/2) • Urine, feces but not exhalation • If within barrier, no out • Multiple enzymes (families) • Constitutively expressed • Inducible • Broad specificity • Polymorphic (allelic variants) • Stereo-isomer specificity: 6-OH in hormones:

  3. Biotransformation Relatively harmless Potentially toxic xenobiotic Metabolic activation Detoxification Inactive metabolite Reactive intermediate

  4. Converting lipophilic to water soluble compounds Lipophilic (non-polar) Xenobiotic Phase I - Activation Reactive intermediate Phase II - Conjugation Conjugate Water soluble (polar) Excretion

  5. Phase I • introduction of functional group • hydrophilicity increases slightly • may inactivate or activate original compound • major player is CYP or mixed function oxygenase (MFO) system in conjunction with NAD(P)H • location of reactions is smooth endoplasmic reticulum

  6. Phase II • conjugation with endogenous molecules (GSH, glycine, cystein, glucuronic acid) • hydrophilicity increases substantially • neutralization of active metabolic intermediates • facilitation of elimination • location of reactions is cytoplasm

  7. O C C C O Phase I reactions Table 6.1 • Oxidation • Hydroxylation (addition of -OH group) • N- and O- Dealkylation (removal of -CH side chains) • Deamination (removal of -NH side chains) • Epoxidation (formation of epoxides) • Oxygen addition (sulfoxidation, N-oxidation) • Hydrogen removal • Reduction • Hydrogen addition (unsaturated bonds to saturated) • Donor molecules include GSH, FAD, NAD(P)H • Oxygen removal • Hydrolysis • Splitting of C-N-C (amide) and C-O-C (ester) bonds epoxide See also Chapter 6 of Casarett and Doull’s “Toxicology”

  8. Biotransformation • Activation of xenobiotics is a key element (e.g. benzene, vinyl chloride) • Reactive intermediates include epoxides and free radical species (unpaired electrons) that are short-lived and hence highly reactive • Protection is provided by • endogenous antioxidant substances, e.g. GSH • vitamins C and E • antioxidant enzymes, SOD, GPX, CAT in coupled reactions • Antioxidant molecules are oxidized in the process but have the capacity to regenerate the reduced form from the oxidized - NAD(P)H is a key player See also p. 40-44 of Casarett and Doull’s “Toxicology”

  9. Cytochrome P450 (CYP) Mixed Function Oxidases (MFO) • Located in many tissues but highly in liver ER • Human: 16 gene families • CYP 1,2,3 perform drug metabolism • >48 genes sequenced • Key forms: CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 • Highly inducible • Alcohol CYP2E1 • Dioxin/PCBs CYP1A • Barbiturates CYP2B • CYP genes have multiple alleles (2D6 has 53, and 2E1 has 13)

  10. The CYP-450 reaction cycle A G (B) C F E D

  11. Oxidation of vinyl chloride to an epoxide

  12. Metabolic enzymes • Microsomal: • CYP450 monooxygenases • Flavin monooxygenase • Non-microsomal • Alcohol dehydrogenase • Aldehyde dehydrogenase • Monoamine and diamine oxidases • Both • Esterases and Amidases • Prostaglandin synthase • Peroxidases

  13. Cooxidation of acetaminophen by prostaglandin endoperoxide synthetase Compare to fig. 6-2

  14. Hydrolysis of esters and amides

  15. Hydrolysis of organophosphates

  16. Hydrolysis of epoxides

  17. Stereoselective hydroxylation

  18. Metabolism of benzo(a)pyrene to 9,10 epoxide: Potent mutagen that binds DNA

  19. Azo- and nitro- reduction

  20. Ready for elimination reabsorption Intestinal flora as part of biotransformation Flora action

  21. Oxidation reactions

  22. Benzene trasformation to leukemia-causing metabolite

  23. Flavin mono-oxygenases (FMO) catalyzed reactions Nitrogen compounds

  24. Phase II reactions • Glycoside conjugation - glucuronidation • Sulfate - sulfation • Glutathione (GSH) • Methylation • Acylation • Acetylation • Amino acid conjugation • Deacetylation • Phosphate conjugation

  25. Glucuronidation of phenol

  26. Sulfation of phenol and toluene

  27. GSH conjugation of acetaminophen

  28. Glutathione -glutamyl-cysteinyl-glycine Active site of a GST:

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