Molecular, Clinical and Environmental Toxicology (eBook)

Contents 6
List of contributors 8
Preface 11
Historical milestones and discoveries that shaped the toxicology sciences 15
Introduction 15
Toxicology etymology and definition 16
Antiquity: 3000 B.C.E.– 90 C.E. 18
The Medieval and Renaissance period of toxicology: 476– 1699 C.E. 25
The Chemical Age of toxicology: 1700– 1899 29
Chemical elixirs, patent medicines and death in a bottle 37
The Poison Squad of 1883, Harvey Wiley and the FDA 38
Chemical warfare toxicology 40
Toxicology impacts society: 1950– present 43
References 48
Physiologically based toxicokinetic models and their application in human exposure and internal dose assessment 50
Introduction 50
Structure and function of biological membranes 51
Quantitative descriptions of absorption, distribution, metabolism, and excretion 53
Emerging problems 58
Future needs 63
Conclusions 65
References 66
The role of biotransformation and bioactivation in toxicity 69
Introduction 69
Phase I and phase II reactions 70
Phase I enzymes and their reactions 71
Phase II enzymes of biotransformation and their reactions 78
Bioactivation of xenobiotics 83
References 95
Genotoxicity: damage to DNA and its consequences 99
Introduction 99
Short-term tests for genotoxicity 101
DNA adducts formed by chemical carcinogens 107
Methods for adduct detection 109
Biological significance of DNA adducts 111
Adducts as biomarkers of occupational and environmental exposure to carcinogens 113
DNA adducts in prospective studies 115
Summary 117
References 117
Role of DNA repair in the protection against genotoxic stress 123
Introduction 123
Repair of double strand breaks 124
Direct reversal of base damage 129
DNA excision repair 133
Base excision repair 135
Nucleotide excision repair 140
Transcription-coupled repair 150
Coordination of DNA repair with cell cycle 153
References 154
On the impact of the molecule structure in chemical carcinogenesis 163
Introduction 163
What chemicals are human carcinogens? 165
Genotoxic potency as function of chemical structure 166
Reprise 182
Conclusions 184
References 185
Chemical induced alterations in p53 signaling 192
Introduction 192
p53 regulation 193
Structure of the p53 protein 195
p53 stabilization and activation induced by stresses 196
Upstream mediators of p53 activation signals 196
Downstream events in the p53 pathway and their role in tumor suppression 199
p53 mutations 203
Epigenetic modifications of p53 205
Metabolic factors affecting p53 signaling 206
Chemically mediated alterations in p53 signaling – Effects of tumor promoters and chemopreventive substances 207
Sex hormones and alterations in the p53 signaling 209
p53 signaling as a biomarker 210
p53, chemical carcinogenesis and cancer risk assessment 210
Future prospects 211
References 212
Molecular pathways involved in cell death after chemically induced DNA damage 220
Introduction 220
Topoisomerase I inhibitors: Camptothecin 220
Topoisomerase II inhibitors 222
Alkylating agents: Cisplatin 223
Selectivity of PARP inhibitors 226
Regulation of the cell cycle by the DNA damage response 229
DNA damage present in precancerous lesions may constitute a barrier for cancer development 234
References 235
The aryl hydrocarbon receptor at the crossroads of multiple signaling pathways 242
Introduction 242
Cross-talk of cellular kinases with the AHR 244
Cross-talk of the AHR with cell cycle progression and apoptosis 250
Cross-talk of the AHR with differentiation pathways 255
Conclusions 262
References 263
Mapping the epigenome – impact for toxicology 269
Introduction 269
Mapping the epigenome – Worldwide efforts and resources 272
Technological approaches to epigenetic analyses 275
Relevance of epigenetic perturbations for toxicology 279
Evidence for epigenetic mechanisms in inflammation 285
Epigenetic mechanisms of non-genotoxic carcinogenesis – Relevance for safety assessment? 286
Opportunities for biomarkers 287
Molecular classification of tumors 288
Potential limitations of DNA methylation profiling for safety assessment 288
Emerging opportunities for epigenomic profiling in drug safety sciences 289
References 291
Receptors mediating toxicity and their involvement in endocrine disruption 299
Introduction 299
Xenobiotics that induce receptor-mediated toxicity 300
Receptors involved in toxicity 308
Endocrine disruption 320
Prospects 326
References 327
Toxicogenomics: transcription profiling for toxicology assessment 334
Introduction 334
Microarray analysis 335
Applications of gene expression profiles in toxicological studies 343
Novel applications of microarrays in toxicological research 363
References 365
The role of toxicoproteomics in assessing organ specific toxicity 376
Introduction 376
Disciplines and platforms for toxicoproteomics research 378
Toxicoproteomics studies in liver injury 386
Toxicoproteomic studies in kidney injury 396
Summary and future prospects 401
References 402
High-throughput screening for analysis of toxicity 410
Introduction 410
State of the art of HTS for in vitro bioassays within pharmacology 411
State of the art of HTS for in vitro bioassays within toxicology 413
Strategy for the development of non-toxic compounds 414
Implementation of HTS in vitro toxicity analysis within the pharmaceutical industry 416
Screening procedures for genotoxicity 417
Screening procedures for cytotoxicity 423
The importance of cellular metabolism by phase I and II enzymes 429
Activation of cellular metabolism by nuclear receptors 431
High content screening or bioimaging techniques 434
Screening for non-genotoxic carcinogenicity with nuclear receptors 435
Screening for competition of CYP and UGT enzymes 438
Screening for embryotoxicity 443
Endocrine disruption and reprotoxicity 445
Other assay types 450
Conclusions 451
References 451
Glossary 462
Index 470