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Metabolism Biotransformation Supplementary readings: Casarett and Doull,Chapter 6 Timbrell, Chapters 4 and 5 Non-polar Hydrophobic (lipophilic) Solubility in water XENOBIOTIC Phase I Metabolism Oxidation Can accumulate in tissues INTERMEDIATE METABOLITE Phase II Metabolism Conjugation May be reactive/toxic WATER-SOLUBLE METABOLITE Lipophobic Hydrophilic (Polar) ELIMINATION What is a xenobiotic ? 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 Overview of oxidations, reductions, hydrolyses • Oxidation –Loss of electrons M M+ + e–Gain of oxygen R + O RO Oxidation reactions OH Benzene Phenol Hydroxylation Epoxidation HC O HC CH2 Styrene CH2 Styrene oxide H O H Benzo[a]pyrene Benzo[a]pyrene 7,8-oxide Overview of oxidations, reductions, hydrolyses • Reduction – Gain of electrons M+ + e- M – Loss of oxygen RO R + O – Gain of hydrogen R + H RH Reduction • Nitro to amino group NO2 NO HNOH • Chromium VI to Chromium III Cr6+ + 3 e- Cr3+ H NH Hydrolysis • Addition of water – Cleavage of R-O or R-N bond accompanied by addition of H2O R’-O-R + H2O R’-N-R + H2O H R’-O-H + R-OH R’-N-H + R-OH H Principal Phase I enzymes • • • • • • • Cytochrome P450 Flavin monooxygenase Monoamine oxidase Esterases Amidases Hydrolases Reductases, dehydrogenases, oxidases 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 Overall reaction R-H + O2 + NADPH + H+ R-OH + H2O + NADP+ 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 Esterases • Hydrolyse esters to carboxylic acid and alcohol functional groups • Non-specific esterases in plasma, more substrate-specific forms in liver cytosol O O C H3C O H2 C Ethyl acetate + H2O CH3 H2 C C H3C OH Acetic acid + HO CH3 Ethanol Amidases • Hydrolyse amides to carboxylic acids and amines (or ammonia) • Found in plasma and in liver cytosol O H R C N H O + H2O R H + C OH H N H Hydrolases • Hydrolyse ethers H2 C H3C H2 C O Diethyl ether H2 C + H2O CH3 H3C H2 C OH Ethanol + HO Ethanol CH3 Reductases, dehydrogenases, oxidases • In cytosol, endoplasmic reticulum, mitochondria Alcohol dehydrogenase H H3C C Aldehyde dehydrogenase NAD+ NADH + H+ OH H3C O NAD+ NADH + H+ C H3C H O C OH H Ethanol Acetaldehyde Acetic acid 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