Mutagenicity of 3'-methyl-N,N-dimethyl-4-amino azobenzene metabolites and related compounds

To elucidate the mechanism of metabolic activation of 3'-methyl-N,N-dimethyl-4-aminoazobenzene (3'-Me-DAB), the mutagenicity of its metabolites and some related azo compounds towards Salmonella typhimurium TA-98 and TA-100 was investigated. Mutagenicity of the metabolites, either N-demethylated or oxidized at the 3'-methyl group, was expressed only in the presence of a 9000 g supernatant of rat liver homogenate (S-9 mix). Of these metabolites, 3'-hydroxymethyl-aminoazo compounds showed potent mutagenic activity towards S. typhimurium TA-98 and TA-100 and gave clear-cut linear dose-response curves. In contrast, 3,3'-bis-(chloromethyl)azobenzene, a model compound for the reactive ester of a 3'-hydroxymethyl-azo compound having no 4-amino group, exerted mutagenicity on both strains of bacteria in the absence of S-9 mix and was, therefore, a direct mutagen. On the other hand, with the exception of 3'-Me-4'-OH-DAB and p-phenylenediamine and its N-methyl and N,N-dimethyl derivatives, all the aryl hydroxylated or azo-reduced metabolites were not mutagenic towards the bacteria. These findings indicate that the 3'-hydroxymethyl group is important in the expression of mutagenicity by these azo compounds and that oxidative metabolism of the 3'-methyl group in 3'-Me-DAB may be one of the mutagenic activation reactions.