Quantitative comparisons between carcinogenicity, mutagenicity and electrophilicity of direct-acting N-nitroso compounds and other alkylating agents.
The quantitative relationship between carcinogenicity in rodents and mutagenicity in S. typhimurium was examined using 10 monofunctional alkylating agents, including N-nitrosamides, alkylmethane sulfonates and epoxides. The compounds were assayed for mutagenicity in two S. typhimurium strains (TA1535, TA100) and in plate and liquid assays. Mutagenic activity was compared with alkylating activity, half-life (solvolysis constant) and carcinogenic activity in rodents (TD50). No correlations between these variables were found. However, there was a good positive relationship between the TD50 values of the carcinogens and the initial ratios of N-7-alkylguanine to 0(6)-alkylguanine formed after reaction with double-stranded DNA in vitro (r = 0.88, p less than 0.01; n = 9). From these results, it is concluded that the N-7/0(6)-alkylguanine ratio is quantitatively related to the carcinogenic activity for this class of compounds and it may therefore be used to predict the carcinogenic potency of new compounds within this class.
D000477:Alkylating Agents / Q000633:toxicity*; D000478:Alkylation; D000818:Animals; D002273:Carcinogens; D004247:DNA / Q000378:metabolism; D051379:Mice; D009153:Mutagens; D009603:Nitroso Compounds / Q000633:toxicity*; D051381:Rats; D012486:Salmonella typhimurium / Q000187:drug effects; D013329:Structure-Activity Relationship
D000477:Alkylating Agents; D002273:Carcinogens; D009153:Mutagens; D009603:Nitroso Compounds; D004247:DNA