Conjugation-Dependent Carcinogenicity and Toxicity of Foreign Compounds (eBook)

Front Cover 1
Conjugation-Dependent Carcinogenicity and Toxicity of Foreign Compounds 4
Copyright Page 5
Contents 6
Contributors 16
Chapter 1. Historical Perspectives on Conjugation-Dependent Bioactivation of Foreign Compounds 18
I. Metabolic Research Leading to Conjugation-Dependent Bioactivation of 4-Dimethylaminoazobenzene and 2-Acetylaminofluorene 18
II. Important Observations Leading to Bioactivation of Foreign Compounds via Glutathione Conjugation, Methylation, and Epoxide Formation and Hydrolysis 25
References 29
Part I: Glutathione-Dependent Toxicity 34
Chapter 1. Enzymology of Microsomal Glutathione S-Transferase 36
I. Introduction 36
II. Catalysis 39
III. Activation 43
IV. The Activated Enzyme 47
V. Thiol Substrates 47
VI. Concluding Remarks 48
References 49
Chapter 2. Enzymology of Cytosolic Glutathione S-Transferases 54
I. Introduction 54
II. The GST Supergene Family 59
III. Structure of GSTs Including Their Active Sites 60
IV. Enzyme Kinetics 63
V. Gene Structure and Gene Regulation 66
VI. Specific Examples Illustrating the Properties of GSTs 71
VII. Conclusions 77
References 79
Chapter 3. Enzymology of Cysteine S-Conjugate ß-Lyases 88
I. Introduction 88
II. Enzymes That Cleave the Thioether Bond of S-Substituted Cysteines 93
III. Bacterial Cysteine S-Conjugate ß-Lyases 95
IV. Mammalian Cysteine S-Conjugate ß-Lyases 100
V. Design of Prodrugs Directed toward Glutamine K/Cysteine S-Conjugate ß-Lyase in the Kidney 115
Vl. Conclusions 120
Note Added in Proof 121
References 121
Chapter 4. Formation and Fate of Nephrotoxic and Cytotoxic Glutathione S-Conjugates: Cysteine Conjugate ß-Lyase Pathway 132
I. Introduction 132
II. Biosynthesis of Toxic Glutathione S-Conjugates 133
III. Fate of S-Conjugates 137
IV. Bioactivation of Cytotoxic and Nephrotoxic Cysteine S-Conjugates 148
V. Cellular Effects of Cytotoxic and Nephrotoxic Cysteine S-Conjugates 154
References 164
Chapter 5. Reversibility in Glutathione-Conjugate Formation 180
I. Introduction 180
II. Classes of Compounds That Undergo Reversible Conjugation 181
III. Conclusions 194
References 195
Chapter 6. Glutathione Conjugation as a Mechanism for the Transport of Reactive Metabolites 200
I. Introduction 200
II. Glutathione Conjugation as a Mechanism for the Transport of Redox Active Compounds 201
III. Transport of Glutathione-Conjugated Redox Compounds to the Kidney as a Common Factor in Chemical-Induced Nephrocarcinogenicity 207
IV. .-Glutamyltranspeptidase and the Toxicity of Glutathione-Conjugated Redox Compounds 213
V. Targeting of Glutathione Conjugates to Neoplastic Tissues Expressing g-Glutamyltranspeptidase 213
VI. Developmental Toxicity o f Glutathione-Conjugated Redox Compounds 214
VII. Transport of Reversible Glutathione Conjugates 215
VIII. Glutathione, Nitric Oxide, and Endothelial-Derived Relaxing Compounds 218
IX. Summary 219
References 219
Chapter 7. Metabolism and Genotoxicity of Dihaloalkanes 228
I. Introduction 228
II. Adducts Derived from 1,2-Dihaloethanes 230
III. Other Dihaloalkanes 239
IV. Basis of Mutagenicity of Ethylene Dibromide 243
V. Conclusions 247
References 247
Chapter 8. Bioactivation of Thiols by One-Electron Oxidation 254
I. Introduction 254
II. Reactions of the Thiyl Radical 255
III. Pathways for One-Electron Oxidation of Thiols 259
IV. Structural Effects on One-Electron Oxidation of Thiols 266
V. Beneficial and Harmful Effects of Thiyl Radical Formation 269
VI. Conclusion 277
References 278
Chapter 9. Glutathione Mercaptides as Transport Forms of Metals 288
I. Introduction 288
II. Formation of Glutathione Mercaptides 289
III. Roles of Glutathione in the Disposition and Toxicity of Metals 291
IV. Summary 307
References 307
Part II: Sulfate Conjugate-Dependent Toxicity 316
Chapter 1. Biochemistry of Cytosolic Sulfotransferases Involved in Bioactivation 318
I. Introduction 318
II. Classes of Cytosolic Sulfotransferase Involved in the Bioactivation of Xenobiotics 323
III. Summary 341
References 342
Chapter 2. Carcinogen Activation by Sulfate Conjugate Formation 348
I. Introduction 348
II. Aromatic Hydroxylamines and Amides 352
III. Hydroxymethyl Aromatics and Alcohols 363
IV. Summary 373
References 374
Part III: Glucuronide Conjugate-Dependent Toxicity 382
Chapter I. UDP-Glucuronosyltransferases and Their Role in Metabolism and Disposition of Carcinogens 384
I. Introduction 384
II. Factors Affecting Glucuronide Formation in Cells 385
Ill. Regulation of UGT lsozymes 390
IV. Roles of UGTs in Metabolism and Disposition of Carcinogens 392
V. Conclusions and Future Prospects 393
Note Added in Proof 395
References 395
Chapter 2. Bioactivation by Glucuronide-Conjugate Formation 402
I. Introduction 402
II. Reactivity of Acyl Glucuronides 404
Ill. Possible Role of Acyl Glucuronides in the Toxicity of Drugs 410
References 411
Part IV: Bioactivation and Bioconversion 416
Chapter I. N-Acetyltransferases, O-AcetyItransferases, and N, O-Acetyltransferases: Enzymology and Bioactivation 418
I. Introduction 418
II. N-Acetyltransferase 419
III. O-Acetyltransferase 422
IV. N -Arylhydroxamic N, O-Acyltransferase 429
V. N-Acyloxyarylamines 434
References 438
Chapter 2. Aminoacylases 448
I. lntroduction 448
II. Enzymology of the Aminoacylases 449
III. Xenobiotic Bioactivation by Aminoacylases 456
References 461
Chapter 3. Bioactivation by S-Adenosylation, S-Methylation, or N-Methylation 466
I. Introduction: Synthesis and Utilization of AdoMet 466
II. Bioactivation of Xenobiotic Methionine Analogs by S-Adenosylation Catalyzed by AdoMet Synthetase 471
III. Xenobiotic Bioactivation by N-Methylation of Azaheterocyclic Compounds 478
IV. Xenobiotic Bioactivation by S-Methylation 486
References 490
Chapter 4. Bioconvetion of Prodrugs by Conjugate-Processing Enzymes 496
I. Introduction 496
II. Bioconversion of Prodrugs by Conjugate-Processing Enzymes 497
III. Future Possibilities for Development of Conjugate-Based Prodrugs 512
References 513