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

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, whereas most hydrocarbons lacking alkyl substituents undergo a bio-alkylation substitution reaction in the mesoanthracenic position(s) or L-region as a necessary first step in carcinogenesis. 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.