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© 1990 Oxford University Press

research-article

Metabolic activation of 9-hydroxymethyl-10-methylanthracene and 1-hydroxymethylpyrene to electrophilic, mutagenic and tumorigenic sulfuric acid esters by rat hepatic sulfotransferase activity

Young-Joon Surh, C. Blomquist, Amy Liem and James A. Miller 1

McArdle Laboratory for Cancer Research and Environmental Toxicology Center, University of Wisconsin Medical School Madison, WI 53706, USA

1To whom correspondence should be addressed

Our previous studies on 7-hydroxymethyl-12-methyl-benz[a]anthracene and 6-hydroxymethylbenzo[a]pyrene showed that cytosolic sulfotransferase activity plays a major role in the formation of hepatic benzylic DNA and RNA adducts by these carcinogens in rats. In the present study, we found similar sulfotransferase activity in rat liver cytosol which activates 9-hydroxymethyl-l0methylanthracene (HMA) and 1-hydroxymethylpyrene (HMP) to electrophilic sulfuric acid ester metabolites. Thus, incubation of these nonbay region hydrocarbons with calf thymus DNA in the presence ofliver cytosol fortified with the sulfo-group donor, 3'-phosphoadenoslne-5'-phosphosulfate (PAPS) produced benzylic DNA adducts that were chromatographically identical to those obtained by the reactions of the corresponding sulfuric acid esters with deoxyguanosine and deoxyadenosine. These adducts were also produced in the livers of infant rats injected i.p. with 0.25 µmol/g body wt of HMA or HMP. Administration of comparable doses of 9-sulfooxymethyl-10-methylanthracene(SMA) and 1-sulfooxymethylpyrene (SMP) resulted in much higher levels of hepatlc benzylic DNA adducts than did the parent hydroxymethyl hydrocarbons. Both HMA and HMP induced His+ revertants in Salmonella typhimurium TA98 when preincubated with these bacteria in the presence of rat liver cytosol and PAPS. This sulfotransferase-mediated mutagenicity of HMA and I-IMP was reduced by dehydroepiandro sterone, an inhibitor of hepatic sulfotransferase activity for these hydrocarbons. SMA and SMP were directly mutagenic and their intrinsic bacterial mutagenicity was inhibited by glutathione (GSH) and GSH-S-transferase activity. Chloride ion at physiological concentrations enhanced the bacterial mutagenicityof SMA through the formation of 9-chloromethyl-10-methylanthracene as previously observed for SMP by Henschler et al. In contrast to the higher mutagenicity of 1-chioromethylpyrene (CMP) than SMP in bacteria, CMP formed smalleramounts of hepatic benzylic DNA adducts in rats than the sulfuric acid ester. SMA and SMP were weak skin tumor Initiators in the mouse, but they were more active than HMA and lIMP in this regard.


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