Genotoxicology of N-Nitroso Compounds

ISBN-13: 9781468445978 / Angielski / Miękka / 2012 / 271 str.

T. Rao

Opis

Toph's in Chemical Mutagenesis is a new series dedicated to studies in the areas of environmental chemical mutagenesis and genetic toxicology. In this series we will explore some of many topics that are emerging in these rapidly developing fields. The purpose of the present volume is to attempt to organize and compare the genotoxic properties of the N-nitroso compounds. This is a particularly interesting class of compounds because of the problems encountered with the Salmonella assay of Ames in generating both false positive and false negative results. The battery approach using a number of assay systems seems more appropriate to evaluate chemicals in this class. Topics to be discussed in other volumes in this series include single-cell mutation monitoring systems, the detection of genetic damage in mammalian germ cells, the mutagenicity of pesticides, problems in monitoring human populations in genetic toxicology, and a glossary of terms in genetic toxicology. All of these books are in various stages of development and should appear within the next few years. Frederick J. de Serres Series Editor vii Preface During the past ten years there has been an explosive development in the number of short-term tests to predict the biological risks, especially risks of cancer, in exposure to xenobiotic chemicals. The number of published articles in this area has reached many thousands a year and there are several new journals devoted almost entirely to the presentation of the results obtained in these tests.

