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1 Metabolism of xenobiotics Seminar No. 8. 2 Q. 2.

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Presentation on theme: "1 Metabolism of xenobiotics Seminar No. 8. 2 Q. 2."— Presentation transcript:

1 1 Metabolism of xenobiotics Seminar No. 8

2 2 Q. 2

3 3 1. Phase of biotransformation = mainly oxidations ReactionXenobiotic (example) Hydroxylation Sulfooxidation Dehydrogenation Reduction Hydrolysis aromatic hydrocarbons disulfides (R-S-R) alcohols nitro compounds (R-NO 2 ) esters Reactions occur mainly in ER, some in cytosol oxidations

4 4 Q. 3

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

6 6 Q R-H + O 2 +

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

8 8 Q. 6

9 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 10 insufficient effect of applied drug CYP inducer higher levels of drug unwanted effects overdosing CYP inhibitor no interference normal (expected) effect of remedy optimal therapy Influence of CYP inducers/inhibitors on the effect of drug (remedy)

11 11 Q. 7

12 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 13 Q. 8

14 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 15 Q. 9

16 16 A. 9 - II. Phase of biotransformation conjugation – synthetic character xenobiotic after I. phase reacts 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 17 A. 9 Overview of conjugation reactions ConjugationReagentGroup in xenobiotic Glucuronidation Sulfatation Methylation Acetylation By GSH By amino acid -OH, -COOH, -NH 2 -OH, -NH 2, -SH -OH, -NH 2 Ar-halogen -COOH

18 18 A. 9 Overview of conjugation reactions ConjugationReagentGroup in xenobiotic Glucuronidation Sulfatation Methylation Acetylation By GSH By amino acid UDP-glucuronate PAPS SAM acetyl-CoA glutathione glycine, taurine -OH, -COOH, -NH 2 -OH, -NH 2, -SH -OH, -NH 2 Ar-halogen -COOH GSH = glutathione, PAPS = phosphoadenosine phosphosulfate SAM = S-adenosyl methionine

19 19 PAPS is sulfatation reagent phospho adenosine phospho sulfate

20 20 The conjugation reactions of phenol glucuronide sulfate conjugation hydroxylation

21 21 Glutathione (GSH) R-X + GSH  R-SG + XH R-X halogen alkanes (arenes)

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

23 23 Biotransformation of toluene (sniffers) toluen benzylalkohol benzoová kys. toluenebenzyl alcoholbenzoic acid glycine hippuric acid (N-benzoylglycine)

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

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

26 26 m alcohol is calculated from volume and density m alc (g) = V alc (ml) × 0.8 (g/ml) volume of pure alcohol is calculated from volume fraction beer 3-6 % wine 6-12 % liquors % density

27 27 Metabolism of ethanol EnzymeSubcellular localization Alcohol dehydrogenase (AD)cytosol MEOSendoplasmic reticulum (ER) Catalase (hem)peroxisome Acetaldehyde dehydrogenasecytosol / mitochondria

28 28 Write AD and AcD reactions

29 29 acetaldehyd dehydrogenase (AcD) alcohol dehydrogenase (AD) acetaldehyde acetaldehyde hydrate acetic acid

30 30 Alternative pathway of alcohol biotransformation occurs in endoplasmic reticulum MEOS (microsomal ethanol oxidizing system, CYP2E1) CH 3 -CH 2 -OH + O 2 + NADPH+H +  CH 3 -CH=O + 2 H 2 O + NADP + activated at higher consumption of alcohol = higher blood level of alcohol (> 0.5 ‰) - chronic alcoholics  increased production of acetaldehyde

31 31 Q. 11

32 32 A. 11 Acetate is converted to acetyl-CoA A)in liver  synthesis of FA  TAG  VLDL B)in other tissues  CAC  CO 2 + energy

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

34 34 Q. 14 Metab. featureChangeExplanation NADH/NAD + Lactate/pyruvate CAC Glycolysis Gluconeogenesis

35 35 A. 14 Metab. featureChangeExplanation NADH/NAD +  NADH overproduction in AD/AcD reactions Lactate/pyruvate  NADH excess in cytosol in removed by LD reaction CAC  NADH is allost. inhibitor of ICDH and 2-OGDH Glycolysis  shortage of NAD + Gluconeogenesis  shortage of pyruvate + OA (= predominate lactate + malate)

36 36 Q. 15

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

38 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 39 Metabolic consequences of EtOH biotransformation Ethanol ADH MEOS acetaldehyde (hangover) part. soluble in membrane PL toxic effects on CNS adducts with proteins, NA, biog. amines acetate acetyl-CoA FA/TAG synth. liver steatosis ADH excess of NADH in cytosol reoxidation by pyruvate lactic acidosis hypoglycaemia various products

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

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

42 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 aromatic hydrocarbons (PAH) (pyrene, chrysene), main components of tar, attack and damage DNA, carcinogens other substances (N 2, CO 2, HCN, CH 4, terpenes, esters …)

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

44 44 Biochemical markers of liver diseases Liver function / conditionBiochemical marker Integrity of hepatocyte membrane Necrosis of liver Bile excretion Proteosynthesis disorder Detoxification functions Disorder of AA metabolism Disorder of glucose metabolism Disorder of lipid metabolism

45 45 Biochemical markers of liver diseases Liver function / conditionBiochemical marker Integrity of hepatocyte membraneALT, GMT, ALP Necrosis of liverAST, GMD Bile excretionALP, bilirubin, bile ac., urobilinogen Proteosynthesis disorder(pre)albumin, CHS, coag. factors Detoxification functionscaffeine test (p.o.) – metabolites in urine Disorder of AA metabolismurea, NH 4 + Disorder of glucose metabolismglucose Disorder of lipid metabolismTAG, HDL

46 46 Selected biochem. markers of liver damage (in serum) Serum analyteReference valuesChange ALT GMD GMT Bilirubin Ammonia Urobilinogens (urine) Pseudocholinesterase Urea Albumin 0,1 - 0,8  kat/l 0,1 - 0,7  kat/l  mol/l  mol/l up to 17  mol/l  kat/l mmol/l g/l  


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