Activation of 1-Hydroxymethylpyrene to an Electrophilic and Mutagenic Metabolite by Rat Hepatic Sulfotransferase Activity

Abstract

Hydroxylation of meso-methyl groups with subsequent formation of reactive benzylic esters bearing a good leaving group (e.g., sulfate, phosphate, acetate, etc.) has been proposed as a possible activation pathway in the DNA binding and carcinogenicity of some methyl-substituted polycyclic aromatic hydrocarbons (Flesher, et al., 1971; Flesher, et al., 1973). The metabolic formation of such reactive esters has recently been reported by Watabe et al. (1982, 1986, 1987; Okuda, H. et al., 1986). Their studies demonstrated the formation of electrophilic and mutagenic sulfuric acid ester metabolites from 7-hydroxymethy1-12-methylbenz[a]anthracene (HMBA) and related aromatic hydrocarbons by rat liver cytosolic sulfotransferase activity (reviewed in ref. 7). Non-enzymatic interaction of these reactive esters with the amino groups of guanine and adenine residues in calf thymus DNA produced the benzylic adducts. More recently we have noted the formation of such benzylic DNA adducts in vivo in the livers of infant rats and mice treated with HMBA, 6- hydroxymethylbenzo[a]pyrene (HMBP), or their electrophilic sulfuric acid esters (Surh, Y.-J. et al., 1987, 1989). The chemically synthesized sulfuric acid ester of 1- hydroxymethylpyrene (HMP) was also found to be highly mutagenic toward Salmonella typhimurium TA98 (Watabe, T. et al., 1982) and this intrinsic mutagenicity increased dramatically in the presence of chloride ion (Henschler, R., et al. 1989). However, the biological formation of such a labile and reactive sulfuric acid ester of HMP has not been reported.