Alkylation of DNA related to organ-specific carcinogenesis by N-nitroso compounds.

Alkylation of DNA by a number of methylating and ethylating carcinogens, mainly N-nitroso compounds, has been examined in target and non-target organs of rats and Syrian hamsters. Six hours after administration by gavage of small doses identical to those given twice weekly for several months to elicit tumours, animals were killed and dissected. DNA was isolated from several organs and hydrolysed, and the content of methyl- and ethylguanines was measured using high-performance liquid chromatography for separation. In most experiments, radiolabelled carcinogen was used, but in some cases measurement of alkylguanines was by fluorescence. Methylation, O6- and N7-, by methylating compounds was much more extensive than ethylation by the corresponding ethyl compounds, irrespective of their relative potencies in inducing tumours. Similar patterns of alkylation were found in target organs and in non-target organs of the carcinogens. Only marginal differences in methylation were seen with N-nitro-sobis(2-oxopropyl)amine between male and female rat livers, although liver tumours are induced only in females, in feminized males and in old males. Deuterium labelling of the methylene of N-nitrosoethylmethylamine had little effect on methylation or ethylation of DNA in rat liver, although the deuterated compound was a much more potent liver carcinogen. The conclusion is that reactions of the carcinogen other than alkylation of DNA are important in giving rise to tumours.