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BIOTRANSFORMATION, Drug metabolism, detoxification Phase 2 conjugation.

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Presentation on theme: "BIOTRANSFORMATION, Drug metabolism, detoxification Phase 2 conjugation."— Presentation transcript:

1 BIOTRANSFORMATION, Drug metabolism, detoxification Phase 2 conjugation

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

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

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

5 Conjugation of salicylic acid

6 Enzyme and transporter in the ER membrane

7

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

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

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

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

12 Sulfate conjugation of coumarine

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

14 Biotransformation of acetaminophen

15 Ways of conjugation 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

16 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

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

18 androstane-dionestron P450 aromatase estron sulfo- transferase estron- sulphate estronEstron-sulphate szteroid szulfatáz 1. phase: ligand activation by oxygenation 2. phase: ligand inactivation by conjugation ligand reactivation by deconjugationl

19 Consequences of Biotransformation actíveinactive drogs, hormones (steroid, prostanoid) inactiveactive drogs (imipramine) hormones (testosterone) vitamin (D vitamin) chemical carcinogenesis (nitrosamines) biosynthesis acetonglucose Synthesis of leukotrienes inactivation, „detoxification” toxicity Role of induction in regulation

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

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

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

24 ethanol acetaldehid acetate CYP2E1 ADH alcohol dehydrogenase catalase K M :0,2-2 mM K M :8-10 mM aldehyde dehydrogenase cytosol SERperoxisome mitokondrium NAD NADH H2O2H2O2 H2OH2O NAD NADH NADPH NADP

25 ethanol acetaldehid acetate CYP2E1 ADH alcohol dehydrogenase catalase K M :0,2-2 mM K M :8-10 mM aldehyde dehydrogenase cytosol SERperoxisome mitokondrium NAD NADH H2O2H2O2 H2OH2O NAD NADH NADPH NADP ↓ Fatty liver → stimulated metabolism of other drugs → acetaldehyde toxicity autoimmune pathology


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