Mutagenic selectivity of carcinogenic nitroso compounds. II. N,N-dimethylnitrosamine.
The genetic properties in the hepatocarcinogen N,N-dimethylnitrosamine (DMN) were examined in Drosophila for the assessment of the role of dose, cellular metabolism and genic target in its mutagenicity. Genetic activity was assayed with respect to the induction of the non-specific X-chromosome recessives (lethals and visibles) relative to the effects on specific genic sites, especially rDNA, which yields bobbed (bb) mutations. Dosses and germ cell types, which indicated that DMN induced at least some multiple-hit mutagenic events. The genetic activity of DMN was favoured by cellular metabolism for all mutational classes, as was indicated by the progressive increase in mutational classes, as was indicated by the progressive increase in mutation yield during spermatogenesis--from the metabolically inert mature sperm to the actively metabolizing spermatocyte and spermatogonia. The role of DNA methylation in the mutagenicity of DMN was deduced from quantitative assays for its genetic activity relative to the methylating nitrosamide--N-methyl-N-nitrosourethane (MNUr)--over the same dose range (1-10 mM) and on identical cell types and genic targets. In the metabolically inert cells (mature sperm), the two compounds were equally active with respect to the non-specific effects (X-recessives), but MNUr, but the two compounds were equally effective on rDNA. These results could not be entirely interpreted by the methylation hypothesis and indicated that a DMN aldehydic metabolite, structurally analogous to MNUr, might be responsible for the induction of the rDNA mutations. The rDNA selectivity index of DMN was significantly lower than for MNUr, which paralleled their relative carcinogenic verstilities. However, DMN was comparatively more effective on the tRNA genes, a feature which might be associated with its oncogenic specificity.
D000818:Animals; D004247:DNA / Q000378:metabolism; D004128:Dimethylnitrosamine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004331:Drosophila melanogaster / Q000187:drug effects / Q000378:metabolism; D005808:Genes, Recessive; D008297:Male; D009153:Mutagens; D009154:Mutation; D009602:Nitrosamines / Q000494:pharmacology*; D009605:Nitrosomethylurethane / Q000494:pharmacology*; D010641:Phenotype; D012730:Sex Chromosomes; D013094:Spermatozoa / Q000187:drug effects; D014520:Urethane / Q000031:analogs & derivatives*
D009153:Mutagens; D009602:Nitrosamines; D014520:Urethane; D009605:Nitrosomethylurethane; D004247:DNA; D004128:Dimethylnitrosamine