The Carcinogenic Effects of Polycyclic Aromatic Hydrocarbons

Contents......Page 18
Preface......Page 8
In Memoriam: Anthony Dipple (1940-1999)......Page 12
List of Contributors......Page 16
1 Polycyclic Aromatic Hydrocarbon-Induced Carcinogenesis - An Introduction......Page 25
2.1 Introduction......Page 43
2.2 Structure-Activity Relationships......Page 45
2.3.1 Monooxygenation and Dihydrodiol Epoxide Pathway......Page 46
2.3.2 Stereochemistry of Activation......Page 57
2.3.3 One-Electron Oxidation......Page 63
2.3.4 Formation of Quinones......Page 66
2.3.5 'Bioalkylation' and Benzylic Ester Pathway......Page 73
2.4 Detoxification......Page 77
2.5 Summary and Perspectives......Page 81
3.1 Introduction......Page 121
3.2 Studies at Work Places/Occupational Exposure to PAHs......Page 123
3.3 Non-Occupational Exposure to PAHs......Page 126
3.4 Metabolism and Excretion of PAHs......Page 127
3.5.2 1-Hydroxypyrene and Its Glucuronide......Page 129
3.5.3 Enzyme Polymorphisms and Excretion Levels of 1-Hydroxypyrene......Page 133
3.5.4 Phenanthrene Metabolites......Page 136
3.5.5 Benzo[a]pyrene Metabolites......Page 138
3.6 Summary......Page 142
3.7 Conclusions......Page 143
4.1 Introduction......Page 161
4.2 Methods of Detection......Page 162
4.3.1 Iron and Steel Production......Page 164
4.3.2 Aluminum Production......Page 165
4.3.3 Coke Ovens and Graphite Electrode Manufacture......Page 166
4.3.4 Other Occupational Exposures......Page 174
4.4 Environmental Exposure to PAHs......Page 176
4.5 Coal Tar Therapy......Page 178
4.6 Diet......Page 179
4.7 Discussion and Summary......Page 181
5.1 Introduction......Page 195
5.2 Evolution of Research on PAHs......Page 196
5.3 Chemistry and Biological Effects......Page 197
5.4 Significance of Stable versus Unstable PAH-DNA Adducts......Page 202
5.5 Mutagenicity of PAH-DNA Adducts......Page 203
5.5.1 Site-Specific Mutagenicity of PAH-DNA Adducts......Page 204
5.5.2 Translesional Synthesis......Page 208
5.6 Cancer Epidemiology and PAH-DNA Adducts......Page 211
5.6.1 Mapping of PAH-DNA Adducts......Page 212
5.6.2 Additional Evidence for the Etiological Relevance of PAHs in Human Carcinogenesis: The Exemplary Case of p53 Mutations in Lung Cancer......Page 215
5.7 Concluding Remarks......Page 217
6.1 Introduction......Page 235
6.2.1 Mammalian DNA Nucleotide Excision Repair......Page 237
6.2.2 Subunits of the Human NER Machinery......Page 239
6.2.3 Transcription-Coupled DNA Repair......Page 241
6.2.4 Global NER Deficiency and Cancer......Page 243
6.3.1 The In Vitro Oligonucleotide Excision Reaction......Page 245
6.3.2 Base Pair Conformation-Dependent Excision of B[a]PDE-dG Adducts......Page 248
6.3.3 Unrepaired Fjord-Region PAH-DNA Adducts in Ras Codon 61 Mutational Hotspots......Page 252
6.3.4 Bipartite Recognition of PAH-DNA Adducts......Page 259
6.3.5 Modulation of Human NER Activity by 5-Methylcytosines......Page 261
6.3.6 Antagonistic Interaction of NER Factors between Substrate and Decoy DNA Adducts......Page 262
6.3.7 Mechanism of PAH Adduct Recognition by the Human NER Machinery......Page 267
6.4 Conclusion......Page 270
7.1 Introduction......Page 283
7.2.1 Ras Activation......Page 284
7.2.2 Effects on p53......Page 287
7.2.4 Disruption of BRCA1 Expression......Page 289
7.2.5 Inhibition of Intercellular Communication......Page 290
7.3 Atherosclerosis-Related Alterations Induced by PAHs......Page 292
7.4 Apoptosis-Related Alterations Induced by PAHs......Page 294
7.5 Summary......Page 295
8.1 Introduction......Page 307
8.2.1 In Vitro Mutagenicity Tests Using Bacterial Target Cells......Page 308
8.2.2 Other Endpoints of Genotoxicity in Bacterial Target Cells......Page 313
8.2.3 Host-Mediated Assays Using Microbial Target Cells......Page 314
8.3.1 Mutations in Mammalian Cells in Culture......Page 315
8.3.2 Other Endpoints of Genotoxicity Using Mammalian Cells in Culture......Page 318
8.3.3 Genotoxicity in Mammalian Cells In Vivo......Page 319
8.4 Characterization of DNA Sequence Changes Induced by PAHs......Page 322
8.5 Summary......Page 323
9.1 Introduction......Page 339
9.2 Environmental Genotoxic Agents......Page 340
9.3.1 Levels and Carcinogenic Potency of PAHs......Page 343
9.3.2 Metabolic Activation of PAHs and Potential Biomarkers......Page 352
9.4.1 Levels and Carcinogenic Potency of NO2-PAHs......Page 354
9.4.2 Metabolic Activation of NO2-PAHs and Potential Biomarkers......Page 358
9.5 Summary and Future Recommendations......Page 362
10.1 Introduction......Page 377
10.2.1 CYP1A1......Page 379
10.2.3 CYP2C9......Page 381
10.3 Epoxide Hydrolase......Page 382
10.4 Glutathione S-Transferases......Page 383
10.5 NAD(P)H:Quinone Oxidoreductase......Page 385
10.7 Combined Genotype Effects......Page 386
10.8 Concluding Remarks......Page 387
11 Polycyclic Aromatic Hydrocarbon-Induced Carcinogenesis - An Integrated View......Page 403
11.1 Exposure and Risk......Page 404
11.2 Incorporation and Biotransformation......Page 407
11.3 Monitoring Human Exposure......Page 410
11.4 Molecular Epidemiology: Individual's Susceptibility?......Page 412
11.5 Molecular Mechanisms of DNA Damage......Page 421
11.6 Reprise......Page 438
List of Abbreviations......Page 477
Index......Page 481