Metabolic Activation and Toxicity of Chemical Agents to Lung Tissue and Cells (eBook)

Front Cover 1
Metabolic Activation and Toxicity of Chemical Agents to Lung Tissue and Cells 4
Copyright Page 5
Table of Contents 8
Preface 6
List of Contributors 16
CHAPTER 1. PULMONARY BRONCHIOLAR EPITHELIAL CYTOTOXICITY: MICRO ANATOMICAL CONSIDERATIONS 18
1. Introduction 18
2. Architecture of the Centriacinus 18
3. Cellular Composition of the Bronchiolar Epithelial Population 19
4. Ultrastructure of Bronchiolar Clara Cells 21
5. Distribution of Bronchiolar Epithelial Cells Throughout the Tracheobronchial Tree 24
6. The Clara Cell as a Site for Xenobiotic Metabolism by the Cytochrome P-450 System 26
7. Role of the Clara Cell as the Progenitor for Bronchiolar Epithelium 28
8. Bronchiolar Epithelium as a Target for Environmental Toxicants 28
9. General Considerations 36
References 36
CHAPTER 2. XENOBIOTIC METABOLISM BY ISOLATED PULMONARY BRONCHIOLAR AND ALVEOLAR CELLS 42
1. Introduction 42
2. Pulmonary Cell Isolation 42
3. Problem of Proteolysis of Isolated Cells 43
4. Cytochrome P-450 System 45
5. Metabolism of Xenobiotics 46
6. Metabolite Interaction with DNA 52
7. Conclusions 53
References 54
CHAPTER 3. LOCALIZATION, DISTRIBUTION AND INDUCTION OF XENOBIOTIC-METABOLIZING ENZYMES AND ARYL HYDROCARBON HYDROXYLASE ACTIVITY WITHIN LUNG 58
1. Introduction 58
2. Overview of Xenobiotic-metabolizing Enzymes 59
3. Intrapulmonary Localization of Xenobiotic-metabolizing Enzymes 62
4. Methods of Study 68
5. Localization and Distribution of Xenobiotic-metabolizing Enzymes and Benzo(a)pyrene Hydroxylase Activity Within Lungs of Untreated Rats 73
6. Effects of 3-Methylcholanthrene and Aroclor 1254 on Xenobiotic metabolizing Enzymes and Benzo(a)pyrene Hydroxylase Activity Within Rat Lung 80
7. Concluding Comments 84
References 86
CHAPTER 4. PURIFICATION AND CHARACTERIZATION OF LUNG ENZYMES INVOLVED IN XENOBIOTIC METABOLISM 94
1. Introduction 94
2. Microsomal Enzymes 94
3. Cytosolic Enzymes 99
4. Conclusions 101
References 101
CHAPTER 5. ACTION BY THE LUNGS ON CIRCULATING XENOBIOTIC AGENTS, WITH A CASE STUDY OF PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELING OF BENZO(a)PYRENE DISPOSITION 106
1. Introduction 106
2. Pulmonary Enzyme Systems that Oxidize Xenobiotic Agents 107
3. Enzyme Content and Location 109
4. Accumulation of Xenobiotic Agents by Lung 109
5. Determinants of Metabolic Clearance of Xenobiotic Agents 110
6. Physiologically Based Pharmacokinetic Modeling: Application to Metabolic Clearance of Benzo(a)pyrene 112
7. Altered Pulmonary Physiology and Metabolic Clearance of Xenobiotic Agents 116
8. Conclusions 119
References 119
CHAPTER 6. METABOLISM OF ENDOGENOUS AND XENOBIOTIC SUBSTANCES BY PULMONARY VASCULAR ENDOTHELIAL CELLS 124
1. Introduction 124
2. Metabolism of Endogenous Substrates by the Pulmonary Endothelium 124
3. Metabolism of Xenobiotic Substances by Pulmonary Endothelium 129
4. Concluding Comments 135
References 136
CHAPTER 7. NAPHTHALENE AND 2-METHYLNAPHTHALENE-INDUCED PULMONARY BRONCHIOLAR EPITHELIAL CELL NECROSIS: METABOLISM AND RELATIONSHIP TO TOXICITY 140
1. Introduction 140
2. Environmental Importance/Occurrence 141
3. Toxicology of Naphthalenes 141
4. Metabolism and Relationship to Toxicity 143
5. Future Directions 155
References 157
CHAPTER 8. PULMONARY TOXICITY OF 4-IPOMEANOL 162
1. Introduction 162
2. Discovery of the Pneumotoxin, 4-Ipomeanol: Relation Between Covalent Binding and Lethal Toxicity 162
3. Activation of 4-Ipomeanol in Vitro 163
