Biosynthesis of the potent carcinogen 7,12-dimethylbenz[ a]anthracene

Abstract

Earlier studies from this laboratory of the metabolism of 7,12-dimethylbenz[ a]anthracene (DMBA) and of benzo[ a]pyrene as well as studies of mutagenic and carcinogenic activity of some of the metabolic products led to the concept that a necessary first step in carcinogenesis by most alkyl substituted polycyclic hydrocarbons is biotransformation to a meso-anthracenic hydroxyalkyl metabolite [5], whereas most hydrocarbons lacking alkyl substituents undergo a bio-alkylation substitution reaction in the mesoanthracenic positions(s) or L-region as a necessary first step in carcinogenesis [6]. According to this unified hypothesis, all strong polycyclic hydrocarbon carcinogens must either, themselves, bear a meso-anthracenic alkyl substituent or else undergo a bio-alkylation substitution reaction in vitro and in vivo. Here we report that the weak carcinogen benz[ a]anthracene undergoes meso-anthracenic methylation by S-adenosyl- l-methionine (SAM), in the presence of a rat liver cytosol preparation, in vitro, to form DMBA and presumably the moderately active carcinogens 7-methylbenz[ a]anthracene and 12-methylbenz[ a]anthracene. These compounds are substrates for further L-region methylation to form the strong carcinogen, DMBA.