Molecular Biology of Mutagens and Carcinogens

I Introduction.- II Chemicals as Environmental Mutagens and Carcinogens.- III Intrinsic Properties of Nucleic Acids.- A. Introduction 15.- B. Reactions with Water.- 1. Depurination and Depyrimidination.- 2. Deamination.- 3. Phosphodiester Cleavage.- C. Reversible Equilibrium Reactions.- 1. Tautomerism.- 2. Ionization.- 3. Syn-Anti Rotation.- D. Fidelity in Nucleic Acid Synthesis.- E. Transcription and Replication of Modified Templates.- IV Reactions of Directly Acting Agents with Nucleic Acids.- A. Introduction.- B. Simple Nonalkylating Agents.- 1. Nitrous Acid.- 2. Bisulfite.- 3. Hydroxylamine, Methoxyamine.- 4. Hydrazine.- 5. Formaldehyde.- C. Monofunctional Alkylating Agents.- 1. Introduction.- 2. Alkylation of Nucleosides and Nucleotides.- 3. Alkylation of Synthetic Polynucleotides.- 4. Alkylation of Nucleic Acids in Vitro.- 5. Alkylation of Nucleic Acids in Vivo.- a. General Considerations.- b. Chemical Reactions.- D. Bifunctional Alkylating Agents.- E. Cyclic Alkylating Agents.- 1. Mustards.- 2. Lactones.- 3. Epoxides.- F. Vinyl Halides.- 1. Reaction of Metabolites with Monomers.- 2. Reaction of Chloroacetaldehyde with Polymers.- 3. Reaction of Vinyl Halides in Vivo.- G. Alkyl Carbamates.- V Metabolic Activation of Carcinogens and Mutagens.- A. Enzymatic Activation of Polycyclic Aromatic Hydrocarbons.- 1. Introduction.- 2. Monooxygenases or Arylhydrocarbon Hydrolases.- a. Distribution.- b. Assay of Arylhydrocarbon Hydrolases.- 3. Cytochrome P-450.- a. Mechanism of Induction.- b. Rabbit Microsomal Cytochromes P-450.- c. Rat Microsomal Cytochromes P-450.- d. Mouse Microsomal Cytochromes P-450.- e. Human Liver Microsomal Cytochomes P-450.- 4. NADPH-Cytochrome P-450 Reductase.- 5. Epoxide Hydrolase.- a. Distribution.- b. Assay of Epoxide Hydrolase.- c. Regulation of Epoxide Hydrolase Induction.- d. Mechanism of Epoxide Hydrolase Action.- 6. Conjugation Enzymes.- a. Glutathione-S-Transferase.- b. Sulfotransferase.- c. UDP-Glucuronyl Transferase.- d. Relationship between Conjugation Reactions and Carcinogenicity.- B. Specific Metabolites of Polycyclic Aromatic Hydrocarbons.- 1. Benzo[a]pyrene.- 2. Other Polycyclic Aromatic Hydrocarbons.- a. Benz[a]anthracene.- b. 7-Methlbenz[a]anthracene.- c. 7,12-Dimethylbenz[a]anthracene.- d. 3-Methlycholanthrene.- C. Enzymatic Activation of N-Substituted Aromatic Compounds and Resulting Metabolites.- 1. N-Oxidation to Arylhydroxamic Acids.- 2. N-Oxidation of Arylamines.- 3. Sulfotransferase.- 4. N,O-Acyltransferase.- 5. Deacetylases.- 6. Free Radical Activation.- 7. O-Glucuronides of Arylhydroxamic Acids.- 8. N-Glucuronides of Arylhydroxylamines.- D. Summary.- VI Reactions of Metabolically Activated Carcinogens with Nucleic Aclds.- A. Detection of DNA-Carcinogen Adducts.- 1. Characterization of DNA-Carcinogen Adducts.- 2. Postlabeling Methods to Detect DNA-Carcinogen Adducts.- 3. Radioimmunoassay of DNA-Carcinogen Adducts.- B. Polycyclic Aromatic Hydrocarbons.- 1. Benzo[a]pyrene.- 2. Benz[a]anthracene.- 3. 7-Methylbenz[a]anthracene.- 4. 7,12-Dimethylbenz[a]anthracene.- 5. 3-Methylcholanthrene.- C. N-Substituted Aromatic Compounds.- 1. N-2-Acetylaminofluorene.- 2. N-Methyl-4-Aminoazobenzene.- 3. 2-Naphthylamine.- 4. 1-Naphthylamine.- 5. Benzidine.- 6. 4-Nitroquinoline-1-0xide.- 7. Heterocyclic Amines from Amino Acid and Protein Pyrolysates.- a. Characterization.- b. Metabolic Activation and Binding to DNA.- D. Naturally Occurring Carcinogens.- 1. Aflatoxins.- a. Biological Effects.- b. Metabolism and Activation of AFB1.- c. Formation of DNA Adducts.- 2. Sterigmatocystin.- 3. Safrole.- 4. Estragole.- VII Conformation of DNA Modified by Bulky Aromatic Carcinogens.- A. Introduction.- B. Methods of Analysis.- C. Conformation of DNA-7,8-Dihydrodiol-9,lO-Oxide-Benzo[a]pyrene Adducts.- D. Conformation of DNA Modified by N-Substituted Aromatic Compounds.- 1. Conformation of Acetylaminofluorene- and AminofluoreneModified DNA.- 2. Conformation of DNA Modified by N-Hydroxy-1-Naphthylamine.- VIII Repair in Mammalian Organs and Cells.- A. Introduction.- B. In Vivo Removal of Alkyl Derivatives.- C. Mechanisms of Repair of Alkyl Derivatives in Eukaryotes.- D. In Vivo Removal of Aromatic Derivatives.- IX Site-Directed Mutagenesis.- Appendix A UV Spectral Characteristics and Acidic Dissociation Constants of Modified Bases, Nucleosides, and Nucleotides.- Appendix B Acid, Neutral, and Basic Spectra of Bases, Nucleosides, Nucleotides, and 55 Modified Derivatives.