title: Oxidation of methylhydrazines to mutagenic methylating derivatives and inducers of the adaptive response of Escherichia coli to alkylation damage.
abstract: The methylhydrazines, monomethylhydrazine, 1,1-dimethylhydrazine, and 1,2-dimethylhydrazine, are known carcinogens but only weak mutagens in the Ames test. Chemical oxidation of these compounds by potassium ferricyanide greatly enhanced their mutagenicity to an Escherichia coli ada mutant and converted them into inducers of the adaptive response of E. coli to alkylation damage. Enzymatic oxidation of monomethylhydrazine by horseradish peroxidase-H2O2 also yielded products which induced the adaptive response. Thus, methylhydrazines can be oxidized to active DNA-methylating derivatives which generate methylphosphotriesters (the inducing signal of the adaptive response), O6-methylguanine and/or O4-methylthymine (the miscoding bases repaired by the Ada protein) in DNA. These observations support the suggestion that metabolic oxidation of methylhydrazines in mammalian systems may be required to generate the mutagenic/carcinogenic derivatives.
authors.affiliation: Imperial Cancer Research Fund, Clare Hall Laboratories, Potters Bar, Hertfordshire, England.
authors.forename: B
authors.initials: B
authors.lastname: Sedgwick
mesh_terms: D019813:1,2-Dimethylhydrazine; D000477:Alkylating Agents / Q000633:toxicity*; D001426:Bacterial Proteins / Q000096:biosynthesis*; D004247:DNA / Q000378:metabolism*; D004249:DNA Damage; D004127:Dimethylhydrazines / Q000378:metabolism* / Q000633:toxicity; D004926:Escherichia coli / Q000187:drug effects*; D029968:Escherichia coli Proteins; D066298:In Vitro Techniques; D009002:Monomethylhydrazine / Q000378:metabolism* / Q000633:toxicity; D009153:Mutagens / Q000378:metabolism*; D019853:O(6)-Methylguanine-DNA Methyltransferase; D010084:Oxidation-Reduction; D014157:Transcription Factors
chemical_list: D000477:Alkylating Agents; D001426:Bacterial Proteins; D004127:Dimethylhydrazines; D029968:Escherichia coli Proteins; D009153:Mutagens; D014157:Transcription Factors; D004247:DNA; C045675:Ada protein, E coli; D019853:O(6)-Methylguanine-DNA Methyltransferase; D019813:1,2-Dimethylhydrazine; D009002:Monomethylhydrazine