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BIOTRANSFORMATION, Drug metabolism, detoxification

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1 BIOTRANSFORMATION, Drug metabolism, detoxification
Phase 2 conjugation

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

3 phase I phase II nucleophilic metabolites glucuronides sulfate esters X electrophilic metabolites GSH conjugates 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 Hyperbilirubinemias unconjugated hyperbilirubinemias Gilbert disease
Low UGT activity treatment: inducer phenobarbital benign, 5-6 % of population Crigler Najjar syndr. bilirubin encephalopathia, fatal

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

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 Overlapping substrate, inducer specificity
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
synthesis conjugation Bile acid synthesis conjugation steroid hormones „Maturation” of D vitamin synthesis conjugation prostaglandin, leukotriene Synthesis of cholesterin synthesis conjugation chatecholamines „synthesis” conjugation bilirubin Synthesis of (poly)unsaturated fatty acids Oxidation of aceton

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

19 Consequences of Biotransformation
actíve inactive drogs, hormones (steroid, prostanoid) 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

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

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

22

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

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

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

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