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Oxidation of Methylhydrazines to Mutagenic Methylating Derivatives and Inducers of the Adaptive Response of Escherichia coli to Alkylation Damage

Imperial Cancer Research Fund, Clare Hall Laboratories, South Mimms, Potters Bar, Hertfordshire, EN6 3LD, England

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 methyl-phosphotriesters (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.

Received 1/30/92. Accepted 4/24/92.

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