Spis treści

1. Formation of N-Nitroso Compounds and Their Significance.- 2. N-Nitrosamine Mutagenicity Using the Salmonella/Mammalian-Microsome Mutagenicity Assay.- 1. Introduction.- 2. Materials and Methods.- 2.1. Chemicals.- 2.2. Bacterial Strains.- 2.3. Experimental Procedures.- 2.4. Preparation of Liver Homogenates.- 3. Mutagenic Activity and Chemical Structure.- 3.1. Cyclic Nitrosamines.- 3.2. Aromatic Nitrosamines and Related Compounds.- 3.3. Acyclic Nitrosamines.- 3.4. Nitrosamides.- 4. Conclusions / Discussion.- 5. References.- 3. Structural Basis for Mutagenic Activity of N-Nitrosamines in the Salmonella Histidine Reversion Assay.- 1. Introduction.- 2. Salmonella typhimurium—Histidine Reversion Assay.- 2.1. Bacterial Strains.- 2.2. Mutagenesis Assay—Procedures.- 2.3. Source of Nitrosamines.- 3. Mutagenesis Studies in Salmonella typhimurium.- 3.1. Mechanism of Mutation Induction by Nitrosamines.- 3.2. Relationship between Chemical Structure and Mutagenic Activity.- 3.3. Nitrosamines—Model Compounds for Mutagenesis Studies.- 4. References.- 4. Effects of pH and Structure on the Mutagenic Activity of N-Nitroso Compounds.- 1. Introduction.- 1.1. Background.- 1.2. Chemistry.- 1.3. Alkylating Properties.- 1.4. Organ Specificity.- 1.5. In Vitro Mutagenesis.- 1.6. Problems with Assays: Metabolism.- 1.7. DNA Repair.- 1.8. Permeation into Bacteria.- 1.9. Optimizing Test Conditions.- 2. Methods.- 2.1. Liver Extracts.- 2.2. Mutagenesis Assays.- 2.3. DMN Demethylase.- 2.4. Isolation of DNA and Analysis of Alkylated Bases.- 3. Effects of pH on Mutagenesis and DNA Alkylation by N-Nitroso Compounds.- 3.1. N-Nitrosamines.- 3.2. Direct-Acting Compounds.- 3.3. Alkylation of Isolated DNA.- 3.4. Alkylation of DNA in Salmonella.- 3.5. Possible Explanations: NMU, MNNG.- 3.6. Possible Explanations: N-Nitrosamines.- 3.7. Possible Relevance to Carcinogenesis.- 3.8. Applications to in Vitro Mutagenesis Assays.- 4. Mutagenesis by N-Nitroso-N’-nitroso-N-alkylguanidines.- 4.1. How to Compare Mutagenic Potencies.- 4.2. MNNG.- 4.3. ENNG.- 4.4. PNNG.- 4.5. Comparisons between Mutagens.- 5. Repair of O6-Methylguanine and Its Effect on Mutagenesis.- 5.1. O6-MeG and 7-MeG in Salmonella DNA.- 5.2. Threshold in O6-MeG Formation.- 5.3. Attempt to Observe Repair of O6-MeG.- 5.4. Dependence of Mutagenesis on O6-MeG.- 6. Alternate Mechanisms of Mutagenesis by N-Nitroso Compounds.- 7. Mutagenesis by a Series of “Weakly Mutagenic” N-Nitrosamines: Effects of Structure.- 7.1. Conditions.- 7.2. Results: Di-N-alkylnitrosamines and Related N-Nitrosamines.- 7.3. ?-Substituted N-Nitrosamines.- 7.4. ?-Substituted N-Nitrosamines.- 8. Correlation between Mutagenic Potencies and Carcinogenic Activities of Some N-Nitroso Compounds.- 9. References.- 5. Induction of Bacteriophage Lambda by N-Nitroso Compounds.- 1. Mechanism of Induction.- 2. Genetics and Methodology.- 3. Factors Affecting Induction by Nitroso Compounds.- 3.1. Bacterial Strain.- 3.2. Source and Amount of Activating Enzymes.- 3.3. Media.- 3.4. Kinetic Parameter.- 4. Structure-Activity Relationships.- 5. Relationships between Mutagenicity, Carcinogenicity, and Phage Induction.- 6. Mechanism of Action of Nitroso Compounds as Inducers of Bacteriophage Lambda.- 7. References.- 6. The Relationship between the Carcinogenicity and Mutagenicity of Nitrosamines in a Hepatocyte-Mediated Mutagenicity Assay.- 7. Mutagenic Activity of Nitrosamines in Mammalian Cells: Study with the CHO/HGPRT and Human Leukocyte SCE Assays.- 1. Introduction.- 2. Mutagenic Activity of Eight Nitrosamines in the CHO / HGPRT Assay.- 2.1. The CHO / HGPRT Assay.- 2.2. Mutagenic Activity of Nitrosodimethylamine as Studied in the CHO / HGPRT Assay.- 2.3. Mutagenicity of Eight Nitrosamines in the CHO / HGPRT Assay and Its Correlation with Carcinogenicity.- 3. Mutagenic Activity of 15 Nitrosamines in the Human Leukocyte SCE Assay.- 3.1. Sister-Chromatid Exchanges (SCE) in the Human Leukocyte Culture System.- 3.2. Induction of SCE by 15 Cyclic Nitrosamines in Human Leukocytes in Vitro and Its Correlation with Carcinogenicity.- 4. Summary and Concluding Remarks.- 5. References.- 8. Dimethylnitrosamine Demethylase and the Mutagenicity of Dimethylnitrosamine: Effects of Rodent Liver Fractions and Dimethylsulfoxide.- 1. Introduction.- 2. Materials and Methods.- 2.1. Chemicals and Media.- 2.2. Mutagenesis Assays.- 2.3. Preparation of S-9 Fractions and Microsomes.- 2.4. Enzyme Assays.- 3. Results.- 3.1. Kinetics of DMN Demethylase in Hamster Liver S-9.- 3.2. Correlation of Mutagenic and Enzyme Activities.- 3.3. Effects of Mixing Liver Fractions from Different Species.- 3.4. Cytosol Requirement for Mutagenicity of DMN.- 3.5. Effects of Dimethylsulfoxide.- 4. Discussion.- 4.1. Apparent Km Values and Regulation of DMN Demethylase.- 4.2. Microsomal Inhibitor of DMN Mutagenesis.- 4.3. Cytosolic Activator of DMN Mutagenesis.- 4.4. Inhibition by Dimethylsulfoxide.- 4.5. Screening Chemicals with Hamster Liver S-9.- 5. References.- 9. The Relationship between Metabolism and Mutagenicity of Two Cyclic Nitrosamines.- 1. Introduction.- 2. Materials and Methods.- 2.1. Chemicals.- 2.2. Preparation of Microsomes.- 2.3. Assay for Nitrosopyrrolidine Metabolism.- 2.4. Large-Scale Production of Metabolites.- 2.5. Mutagenesis Assay of NPYR with E. coli WU 3610 (tyr,leu).- 2.6. Mutagenesis Assay of Nitrosohexamethyleneimine.- 3. Results and Discussion.- 3.1. Nitrosopyrrolidine.- 3.2. Nitrosohexamethyleneimine.- 4. Conclusion.- 5. References.- 10. Structure—Activity Relations in Carcinogenesis by N-Nitroso Compounds.- 1. Introduction.- 2. Nitrosoalkylamides.- 3. Alkylation by Nitrosamines.- 4. Nitrosomethylalkylamines (X).- 5. Substituted Acyclic Nitrosamines.- 6. Cyclic Nitrosamines.- 7. Substituted Cyclic Nitrosamines.- 8. Derivatives of Nitrosopiperidine.- 9. Conclusion.- 10. References.- 11. Comparison of Mutagenic and Carcinogenic Properties: A Critique.- 1. Introduction.- 2. Tabular Summation and Integration of Results.- 2.1. Selection of Nitroso Compounds for the Comparative Study.- 2.2. In Vitro Assays.- 2.3. In Vivo Assay.- 3. Comparison of Mutagenic End Points.- 4. Relationship between Short-Term Test Results and Carcinogenicity.- 4.1. Qualitative Relationships.- 4.2. Quantitative Relationships.- 5. Precautions in Interpretation and Extrapolation.- 6. References.