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Metabolism of Xenobiotics

ENVR/TOXC 442 Fall 2009. Metabolism of Xenobiotics. II. Phase 1 Metabolism Sept 1, 2009 L.M. Ball Rosenau 158 lmball@unc.edu. Phase I reactions. Chemical modification of xenobiotics Introduces or uncovers polar functional groups that provide sites for Phase II metabolism

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Metabolism of Xenobiotics

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  1. ENVR/TOXC 442 Fall 2009 Metabolism of Xenobiotics II. Phase 1 Metabolism Sept 1, 2009 L.M. Ball Rosenau 158 lmball@unc.edu

  2. Phase I reactions • Chemical modification of xenobiotics • Introduces or uncovers polar functional groups that provide sites for Phase II metabolism • Major classes of reaction: • Oxidation • Reduction • Hydrolysis

  3. Overview of oxidations, reductions, hydrolyses • Oxidation • Loss of electrons M M+ + e- • Gain of oxygen R + O RO

  4. Oxidation reactions Hydroxylation

  5. Epoxidation

  6. Overview of oxidations, reductions, hydrolyses • Reduction • Gain of electrons M+ + e- M • Loss of oxygen RO R + O • Gain of hydrogen R + H RH

  7. Reduction • Nitro to amino group • Chromium VI to Chromium III Cr6+ + 3 e- Cr3+

  8. Hydrolysis • Addition of water • Cleavage of R-O or R-N bond accompanied by addition of H2O R’-O-R + H2O R’-O-H + R-OH R’-N-R + H2O R’-N-H + R-OH H H

  9. Principal Phase I enzymes • Cytochrome P450 • Flavin monooxygenase • Monoamine oxidase • Esterases • Amidases • Hydrolases • Reductases, dehydrogenases, oxidases

  10. Flavin monooxygenase • Flavoprotein • Mixed-function amine oxidase • Located in smooth endoplasmic reticulum, in human, pig, rabbit liver, guinea-pig lung, human kidney • Uses NADPH as a source of reducing equivalents • Not inducible

  11. Overall reaction R-H + O2 + NADPH + H+ R-OH + H2O + NADP+

  12. Monoamine oxidase • Metabolizes endogenous monoamine neurotransmitters • Uses NADPH as a source of reducing equivalents • Found in the endoplasmic reticulum and in mitochondria, of nerve endings and liver

  13. Esterases • Hydrolyse esters to carboxylic acid and alcohol functional groups • Non-specific esterases in plasma, more substrate-specific forms in liver cytosol

  14. Amidases • Hydrolyse amides to carboxylic acids and amines (or ammonia) • Found in plasma and in liver cytosol

  15. Hydrolases • Hydrolyse ethers

  16. Reductases, dehydrogenases, oxidases • In cytosol, endoplasmic reticulum, mitochondria

  17. Cytochrome P450 • Heme protein • Terminal oxidase of the mixed-function oxidase (MFO) electron-transfer system • Located in the smooth endoplasmic reticulum of all major organs and tissues • Uses NADPH as a source of reducing equivalents • Inducible

  18. Cytochrome P450 • Heme protein • Terminal oxidase of the mixed-function oxidase (MFO) electron-transfer system • Located in the smooth endoplasmic reticulum of all major organs and tissues • Uses NADPH as a source of reducing equivalents • Inducible

  19. Overall reaction R-H + O2 + NADPH + H+ R-OH + H2O + NADP+

  20. Ferric protoporphyrin IX

  21. Protoporphyrin IX

  22. NADH NADPH Catalytic cycle of cytochrome P450 ROH H+ Fe3+ + RH HO22- Fe3+-RH H2O Fe3+-RH + e- from NADPH-cytC reductase H2O2 H+ HO2- [Fe2+-RH] Fe2+-RH O2 [Fe2+-RH] +O2 O2-. H+ + e-

  23. P450 and reductase in endoplasmic reticulum

  24. The P450 gene superfamily • Format of nomenclature: CYPFamily/Subfamily/Gene • Family = 1, 2, …150 and counting • ~40% aa similarity • Subfamily = A, B,…H… • 55-65% aa similarity • Gene = 1, 2..10 or above • >97% aa similarity (allelic variants) • Families grouped in Clans

  25. Sub- Family family Gene CYP1 A 1 BaP hydroxylation, O-deethyl’n (PAC-inducible 2 N-hydroxylation, O-deethylation CYP2 A 1 Testosterone 7-hydroxylation 2 Testosterone 15-hydroxylation B 1 Aliphatic hydroxylation 2 O-deethylation C 1 - 20+ 2C19, mephenytoin hydroxylase

  26. Demethylation Deethylation

  27. Sub- Family family Gene CYP1 A 1 BaP hydroxylation, O-deethyl’n (PAC-inducible 2 N-hydroxylation, O-deethylation CYP2 A 1 Testosterone 7-hydroxylation 2 Testosterone 15-hydroxylation B 1 Aliphatic hydroxylation 2 O-deethylation C 1 - 20+ 2C19, mephenytoin hydroxylase

  28. Sub- Family family Gene CYP2 D 1 - 6+ 2D6, debrisoquine hydroxylase E 1 C- and N-hydroxylation small molecules 2 F 1 CYP3 A 1-4 3A4 CYP4 A 1 Lauric acid - and -1 hydroxylation

  29. Sub- Family family Gene CYP11 (mito) A 1 Steroid 11-hydroxylation CYP17 A 1 Steroid 17-hydroxylation CYP21 A 1 Steroid 21-hydroxylation CYP51 A 1 (Plants, yeast) CYP52-66 A Yeasts, fungi CYP71-99, 701 Plants CYP101 A 1 Pseudomonas putida P450cam CYP102-132 A Bacteria

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

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