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Metabolism of xenobiotics

Metabolism of xenobiotics. Seminar No. 8. Q. 2. 1 . Phase of biotransforma tion = mainly oxidations. oxidations. Rea ctions occur mainly in ER, some in cytosol. Q. 3. A. 3. The s yst em of cytochrom e P-450 is composed from:

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Metabolism of xenobiotics

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  1. Metabolism of xenobiotics Seminar No. 8

  2. Q. 2

  3. 1. Phase of biotransformation = mainly oxidations oxidations Reactions occurmainly in ER, some in cytosol

  4. Q. 3

  5. A. 3 • The systemof cytochrome P-450 is composed from: • two enzymes (cytochrome reductase, cytochrome P-450) • three cofactors (NADPH, FAD, hem) • in ER, mitochondria

  6. Q. 4 + 5 R-H + O2 +

  7. A. 4 + 5 Hydroxylation R-H + O2 + NADPH + H+ R-OH + H2O + NADP+ • substrate R-H reacts with O2 • monooxygenase = from O2one atom Ois inserted into substrate (between carbon and hydrogen atom) • the second O atom makes H2O,2H come from NADPH+H+ • dioxygen is reduced to -OH group and water

  8. Q. 6

  9. A. 6 • Inducer may act on several levels: • Inducer in complex with intracellular receptor enters nucleus and binds to DNA  enhances the transcription of mRNA • Decreases the degradation of mRNA and/or CYP • Influences the poststranscription modifications of mRNA • May cause the hypertrophy of ER

  10. Influence of CYP inducers/inhibitors on the effect of drug (remedy) CYP inhibitor CYP inducer no interference higher levels of drug unwanted effects overdosing normal (expected) effect of remedy optimal therapy insufficient effect of applied drug

  11. Q. 7

  12. A. 7 • if concurrently aplied inducer + medicament metabolized with the same CYP isoform  remedy is catabolized faster  is less effective • diclofenac is less effective

  13. Q. 8

  14. A. 8 • if concurrently aplied inhibitor + medicament metabolized with the same CYP isoform  remedy is catabolized more slowly  higher concentration in blood  adverse effects (overdosing)

  15. Q. 9

  16. A. 9 - II. Phase of biotransformation • conjugation – synthetic character • xenobioticafter I. phasereacts with conjugation reagent • the product is more polar – easily excreated by urine • conjugation reactions are endergonnic – they require energy • reagent or xenobiotic has to be activated

  17. A. 9 Overview of conjugation reactions

  18. A. 9 Overview of conjugation reactions GSH = glutathione, PAPS = phosphoadenosine phosphosulfate SAM = S-adenosyl methionine

  19. PAPS is sulfatation reagentphospho adenosine phospho sulfate

  20. The conjugation reactions ofphenol hydroxylation conjugation glucuronide sulfate

  21. Glutathione (GSH) R-X + GSH  R-SG + XH R-Xhalogenalkanes (arenes)

  22. Conjugation with aminoacids • glycine, taurine • xenobiotics with -COOH groups • the products of conjugation are amides • endogenous substrates – bile acids

  23. Biotransformation of toluene (sniffers) toluene benzyl alcohol benzoic acid toluen benzylalkohol benzoová kys. glycine hippuric acid (N-benzoylglycine) benzoic acid

  24. Ethanol How can you calculate the level of alcohol in blood?

  25. Per milles of alcohol in blood ‰ = per mille = 1/1000 alcohol in blood (‰) = 0.67 (males) 0.55 (females) How do you calculate malcohol ?

  26. malcohol is calculated from volume and density malc (g) = Valc (ml) × 0.8 (g/ml) density volume of pure alcohol is calculated from volume fraction beer 3-6 % wine 6-12 % liquors 40-50 %

  27. Metabolism of ethanol

  28. Write AD and AcD reactions

  29. alcohol dehydrogenase (AD) acetaldehyde acetaldehyddehydrogenase (AcD) acetic acid acetaldehyde hydrate

  30. Alternative pathway ofalcohol biotransformation occurs in endoplasmic reticulum MEOS (microsomalethanol oxidizingsystem, CYP2E1) CH3-CH2-OH + O2 + NADPH+H+ CH3-CH=O + 2 H2O + NADP+ activated at higher consumption of alcohol = higher blood level of alcohol (>0.5 ‰) - chronic alcoholics  increased production of acetaldehyde

  31. Q. 11

  32. A. 11 Acetate is converted to acetyl-CoA • in liver  synthesis of FA  TAG  VLDL • in other tissues  CAC  CO2 + energy

  33. A. 13 Mr = 46 density = 0,8 g/ml  0,06 ‰

  34. Q. 14

  35. A. 14

  36. Q. 15

  37. A. 15 • Decreased gluconeogenesis due to lack of oxaloacetate – hypoglycemia especially after fasting ingestion of alcohol (+ usually poor dietary habits in chronic alcoholics) • Excess of lactate in cytosol  increased lactate in blood plasma  lactic acidosis • Excess of acetyl-CoA  synthesis of FA +TAG  liver steatosis

  38. ! Consider that ethanol is soluble both in polar water and non-polar lipids easily penetrates cell membranes goes through hydrophilic protein channels or pores as well as hydrophobic phospholipid bilayer

  39. Metabolic consequences of EtOH biotransformation Ethanol ADH ADH MEOS excess of NADH in cytosol part.soluble in membrane PL acetaldehyde (hangover) reoxidation by pyruvate acetate adducts with proteins, NA, biog. amines lactic acidosis hypoglycaemia toxic effects on CNS acetyl-CoA various products FA/TAG synth.liver steatosis

  40. Acetaldehyde reacts with biogenic amines to tetrahydroisoquinoline derivatives - H2O dopamine salsolinol 6,7-dihydroxy-1-methyl-1,2,3,4-tetrahydroisoquinoline acetaldehyde Neurotoxin ?

  41. Nicotine- the main alkaloid of tobacco On cigarette box: Nicotine: 0.9 mg/cig. Tar: 11 mg/cig. 3-(1-methylpyrrolidin-2-yl)pyridine

  42. Cigarette smoke contains a number of different compounds • free nicotine – binds to nicotine receptors in brain and other tissues • CO –binds to hemoglobin carbonylhemoglobin • nitrogen oxides – can generate free radicals • polycyclic aromatichydrocarbons(PAH) (pyrene, chrysene), main components of tar, attack and damage DNA, carcinogens • other substances (N2, CO2, HCN, CH4, terpenes, esters …)

  43. Example Biotransformation of nicotine nikotin nicotine 5-hydroxynikotin 5-hydroxynicotine nornikotin nornicotine nikotin-N-glukuronát nicotine-N-glucuronide cotinine-N-glucuronide kotinin-N-glukuronát kotinin cotinine

  44. Biochemical markers of liver diseases

  45. Biochemical markers of liver diseases

  46. Selectedbiochem. markers of liver damage (in serum)

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