Mutagenicity of carcinogenic methylating agents is associated with a specific DNA modification

Abstract

The carcinogenic potency of simple aliphatic alkylating agents such as the alkylnitrosamides and the alkylmethanesulphonates is positively correlated with their ability to alkylate the relatively weakly nucleophilic oxygen atoms in DNA, particularly the O⁶-atom of guanine^1–4. Differences in the spectrum of DNA alkylations produced by these agents can be rationalised on chemical grounds in that the electrophilic reactivity of the alkylating species determines the extent to which it will react at sites of weaker nucleophilicity^4–6. Alkylation of the more strongly nucleophilic ring nitrogen atoms of the purine bases, which is the main site of reaction with all these agents, appears to be much less important in alkylation carcinogenesis. O⁶-alkyI-ation of guanine is likely to interfere with DNA base-pair hydrogen bonding⁷ and is possibly the major DNA modification responsible for the induction of GC → AT transition mutations in bacteria and bacteriophage by alkylating agents^8–10. Here, we have studied the effects of three methylating agents of contrasting carcinogenic potency on mammalian (V79 Chinese hamster) cells in culture. We report that the mutagenicity but not the cytotoxicity of each agent reflects its carcinogenicity and, furthermore, that the marked differences in mutagenicity are closely paralleled by differences in levels of O⁶-guanine methylation.