Genetic properties of N-alpha-acetoxymethyl-N-methylnitrosamine in relation to the metabolic activation of N,N-dimethylnitrosamine.
A genetic study was undertaken in Drosophila with N-alpha-acetoxymethyl-N-methylnitrosamine, a precursor of the alpha-hydroxymethyl derivative of N,N-dimethylnitrosamine, to assess the role of alpha-carbon oxidation in toxicological activation. Genetic activity was measured for the whole testicular tissue with respect to the general response of the X chromosome (recessive lethals and visibles), as well as certain specific genic sites, including representatives of the RNA genes. The biological activity of the acetoxy compound proved to be considerably higher than that of the parent amine with respect to both cytotoxicity and mutagenicity. At low and equitoxic molarities of the 2 agents (0.1 to 1.0 and 1.0 to 10.0 mM, respectively), dose-dependence for all the investigated genetic functions followed identical patterns, which were best described by quadratic dose curves. However, the regression coefficients for the acetoxy derivative were at least 1 order of magnitude higher than the corresponding values for the amine, indicating a consistent level of mutagenic activation as a result of the alpha-acetoxymethyl substitution. At mutagenically equivalent doses, the 2 compounds gave statistically comparable frequencies of mosaicism among corresponding mutational classes and equal ribosomal DNA selectivity indices, indicating identical molecular mechanisms of mutagenesis. The higher mutagenicity of N-alpha-acetoxymethyl-N-methylnitrosamine compared to N,N-dimethylnitrosamine was paralleled by its higher carcinogenicity which would suggest that the same effective metabolites might be involved in both processes.
D004247:DNA; D004128:Dimethylnitrosamine / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004331:Drosophila melanogaster / Q000187:drug effects; D005796:Genes / Q000187:drug effects*; D005804:Genes, Lethal / Q000187:drug effects; D005808:Genes, Recessive / Q000187:drug effects; D009030:Mosaicism; D009153:Mutagens; D009602:Nitrosamines / Q000494:pharmacology*; D012335:RNA, Ribosomal / Q000096:biosynthesis; D012730:Sex Chromosomes / Q000187:drug effects
D009153:Mutagens; D009602:Nitrosamines; D012335:RNA, Ribosomal; D004247:DNA; D004128:Dimethylnitrosamine