Quantitative structure-activity relationship (QSAR) models of mutagens and carcinogens

Quantitative Structure-Activity Relationship QSAR Models of Mutagens and Carcinogens......Page 2
Preface......Page 4
The Editor......Page 6
Contributors......Page 7
Abstract......Page 8
Table of Contents......Page 9
1.1 INTRODUCTION......Page 11
1.2 SOME BASIC PRINCIPLES......Page 12
1.3 FREE?WILSON ANALYSIS......Page 13
1.4.1 BASIC ASSUMPTIONS......Page 17
1.4.2.1 Electronic Parameters......Page 18
1.4.2.2 Hydrophobic Parameters......Page 21
1.4.2.3 Steric Parameters......Page 24
1.4.2.4 Indicator Variables......Page 25
1.4.3 BUILDING AND EVALUATING HANSCH EQUATIONS......Page 27
1.5.1 PRINCIPAL COMPONENTS AND PLS......Page 35
1.5.2 THREE-DIMENSIONAL QSAR......Page 38
1.5.3 CLASSIFICATION METHODS......Page 40
1.6 SOME OTHER QSAR-RELATED METHODS......Page 42
1.7 CONCLUDING REMARKS......Page 44
REFERENCES......Page 45
CONTENTS......Page 51
2.2 IMPORTANCE OF MECHANISTIC UNDERSTANDING IN SAR ANALYSIS......Page 52
2.3.1 E XAMPLES OF C HEMICAL C ARCINOGENS T HAT A CT P REDOMINANTLY BY G ENOTOXIC M ECHANISMS......Page 55
2.3.2.1 Peroxisome Proliferators......Page 57
2.3.2.2 Ah Receptor-Mediated and Other Enzyme Inducers......Page 61
2.3.2.3 Inhibitors of Gap Junctional Intercellular Communication......Page 63
2.3.2.4 Agents That Cause Oxidative Stress......Page 64
2.3.2.5 Agents That Cause Alteration of DNA Methylation......Page 66
2.3.2.6 Agents That Cause Hormonal Imbalance......Page 67
2.3.2.7 Cytotoxic Agents That Induce Regenerative Cell Proliferation......Page 73
2.3.2.8 Miscellaneous Other Mechanisms......Page 76
2.4 ROLE OF MECHANISM IN CANCER HAZARD IDENTIFICATION AND RISK ASSESSMENT......Page 78
REFERENCES......Page 80
CONTENTS......Page 91
3.1 INTRODUCTION......Page 92
3.2.1 M UTAGENICITY OF A ROMATIC AND H ETEROAROMATIC N ITRO C OMPOUNDS , P ART I......Page 93
3.2.2 M UTAGENICITY OF A ROMATIC AND H ETEROAROMATIC N ITRO C OMPOUNDS , P ART II......Page 94
3.2.3 M UTAGENICITY OF N ITROAROMATIC C OMPOUNDS......Page 95
3.2.5 MUTAGENICITY OF NITROARENES......Page 96
3.2.6 MUTAGENICITY OF QUINOLINES......Page 97
3.2.7 MUTAGENICITY AND CYTOTOXICITY OF QUINOLINES......Page 98
3.2.9 MUTAGENICITY OF NITRO- AND AMINO-SUBSTITUTED CARBAZOLES, O-AMINONITRO DERIVATIVES OF 9H-CARBAZOLE......Page 99
3.2.10 MUTAGENICITY OF PHENYLAZOANILINE DYES......Page 100
3.2.11 MUTAGENICITY OF PHENYL AND HETEROCYCLIC 3,3-DIMETHYL TRIAZENES......Page 101
3.2.13 MUTAGENICITY OF N-ACYLOXY-N-ALKOXYAMIDES......Page 102
3.2.14 MUTAGENICITY OF CHLORINE-SUBSTITUTED FURANONES AND HALOPRENALS......Page 103
3.2.16 MUTAGENICITY OF HALOGENATED FURANONES......Page 104
3.2.17 MUTAGENICITY OF HALOGENATED METHANES......Page 105
3.2.18 MUTAGENICITY OF 2-FURYLETHYLENE DERIVATIVES......Page 106
3.2.19 MUTAGENICITY OF PROPYLENE OXIDES......Page 108
3.2.20 MUTAGENICITY OF STYRENE OXIDES......Page 109
3.2.21 MUTAGENICITY AND GENOTOXICITY OF POLYCYCLIC AROMATIC NITRO COMPOUNDS......Page 110
3.2.22 MUTAGENICITY AND GENOTOXICITY OF NITROFURANS......Page 111
3.2.23 MUTAGENICITY AND CARCINOGENICITY OF HETEROCYCLIC COMPOUNDS......Page 112
3.2.24 MUTAGENICITY AND CYTOTOXICITY OF SHORT-CHAIN CHLORINATED HYDROCARBONS......Page 114
3.2.25 MUTAGENICITY AND CARCINOGENICITY OF METHYLBENZANTHRACENES......Page 116
3.2.26 GENOTOXICITY OF NITROARENOFURANS......Page 117
3.3.2 CARCINOGENICITY OF N-NITROSO COMPOUNDS......Page 118
3.3.3 CARCINOGENICITY OF N-NITROSAMINES......Page 119
3.3.4 CARCINOGENICITY OF METHYLBENZ[C]ACRIDINES......Page 121
3.3.5 CARCINOGENICITY OF POLYCYCLIC AROMATIC HYDROCARBONS......Page 122
