Biotransformation Xenobiotic metabolism “Essentials of...

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Transcript of Biotransformation Xenobiotic metabolism “Essentials of...

  • BiotransformationXenobiotic metabolismEssentials of Toxicologyby Klaassen Curtis D. and Watkins John B Chapter 6

  • BiotransformationWater soluble xenobiotics are easier to eliminate ( t1/2)Urine, feces but not exhalationIf within barrier, no outMultiple enzymes (families)Constitutively expressedInducibleBroad specificityPolymorphic (allelic variants)Stereo-isomer specificity: 6-OH in hormones:

  • BiotransformationPotentially toxic xenobioticInactive metaboliteRelatively harmlessReactive intermediateDetoxificationMetabolic activation

  • Converting lipophilic to water soluble compoundsXenobioticReactive intermediateConjugatePhase I - ActivationPhase II - ConjugationExcretionLipophilic(non-polar)Water soluble(polar)

  • Phase Iintroduction of functional group

    hydrophilicity increases slightlymay inactivate or activate original compoundmajor player is CYP or mixed function oxygenase (MFO) system in conjunction with NAD(P)Hlocation of reactions is smooth endoplasmic reticulum

  • 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

  • Phase I reactions

    OxidationHydroxylation (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

    ReductionHydrogen addition (unsaturated bonds to saturated)Donor molecules include GSH, FAD, NAD(P)HOxygen removal

    HydrolysisSplitting of C-N-C (amide) and C-O-C (ester) bondsSee also Chapter 6 of Casarett and Doulls ToxicologyTable 6.1epoxide

  • BiotransformationActivation 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 reactiveProtection is provided by endogenous antioxidant substances, e.g. GSHvitamins C and Eantioxidant enzymes, SOD, GPX, CAT in coupled reactionsAntioxidant molecules are oxidized in the process but have the capacity to regenerate the reduced form from the oxidized - NAD(P)H is a key playerSee also p. 40-44 of Casarett and Doulls Toxicology

  • Cytochrome P450 (CYP) Mixed Function Oxidases (MFO)Located in many tissues but highly in liver ERHuman: 16 gene familiesCYP 1,2,3 perform drug metabolism>48 genes sequencedKey forms: CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4Highly inducibleAlcoholCYP2E1Dioxin/PCBs CYP1ABarbituratesCYP2BCYP genes have multiple alleles (2D6 has 53, and 2E1 has 13)

  • The CYP-450 reaction cycleAEDCFG(B)

  • Oxidation of vinyl chloride to an epoxide

  • Metabolic enzymesMicrosomal:CYP450 monooxygenasesFlavin monooxygenaseNon-microsomalAlcohol dehydrogenaseAldehyde dehydrogenaseMonoamine and diamine oxidasesBothEsterases and AmidasesProstaglandin synthase Peroxidases

  • Cooxidation of acetaminophenby prostaglandin endoperoxide synthetaseCompare to fig. 6-2

  • Hydrolysis of esters and amides

  • Hydrolysis of organophosphates

  • Hydrolysis of epoxides

  • Stereoselectivehydroxylation

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

  • Azo- and nitro- reduction

  • Flora actionIntestinal flora as part of biotransformation

  • Oxidation reactions

  • Benzene trasformation to leukemia-causing metabolite

  • Flavin mono-oxygenases(FMO) catalyzed reactions

    Nitrogen compounds

  • Phase II reactionsGlycoside conjugation - glucuronidationSulfate - sulfationGlutathione (GSH)MethylationAcylationAcetylationAmino acid conjugationDeacetylationPhosphate conjugation

  • Glucuronidation of phenol

  • Sulfation of phenol and toluene

  • GSH conjugation of acetaminophen

  • Glutathione-glutamyl-cysteinyl-glycineActive site of a GST: