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

The mrili) lliulr;t/ini"s. monomi lli>llmlra/inr, 1,1-dimethylhydrazinc, and 1,2-dimethyHiydrazinc, are known carcinogens but only weak mutagens in the Ames test. Chemical oxidation of these compounds by potassium fcrricyanide greatly enhanced their mutagenicity to an Escherichia coli atla mutant and converted them into inducers of the adaptive response of /•'. col! to alkylation damage. Knzymatic oxidation of monomethylhydrazinc by horseradish peroxidase-H2Oj 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), ""methylguanine and/or {/-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 mutagcnic/carcinogcnic derivatives.