Toxic Interactions (eBook)

Front Cover 1
Toxic Interactions 4
Copyright Page 5
Table of Contents 6
CONTRIBUTORS 12
PREFACE 14
PART I: PRINCIPLES 16
CHAPTER 1. FACTORS TO CONSIDER IN THE DESIGN AND EVALUATION OF CHEMICAL INTERACTION STUDIES IN LABORATORY ANIMALS 18
I. Introduction 19
II. Theoretical Considerations 19
III. Dose–Response Considerations 23
IV. Endpoint Considerations 29
V. Time-Interval Considerations 33
VI. Biotransformation Considerations 39
VII. Concluding Remarks 42
References 43
CHAPTER 2. THE ROLE OF THE MIXED-FUNCTION OXIDASE SYSTEM IN THE TOXICATION AND DETOXICATION OF CHEMICALS: RELATIONSHIP TO CHEMICAL INTERACTIONS 46
I. Introduction 46
II. Characteristics of the Mixed-Function Oxidase System 47
III. Relationship of the Mixed-Function Oxidase System to Chemical Interactions 60
IV. Summary 69
References 70
CHAPTER 3. OXIDATION OF XENOBIOTICS BY PROSTAGLANDIN H SYNTHASE 76
I. Introduction 77
II. Prostaglandin H Synthase 80
III. Involvement of Peroxidatic Enzymes in Toxic and Carcinogenic Processes 83
IV. Mechanism of Prostaglandin H Synthase Metabolism of Xenobiotics 89
V. Modifying and Preventing Toxic and Carcinogenic Reactions Mediated by Peroxidases 95
VI. Summary 98
References 99
CHAPTER 4. The Role of Glutathione in Protection against Chemically Induced Cell Injury 102
I. Introduction 102
II. Glutathione: Physiological and Biochemical Aspects 103
III. Normal Cellular Functions of Glutathione 110
IV. Chemically Induced Perturbations in Cellular Glutathione Status . 114
V. Glutathione and Cell Death 119
VI. Conclusion 122
References 123
CHAPTER 5. DISPLACEMENT INTERACTIONS RESULTING FROM COMPETITION FOR BINDING SITES ON PROTEINS 130
I. Introduction 131
II. General Discussion of Sites of Interactions 131
III. Serum Proteins as Sites for Toxic Interactions 136
IV. Methods of Experimental Analysis 139
V. Analysis of Binding 144
VI. Competition 157
VII. Prospects for the Future 159
VIII. Significance in Medicine and Toxicology 159
References 160
CHAPTER 6. THE IMPACT OF RENAL DYSFUNCTION ON DRUG HANDLING AND HOW TO COMPENSATE FOR IT 164
I. Introduction 164
II. Effects of Renal Dysfunction on Handling of Drugs 165
III. Effects of Renal Dysfunction on Response to Drugs 174
IV. Impact of Renal Dysfunction on Drug–Drug Interactions 174
V. Strategies for Dose Adjustment in Renal Dysfunction 175
VI. Conclusion 183
References 184
PART II: CHEMICAL INTERACTIONS AND HEPATOTOXICITY 190
CHAPTER 7. USE OF MICROFLUOROMETRIC AND MICROPOLAROGRAPHIC TECHNIQUES TO STUDY ZONE-SPECIFIC HEPATOTOXICITY 192
I. Introduction 193
II. Development of Techniques to Study Functional Aspects of Metabolic Zonation 195
III. Characterization of Mixed-Function Oxidation in Periportal and Pericentral Regions 197
IV. Conjugation in Periportal and Pericentral Regions 203
V. Metabolism of Alcohols in Periportal and Pericentral Regions of the Liver Lobule 208
VI. Future Directions 216
References 217
CHAPTER 8. CHEMICAL ALTERATIONS OF VOLATILE, ANESTHETIC AGENT-INDUCED HEPATO- AND NEPHROTOXICITY 222
I. Introduction 222
II. Metabolism of Anesthetic Agents and Toxicological Consequences 224
III. Chemical Alterations of Anesthetic Agent-Induced Hepato- and Nephrotoxicity 233
References 242
CHAPTER 9. Prevention of Chemically Induced Liver Injury 248
I. Introduction 248
II. Inhibition of Metabolic Activation to Reactive Metabolites 250
III. Chemical Trapping of Necrogenic Reactive Metabolites 256
IV. Increased Intensity of Inactivating Biotransformations 257
V. Inhibition of Lipid Peroxidation 259
VI. Modulation of Late Stages of the Process 264
References 268
PART III: ALTERATION OF CHEMICALLY INDUCED NEPHROTOXICITY 274
CHAPTER 10. BIOCHEMICAL MECHANISMS OF CHEMICALLY INDUCED NEPHROTOXICITY 276
I. Introduction 277
II. General Aspects of Renal Damage Produced by Toxic Chemicals 277
III. Biotransformation of Toxic Chemicals in the Kidney 289
IV. Mechanisms Responsible for Chemically Induced Nephrotoxicity 301
V. Potentiation of the Action of Nephrotoxicants by Environmental Contaminants 307
VI. Conclusion 309
References 310
CHAPTER 11. TOXIC ACTIONS OF THE AMINOGLYCOSIDE ANTIBIOTICS ON THE KIDNEY 314
I. Introduction 314
II. Pathogenesis 315
III. Molecular Determinants of Aminoglycoside Toxicity 322
IV. Clinical Features of Aminoglycoside Nephrotoxicity 324
V. Interactions with Other Drugs 329
References 331
CHAPTER 12. KETONIC POTENTIATION OF HALOALKANE-INDUCED NEPHROTOXICITY 336
I. Introduction 336
II. Ketonic Solvent Potentiation of CHCI3 Nephrotoxicity 338
III. Interactions between 2–Hexanone and Other Nephrotoxicants 340
IV. Mechanisms Involved in 2-Hexanone Potentiation of Nephrotoxicity 355
V. Conclusions 376
References 377
CHAPTER 13. Chronic Chemical Injury to the Kidney 382
I. Introduction 383
II. Chronic Chemical Nephropathies Recognized in Humans 386
III. Chronic Chemical Nephrotoxicity in Experimental Systems 392
IV. Conclusions 414
References 417
PART IV: CHEMICAL INTERACTIONS AND OTHER TARGET ORGAN TOXICITIES 422
CHAPTER 14. TOXICOLOGICAL INTERACTIONS IN THE PATHOGENESIS OF LUNG INJURY 424
I. Toxicological Interactions and Human Lung Disease 424
II. Mechanisms of Toxicological Interaction in the Lung 429
III. Conclusions 451
References 453
CHAPTER 15. Drug-Induced Cardiotoxicity 458
I. Introduction 458
II. Regulation of Calcium Transport in Cardiac Muscle 460
III. Role of Calcium in the Cardiotoxic Actions of Drugs 464
IV. Interactions of Cardiotoxic Drugs 472
References 477
INDEX 484