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Methylation

Methylation. Methyltransferases Target: Hydroxyl groups, amines, thiols Substrates mainly endogenous: Catechols, noradrenalin, histamine Conjugating moiety: Methyl group Co-factor: S-adenosylmethionine. S-adenosylmethionine. Methylation Reaction. Substrate: Catechol. Enzyme:

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Methylation

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  1. Methylation • Methyltransferases • Target: Hydroxyl groups, amines, thiols • Substrates mainly endogenous: Catechols, noradrenalin, histamine • Conjugating moiety: Methyl group • Co-factor: S-adenosylmethionine

  2. S-adenosylmethionine

  3. MethylationReaction Substrate: Catechol Enzyme: Catechol-O-methyltransferase (COMT)

  4. Acetylation • N-acetyltransferases (NAT) • Target: Aromatic amines, sulfonamides • Conjugating moiety: Acetyl group • Co-factor: Acetyl-CoA • Few forms: NAT1, NAT2. NAT3: mice • Genetic polymorphisms: “slow and fast acetylators”

  5. AcetylationReaction 2-Naphthylamine 2-Aminonaphthalene 2-Acetylaminonaphthalene 2-Acetamidonaphthalene

  6. Non-polar (lipophilic) Hydrophobic XENOBIOTIC Phase I Metabolism Oxidation Can accumulate in tissues Solubility in lipids INTERMEDIATE METABOLITE Phase II Metabolism Conjugation Solubility in water May be reactive/toxic WATER-SOLUBLE METABOLITE Lipophobic Hydrophilic (Polar) Phase III (?) Transport into bile, urine ELIMINATION

  7. Transporters (Phase III)

  8. Lethal Synthesis Methylation of Mercury: Methylmercury CH3-Hg+ Dimethylmercury CH3-Hg-CH3 http://www.chm.bris.ac.uk/motm/dimethylmercury/dmmh.htm Glutathione conjugation of 1,2-dihaloalkanes GSH + Br-CH2-CH2-Br GS-CH2-CH2-Br Ethylene dibromide CH2 GS+ CH2 Episulfonium ion

  9. Major reactive species Electrophiles Epoxides (Epoxide hydrolase Glutathione S-transferase) Carbonium ions Arylnitrenium ions Episulfonium ions Reactive Oxygen Species

  10. Reactive Oxygen Species (ROS) • Peroxides • Hydrogen peroxide HOOH • Peroxynitrite OONO- • Lipid hydroperoxide LOOH • Free radicals • Superoxide anion O2•- • Hydroxyl radical HO• • Nitric oxide NO•

  11. Non-enzymic reaction with anti-oxidants • Ascorbic acid (Vitamin C) • alpha-Tocopherol (Vitamin E) • Glutathione

  12. Superoxide dismutase Converts superoxide anions to hydrogen peroxide O2•- +O2•- + 2H+ O2 + H2O2

  13. Peroxidases Couple reduction of hydrogen peroxide (or other peroxide) to oxidation of another substrate (co-oxidation) ROOH + R’H ROH + R’OH

  14. Peroxidases • Catalase • Prostaglandin synthetase • Myeloperoxidase • Lactoperoxidase • Glutathione peroxidase

  15. Glutathione peroxidase GSH + GSH GSSG HOOH HOH + HOH

  16. Metabolic Activation/Metabolic Detoxication • “Metabolism is a double-edged sword” • Generation of (re)active intermediates • Detoxication of (re)active intermediates Pharmacologically active Chemically reactive

  17. The main purpose of this pilot study is to identify an optimal concentration of diesel exhaust which can be used to study the risks of cardiac changes in healthy older subjects. Results from this study may increase the understanding of how gaseous and particulate air pollutants (which causes the haze seen in some polluted cities) may adversely affect the functioning of the human cardiovascular and respiratory systems. This pilot research will study the responses to diesel exhaust in healthy older subjects with the specific GSTM1 and GSTP1 genotype. For more information, please visit our web site at www.epastudies.org or call Westat EPA Recruiting at 966-0604. Approved June 08, 2007 by the Committee on the Protection of the Rights of Human Subjects Biomedical Institutional Review Board. IRB # 07-0190 (GCRC #2579). This email is sponsored by: U.S. Environmental Protection Agency Human Studies Division located on the UNC-Chapel Hill campus. This email is sponsored by: U.S. Environmental Protection Agency Human Studies Division This email is sponsored by: CEMALB

  18. Another example Organophosphate Insecticides: • Parathion • Malathion

  19. Parathion

  20. Malathion

  21. Hydrolysis enzymes • Serum cholinesterase BChE • Serum paraoxonase PON1 • Polymorphisms in PON1 – differential sensitivity Heart disease Atherosclerosis Gulf War Syndrome

  22. Effect is the outcome of interaction between susceptibility and exposure

  23. Target organs • What makes a particular organ a target for toxicity / infection ? • What makes a particular organ or species susceptible ?

  24. Portal of entry to Blood to Target Organ Location, location, location e.g. Intestine to hepatic portal vein to liver to vena cava to heart to lungs back to heart to aorta to rest of body

  25. Lungs Vena cava Aorta Liver Hepatic portal vein Intestines

  26. Gut flora • Reductions • nitro to amine • Hydrolyses • Cleavage of glucuronides

  27. Reaction Glucuronidation

  28. C O O H O H o o H O O H O H Reaction De-glucuronidation b-glucuronidase Aglycone Conjugate

  29. Enterohepatic recirculation(EHC) Liver Intestine

  30. Presence/absence of receptors • Estrogen receptors, Ah receptor • Presence/absence of transporters/carriers • Resistance to chemotherapy • Presence of repair mechanisms • DNA repair • Balance of metabolic activation/detoxication

  31. Factors affecting xenobiotic metabolism • Intrinsic • Species, strain, gender, age, genotype • Physiological status • Temperature, time of day, season, • Health status, disease, stress • Diet, nutritional status • Related to exposure • Route of administration, frequency and size of dose, co-exposures (induction, inhibition)

  32. Genetic polymorphisms • CYP2D6 Debrisoquine hydroxylation (poor and extensive metabolizers) • Acetylation (fast and slow acetylators) • GSTM null genotype

  33. Changes in P450 levels with ageRats M: 2C6, 2C11, 3A2 F: 2A1, 2C6, 2C12 2A1 2C6 3A2

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