Role of Hydroxymethyl Sulfate Esters in Aromatic Hydrocarbon Carcinogenesis

The unified hypothesis, for the carcinogenic properties of aromatic hydrocarbons, predicts that hydroxylation of meso-methyl groups followed by the formation of electrophilic esters bearing a good leaving group, such as sulfate, phosphate, or acetate, play a role in the DNA damage, mutagenesis and carcinogenesis of alkyl-substituted hydrocarbons such as 7,12-dimethylbenz[a]anthracene, 3-methylcholanthrene, and 6-methylbenzo[a]pyrene, and even unsubstituted hydrocarbons such as benzo[a]pyrene. Activation of hydroxyalkyl metabolites to electrophilic mutagens has been shown to be catalyzed by 3′-phosphoadenosine-5′-phosphosulfate-dependent sulfotransferase activity. Recent studies demonstrate that a number of sulfate esters account for most, if not all, of the complete carcinogenic activity of their hydroxyalkyl precursors by repeated s.c. injection in female Sprague-Dawley rats. In addition to hydroxymethyl hydrocarbons, some aromatics with secondary benzylic hydroxyl groups are also metabolically activated through sulfuric acid esterification to electrophilic mutagens and potential ultimate carcinogens.