3.3.7 CARCINOGENICITY OF AROMATIC HYDROCARBONS......Page 124
3.3.8 CARCINOGENESIS OF AROMATIC HYDROCARBONS AND HETEROCYCLES......Page 125
3.3.9 TOXICITY AND CARCINOGENICITY OF POLYCHLORINATED DIBENZODIOXINS PCDD, POLYCHLORINATED HYDROCARBONS, CHLORINATED INSECTICIDES......Page 126
REFERENCES......Page 131
4.1 INTRODUCTION......Page 134
4.2 CARCINOGENICITY OF THE AROMATIC AMINES: MECHANISMS OF ACTION......Page 135
4.3 STRUCTURE?ACTIVITY RELATIONSHIPS: QUALITATIVE FINDINGS......Page 136
4.4 QSARS FOR THE MUTAGENIC ACTIVITY OF THE AROMATIC AMINES......Page 137
4.5 QSARS FOR THE CARCINOGENIC ACTIVITY OF THE AROMATIC AMINES......Page 143
4.6 THE QSARS OF THE AROMATIC AMINES: AN OVERALL COMPARISON......Page 147
4.7 CONCLUSIONS......Page 149
REFERENCES......Page 150
CONTENTS......Page 154
5.1 INTRODUCTION......Page 155
5.2.2 C HEMICAL S TRUCTURES A VAILABILITY......Page 157
5.3.1 N ATURE OF E XISTING D ATA......Page 161
5.3.2 S UMMARY T OXICITY R ESULTS......Page 164
5.3.3 NTP AND CPDB R ODENT C ARCINOGENICITY D ATABASES......Page 166
5.3.4 D ATA Q UALITY AND R EPRODUCIBILITY OF R ODENT B IOASSAY R ESULTS......Page 167
5.4.1 DATABASE INFORMATICS ANALYSES......Page 168
5.4.3 INFLUENCE OF TOXICITY PROTOCOL ON SAR MODELS......Page 171
5.5.1 COMMERCIAL RELATIONAL AND DATA-MINING APPLICATIONS......Page 173
5.5.2 PUBLIC TOXICITY DATABASE INITIATIVES......Page 174
5.6 CONCLUSIONS......Page 178
REFERENCES......Page 179
6.1 INTRODUCTION......Page 183
6.2.1 T HE SAR M ODEL......Page 185
6.2.4 D ETERMINATION OF S TRUCTURAL O VERLAPS......Page 186
6.3 RESULTS......Page 187
6.3.1 MECHANISTIC STUDIES......Page 203
REFERENCES......Page 208
CONTENTS......Page 215
7.1 INTRODUCTION......Page 216
7.2 BASIC CONCEPTS OF MOLECULAR STRUCTURE AND CHEMICAL GRAPH THEORY......Page 217
7.2.1 THE MOLECULAR STRUCTURE CONUNDRUM......Page 219
7.2.2 REPRESENTATION OF MOLECULAR STRUCTURES USING GRAPHS......Page 220
7.2.3 C HARACTERIZATION OF M OLECULAR G RAPHS U SING T OPOLOGICAL I NDICES......Page 221
7.3.1 DATABASES......Page 224
7.3.2 CALCULATION OF MOLECULAR DESCRIPTIORS......Page 225
7.3.3 STATISTICAL METHODS......Page 229
7.3.4 THE HIERARCHICAL QSAR HIQSAR APPROACH......Page 233
7.4.2 DIVERSE SET OF 508 MUTAGENS/NONMUTAGENS......Page 234
7.5 DISCUSSION......Page 236
REFERENCES......Page 238
CONTENTS......Page 243
8.2 ACUTE TOXICITY DATA......Page 244
8.3 DEVELOPMENT OF QSARS FOR ACUTE AQUATIC ENDPOINTS......Page 245
8.4 NONPOLAR NARCOSIS......Page 247
8.5 OTHER NARCOTIC EFFECTS, POLAR NARCOSIS......Page 250
8.6 WEAK ACID RESPIRATORY UNCOUPLERS......Page 251
8.7 ELECTROPHILIC MECHANISMS OF ACTION......Page 252
8.8 FREE RADICAL TOXICITY......Page 254
8.9 SPECIFIC TOXICITY PESTICIDES......Page 255
8.10 SOFTWARE FOR THE PREDICTION OF AQUATIC TOXICITY......Page 256
8.12 REGULATORY USE OF QSARS FOR ACUTE AQUATIC ENDPOINTS......Page 258
8.13 FUTURE USE AND NEEDS OF QSARS FOR ACUTE AQUATIC TOXICITY......Page 260
REFERENCES......Page 261
CONTENTS......Page 267
9.2 WHAT DATA FOR QSAR MODELING?......Page 268
9.3 QSARS FOR INDIVIDUAL CHEMICAL CLASSES......Page 270
9.4 RISK ASSESSMENT: FILLING THE GAPS IN THE DATABASE......Page 271
9.4.2 T HE F IRST NTP C OMPARATIVE E XERCISE ON THE P  PREDICTION OF RODENT CARCINOGENICITY......Page 272
9.4.3 T HE S ECOND NTP C OMPARATIVE E XERCISE ON THE P REDICTION OF R ODENT   CARCINOGENICITY......Page 275
9.4.4 LESSONS FROM THE COMPARATIVE EXERCISES ON THE PREDICTION OF CARCINOGENICITY......Page 279
9.5 DIFFERENT DATABASES: PHARMACEUTICAL DRUGS VS. GENERAL CHEMICALS......Page 283
9.6 CONCLUSIONS......Page 285
References......Page 286