Presentation is loading. Please wait.

Presentation is loading. Please wait.

BIOTRANSFORMATION, Drug metabolism, detoxification

Published byAlexus Loar Modified over 10 years ago

Similar presentations

Presentation on theme: "BIOTRANSFORMATION, Drug metabolism, detoxification"— Presentation transcript:

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

Download ppt "BIOTRANSFORMATION, Drug metabolism, detoxification"

Similar presentations

Drug Metabolism Most metabolic products are less pharmacologically active Important exceptions: Where the metabolite is more active (Prodrugs, e.g. Erythromycin-succinate.

Drug Metabolism Most metabolic products are less pharmacologically active Important exceptions: Where the metabolite is more active (Prodrugs, e.g. Erythromycin-succinate.
Drug/xenobiotic metabolism and pharmacogenetics George Howell III, Ph.D.

Drug/xenobiotic metabolism and pharmacogenetics George Howell III, Ph.D.
1 PHM142 UNIT 9A Mitochondrial Diseases and the Brain Instructions and materials: Read ONLY sections in paper by Chaturvedi and Beal, 2013 (included in.

1 PHM142 UNIT 9A Mitochondrial Diseases and the Brain Instructions and materials: Read ONLY sections in paper by Chaturvedi and Beal, 2013 (included in.
PHASE II: Conjugation Reaction R O S E L Y N A. N A R A N J O.

PHASE II: Conjugation Reaction R O S E L Y N A. N A R A N J O.
Drug metabolism Refers to enzyme-mediated biotransformations (detoxication) that alter the pharmacological activity of both endogenous and exogenous compounds.

Drug metabolism Refers to enzyme-mediated biotransformations (detoxication) that alter the pharmacological activity of both endogenous and exogenous compounds.
DISTRIBUTION The body is a container in which a drug is distributed by blood (different flow to different organs) - but the body is not homogeneous. Factors.

DISTRIBUTION The body is a container in which a drug is distributed by blood (different flow to different organs) - but the body is not homogeneous. Factors.
3. Metabolism Many xenobiotics undergo chemical transformation (biotransformation; metabolism) when introduced into biologic systems like the human body.

3. Metabolism Many xenobiotics undergo chemical transformation (biotransformation; metabolism) when introduced into biologic systems like the human body.
Drug Metabolism 1 n Clinical Biochemistry 2003 n Nigel Atkinson n

Drug Metabolism 1 n Clinical Biochemistry 2003 n Nigel Atkinson n
Phase-II Drug Metabolism

Phase-II Drug Metabolism
Ecotoxicology Biotransformation. RÉSUMÉ UPTAKE IN ORGANISM DEPENDS ON: Concentration Route of uptake Molecular size Lipophilicity (polarization, ionization)

Ecotoxicology Biotransformation. RÉSUMÉ UPTAKE IN ORGANISM DEPENDS ON: Concentration Route of uptake Molecular size Lipophilicity (polarization, ionization)
Drug Detoxification Dr. Howaida Supervised by : Prepared by:

Drug Detoxification Dr. Howaida Supervised by : Prepared by:
Metabolism of Xenobiotics

Metabolism of Xenobiotics
Metabolism Basics Title - metabolism basics.

Metabolism Basics Title - metabolism basics.
Biotransformation Xenobiotic metabolism “Essentials of Toxicology” by Klaassen Curtis D. and Watkins John B Chapter 6.

Biotransformation Xenobiotic metabolism “Essentials of Toxicology” by Klaassen Curtis D. and Watkins John B Chapter 6.
Metabolism - Biotransformation Supplementary readings: Casarett and Doull,Chapter 6 Timbrell, Chapters 4 and 5.

Metabolism - Biotransformation Supplementary readings: Casarett and Doull,Chapter 6 Timbrell, Chapters 4 and 5.
Prepared by Prof .Abdulkader.H.El Daibani

Prepared by Prof .Abdulkader.H.El Daibani
Chapter 13. Drug Metabolism

Chapter 13. Drug Metabolism
XENOBIOTICS The Metabolism of Reported by Group III, 1-C2.

XENOBIOTICS The Metabolism of Reported by Group III, 1-C2.
Biochemical functions of liver

Biochemical functions of liver
Pentose phosphate pathway A.Functions 1. NADPH for reductive biosyntheses. 2. ribose-5-phosphate for nucleic acid biosynthesis. 3. a route for the conversion.

Pentose phosphate pathway A.Functions 1. NADPH for reductive biosyntheses. 2. ribose-5-phosphate for nucleic acid biosynthesis. 3. a route for the conversion.

Similar presentations

Ads by Google