4. Electrophilic Metabolite Formed In Vivo Conjugated with Endogenous Glutathione Depletion of Glutathione Increases Covalent Binding and Lethal Toxicity
5. The Non-Ciliated Bronchiolar Epithelial (Clara) Cell as a Site of Activation and Necrosis Produced by 4-Ipomeanol: Birds Devoid of Clara Cells Exhibit No Pulmonary Toxicity 163
6. Subacute Tolerance to 4-Ipomeanol Probably Results From Impaired Activation 167
7. The Nature of the 'Reactive Metabolite' 167
References 168
CHAPTER 9. PULMONARY TOXICITY INDUCED BY PHOSPHOROTHIOATE IMPURITIES PRESENT IN ORGANOPHOSPHATE INSECTICIDES 170
1. Introduction 170
2. Cellular Responses in the Lung to Trialkyl Phosphorothioateinduced Injury 172
3. Cellular Kinetics 175
4. Metabolic Considerations of Phosphorothioate-induced Lung Toxicity 176
5. Protection Offered by a Phosphorothionate Isomer 176
6. Potential Human Risks Associated with Insecticide Impurities 178
References 178
CHAPTER 10. THE METABOLIC BASIS OF 3-METHYLINDOLE-INDUCED PNEUMOTOXICITY 182
1. Introduction 182
2. 3-Methylindole-induced Lung Disease 182
3. Direct Effects of 3MI as the Parent Compound 183
4. Metabolism of 3MI 184
5. Metabolic Activation by the MFO System 184
6. Metabolic Activation by PHS System 189
7. Tissue-specific Metabolic Changes Induced by 3MI 194
8. Conclusion 197
References 198
CHAPTER 11. METABOLISM AND PULMONARY TOXICITY OF BUTYLATED HYDROXYTOLUENE 202
1. Introduction 202
2. Metabolism and Disposition of BHT 203
3. Lung Damage Produced by BHT 209
4. The Use of BHT as an Experimental Tool 218
5. BHT Toxicity in Man 222
References 223
CHAPTER 12. HEPATIC NONALTRUISM AND PULMONARY TOXICITY OF PYRROLIZIDINE ALKALOIDS 230
1. Occurrence of Pyrrolizidine Alkaloids 230
2. Metabolic Activation of Pyrrolizidine Alkaloids and Structure-Activity Requirements 230
3. Cardiopulmonary Toxicity 232
4. Changes Produced in Lungs by Pyrrolizidines and Pyrroles 235
5. Dose Relationship 242
6. Modification of Pyrrolizidine Toxicity 243
7. What is the Pneumotoxic Metabolite? 245
References 249
CHAPTER 13. CYCLOPHOSPHAMIDE: PULMONARY METABOLISM, TOXICITY AND PROTECTIVE EFFECT OF VITAMIN . 256
1. Introduction 256
2. Metabolism of Cyclophosphamide 258
3. Cyclophosphamide-induced Alterations in Microsomal Membrane Structure 260
4. Effect of Oxygen on Cyclophosphamide-induced Pulmonary Toxicity 266
5. Effect of Vitamin . on Cyclophosphamide-induced Pulmonary Toxicity 267
References 268
CHAPTER 14. METABOLIC ACTIVATION AND BIOLOGICAL EFFECTS OF NITROSAMINES IN THE MAMMALIAN LUNG 272
1. Introduction 272
2. In Vivo Studies in Experimental Animals 273
3. In Vitro Studies in Human and Animal Lung Cells 279
4. Conclusions 280
References 281
CHAPTER 15. THE USE OF BLEOMYCIN IN MODEL SYSTEMS TO STUDY THE PATHOGENESIS OF INTERSTITIAL PULMONARY FIBROSIS 284
1. Introduction 284
2. Clinical Pulmonary Toxicity of Bleomycin 286
3. Animal Models for Bleomycin-induced Pulmonary Fibrosis 287
4. Pulmonary Disposition and Metabolism of Bleomycin 289
5. Mechanisms for Pulmonary Fibrosis by Bleomycin 293
6. Pharmacological Approaches to Preventing Bleomycin-induced Fibrosis 296
7. Conclusions 297
References 297
CHAPTER 16. THE PULMONARY TOXICITY OF NITROSOUREAS 302
1. Introduction 302
2. 1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU, Carmustine) 303
3. 1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU, Lomustine) 314
4. Chlorozotocin [DCNU, 2-(((2-Chloroethyl)-nitrosamino)-carbonylamino)-2-deoxy-D-glucopyranose] 315
5. 1-(2-Chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (methyl-CCNU, Semustine) 315
6. Other Nitrosoureas 316
7. Summary 316
References 316
Index 322