MUTAGENICITY AND TOXICITY OF THE DNA ALKYLATION CARCINOGENS 1,2-DIMETHYLHYDRAZINE AND AZOXYMETHANE IN ESCHERICHIA-COLI AND SALMONELLA-TYPHIMURIUM

DNA alkylating agents such as 1,2-dimethylhydrazine (SDMH) and azoxyme thane (AOM) are potent carcinogens and are widely used to induce colon tumors in experimental animals, However, standard bacterial mutagenes is assays have failed to detect the mutagenic effects of these chemica ls, Using derivatives of a set of Escherichia coli test strains develo ped by Cupples and Miller (Proc. Natl, Acad. Sci, USA, 86, 5345, 1989) , we have demonstrated that under two conditions, SDMH and AOM induced point mutations by several-fold in a dose-dependent manner: (i) of si x possible base substitutions, they only induced GC-->AT transitions; and (ii) the cells must be deficient in O-6-methylguanine (O(6)MeG) DN A methyltransferase (MTase) activity, SDMH and AOM up to 200 mu g/ml w ere unable to induce His(+) revertants in a Salmonella Ames test strai n TA1535 (GC-->AT); however, in the absence of mammalian S9 extract, H is(+) revertants increased up to 55-fold upon treatment of an isogenic Salmonella strain deficient in MTase activity, These results indicate that SDMH and AOM are indeed bacterial mutagens and that lesions indu ced by them are the target of]DNA repair MTases, which probably includ e mutagenic and carcinogenic lesions such as O(6)MeG, Furthermore, var iable responses of bacterial species to SDMH- and AOM-induced mutageni city suggests a difference either in the metabolism of potential mutag ens or in the repair of specific lesions, Since O(6)MeG is not only a mutagenic lesion but also a lethal lesion if left unrepaired, we compa red the mutagenicity and toxicity of SDMH and AOM with an S(N)1-type m ethylating carcinogen, N-methyl-N'-nitro-N-nitrosoguanidine, and concl ude that SDMH and AOM are weak bacterial mutagens.