Detoxification which Challenge Drug Candidates and Drugs

B Oesch-Bartlomowicz and F Oesch, University of Mainz, Mainz, Germany © 2007 Elsevier Ltd. All Rights Reserved.

5.08.1 Introduction 193

5.08.1.1 Scope of Drug Metabolism toward Xenobiotic Detoxification 193

5.08.1.2 Toxification versus Detoxification 194

5.08.2 The Phase Concept of Drug Metabolism and Its Importance for Toxification versus Detoxification 194

5.08.3 Toxicologically Relevant Properties of Individual Drug-Metabolizing Enzymes 195

5.08.3.1 Phase I Enzymes 195

5.08.3.1.1 Oxidoreductases 195

5.08.3.1.2 Hydrolases 203

5.08.3.2 Phase II Enzymes: Transferases 205

5.08.3.2.1 Glutathione S-transferases (E.C. 2.5.1.18) 205

5.08.3.2.2 UDP-glucuronosyltransferases (E.C. 2.4.1.17) 207

5.08.3.2.4 Acetyltransferases (included in E.C. 2.3.1) 208

5.08.4 Factors Influencing Drug Metabolism and Consequent Drug

Toxicities 209

5.08.4.1 Modulation of Expression and Activity of Drug-Metabolizing Enzymes and Consequences for Drug Toxicities 209

5.08.4.2 Significance of Interindividual Differences for Drug Metabolism-Associated Toxicities 209

5.08.4.3 Species Differences 210

5.08.4.4 Consequences of Stereoselectivity in Drug Metabolism for Metabolic Toxification 211

5.08.5 Conclusion 211 References 211

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