Intrinsic mutagenicity and electrophilicity of 1-sulfooxy-3-methylcholanthrene: Implications for metabolic activation of the carcinogen 3-methylcholanthrene

Abstract

Hydroxylation of a meso-anthracenic carbon atom with subsequent formation of a reactive ester bearing a good leaving group (e.g., sulfate) has been proposed as a possible biochemical mechanism responsible for DNA binding, mutagenicity and tumorigenicity of 3-methylcholanthrene, one of the most potent carcinogenic polycyclic aromatic hydrocarbons in experimental animals. In support of this supposition, the chemically synthesized sulfuric acid ester, 1-sulfooxy-3-methylcholanthrene (1-SMC) was directly mutagenic in bacteria and covalently bound to DNA without metabolic activation. The intrinsic mutagenicity of this reactive ester was significantly potentiated by addition of extra acetate or chloride anions to the media. Reduced glutathione and ascorbic acid protected against 1-SMC-induced mutagenesis. These findings suggest 1-SMC as a potential ultimate electrophilic and tumorigenic metabolite of 3-methylcholanthrene.