Surh Y J, Blomquist J C, Liem A, Miller J A
McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, Madison 53706.
Carcinogenesis. 1990 Sep;11(9):1451-60. doi: 10.1093/carcin/11.9.1451.
Our previous studies on 7-hydroxymethyl-12-methylbenz[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-10-methylanthracene (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 of liver cytosol fortified with the sulfo-group donor, 3'-phosphoadenosine-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 mumol/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 hepatic 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 HMP was reduced by dehydroepiandrosterone, 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 mutagenicity of 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-chloromethylpyrene (CMP) than SMP in bacteria, CMP formed smaller amounts 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 HMP in this regard.
我们之前对7-羟甲基-12-甲基苯并[a]蒽和6-羟甲基苯并[a]芘的研究表明，胞质磺基转移酶活性在大鼠肝脏中这些致癌物形成苄基DNA和RNA加合物的过程中起主要作用。在本研究中，我们在大鼠肝脏胞质溶胶中发现了类似的磺基转移酶活性，该活性可将9-羟甲基-10-甲基蒽（HMA）和1-羟甲基芘（HMP）激活为亲电硫酸酯代谢物。因此，在添加了磺基供体3'-磷酸腺苷-5'-磷酸硫酸酯（PAPS）的肝脏胞质溶胶存在下，将这些非湾区烃与小牛胸腺DNA一起温育，产生的苄基DNA加合物在色谱上与相应硫酸酯与脱氧鸟苷和脱氧腺苷反应得到的加合物相同。这些加合物也在腹腔注射0.25 μmol/g体重HMA或HMP的新生大鼠肝脏中产生。给予相当剂量的9-磺氧基甲基-10-甲基蒽（SMA）和1-磺氧基甲基芘（SMP）导致肝脏苄基DNA加合物水平比母体羟甲基烃高得多。当在大鼠肝脏胞质溶胶和PAPS存在下与这些细菌预孵育时，HMA和HMP均可在鼠伤寒沙门氏菌TA98中诱导His +回复突变。脱氢表雄酮可降低HMA和HMP的这种由磺基转移酶介导的致突变性，脱氢表雄酮是这些烃的肝脏磺基转移酶活性的抑制剂。SMA和SMP具有直接致突变性，其内在的细菌致突变性受到谷胱甘肽（GSH）和GSH-S-转移酶活性的抑制。生理浓度的氯离子通过形成9-氯甲基-10-甲基蒽增强了SMA的细菌致突变性，正如Henschler等人之前对SMP所观察到的那样。与1-氯甲基芘（CMP）在细菌中的致突变性高于SMP相反，CMP在大鼠肝脏中形成的苄基DNA加合物比硫酸酯少。SMA和SMP是小鼠中的弱皮肤肿瘤启动剂，但在这方面它们比HMA和HMP更具活性。
