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BIOTRANSFORMATION, Drug metabolism, detoxification

BIOTRANSFORMATION, Drug metabolism, detoxification. Phase 2 conjugation. GSH conjugation. acetylation. sulfation. Glucuronidation (80%) Conjugation with amino acids glycosylation. 12%. su. phase I. phase II. nucleophilic metabolites. glucuronides sulfate esters. X. electrophilic

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BIOTRANSFORMATION, Drug metabolism, detoxification

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  1. BIOTRANSFORMATION,Drug metabolism,detoxification Phase 2 conjugation

  2. GSH conjugation acetylation sulfation Glucuronidation (80%) Conjugation with amino acids glycosylation 12% su

  3. phase I phase II nucleophilic metabolites glucuronides sulfate esters X electrophilic metabolites GSH conjugates DNA, RNA, protein

  4. Glucuronidation – UDP glucuronate – UDP-glucuronosyl transferases Ways of conjugation

  5. Conjugation of salicylic acid

  6. Enzyme and transporter in the ER membrane

  7. Role of UGT-s in activation of drugs morphin steroids bile acids retinoids policyclic aromatic hydrocarbons heterocyclic aromatic amines

  8. Hyperbilirubinemias unconjugated hyperbilirubinemias Gilbert disease Low UGT activity benign, 5-6 % of population treatment: inducer phenobarbital Crigler Najjar syndr. bilirubin encephalopathia, fatal

  9. Hyperbilirubinemias Conjugated hyperbilirubinemias Transport of conjugates is disturbed Expression of MRP2 is depressed Dubin Johnson syndr. Rotor syndr.

  10. Glucuronidation – UDP glucuronate – UDP-glucuronosyl transferases Sulfation – PAPS- sulfotransferases Ways of conjugation

  11. Sulfate conjugation of coumarine

  12. Glucuronidation – UDP glucuronate – UDP-glucuronosyl transferases Sulfation – PAPS– sulfotransferases GSH conjugation - GSH, acetyl CoA - GSH transferases Ways of conjugation

  13. Biotransformation of acetaminophen

  14. Glucuronidation – UDP glucuronate – UDP-glucuronosyl transferases Sulfation – PAPS– sulfotransferases GSH conjugation - GSH, acetyl CoA - GSH transferases Acetylation – acetyl CoA Amino acid conjugation – amino acids Methylation - SAM Ways of conjugation

  15. Phisiological substrates: steroids Eicosanoids Fatty acids lipids hydroperoxides retinoids aceton (inducers ?) Xenogenic substrates (inducers ?) Ah receptor: aromatic hydrocarbon receptor intracellular receptors: CAR, PXR, VDR, FXR, RXR, HNF4 Overlapping substrate, inducer specificity

  16. Biotranszformation reactions in intermediery metabolism „synthesis” synthesis synthesis synthesis synthesis Oxidation of aceton Bile acid bilirubin steroid hormones Synthesis of cholesterin Synthesis of (poly)unsaturated fatty acids prostaglandin, leukotriene „Maturation” of D vitamin chatecholamines conjugation conjugation conjugation conjugation conjugation

  17. sulfo- transferase estron estron- sulphate Estron-sulphate estron P450 aromatase androstane-dion estron ligand reactivation by deconjugationl 2. phase: ligand inactivation by conjugation szteroid szulfatáz 1. phase: ligand activation by oxygenation

  18. Consequences of Biotransformation inactive active drogs (imipramine) hormones (testosterone) vitamin (D vitamin) chemical carcinogenesis (nitrosamines) biosynthesis aceton glucose Synthesis of leukotrienes inactivation, „detoxification” toxicity Role of induction in regulation actíve inactive drogs, hormones (steroid, prostanoid)

  19. Toxicity 1. dosis 5-10 different drugs/patient Logarythmic increase of adverse drug effects with the number of drugs nutrition Intracellular cofactors NADPH UDPGA PAPSGSH vitamines alkoholism

  20. Toxicity 2. Biotransformation enzymes in livers of newborns Treatment of mothers at delivery chloramphenicol morfin gray baby szindróma Hyperbilirubinaemia of newborns low UGT Aspecific enzyme systems Competition of substrates Addition of various drugs Changes in induction e.g. Coumarine

  21. Toxicity 3. diabetes mellitus Liver diseases Genetic differences Treatment of populations INH (isoniazid) N acetyl transferase Pathological circumstances ageing Gender differences

  22. NAD NAD NADH NADH H2O2 H2O ethanol cytosol SER peroxisome NADPH ADH alcohol dehydrogenase CYP2E1 catalase NADP KM:8-10 mM KM:0,2-2 mM acetaldehid mitokondrium aldehyde dehydrogenase acetate

  23. NAD NAD NADH NADH H2O2 H2O → stimulated metabolism of other drugs ethanol cytosol SER peroxisome NADPH ADH alcohol dehydrogenase CYP2E1 catalase NADP KM:8-10 mM KM:0,2-2 mM acetaldehid mitokondrium ↓ Fatty liver aldehyde dehydrogenase acetate → acetaldehyde toxicity autoimmune pathology

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