Metabolic activation of the N-hydroxy derivative of the carcinogen 4-aminobiphenyl by human tissue sulfotransferases.

The role of human sulfotransferase(s) in the bioactivation of the N-hydroxy (N-OH) metabolite of the human bladder carcinogen 4-aminobiphenyl (ABP) was investigated in vitro with human tissue cytosols. Using an enzymatic assay consisting of a PAPS-regenerating system, [3H]N-OH-ABP, calf thymus DNA and tissue cytosols, the sulfotransferase-mediated metabolic activation of N-OH-ABP was determined as the PAPS-dependent covalent binding of the N-OH substrate to DNA. With cytosols prepared from various tissues, we found that the sulfotransferase(s) in human liver, and to a lesser extent colon, can readily metabolize N-OH-ABP. No PAPS-dependent metabolic activation was detected with cytosols prepared from human pancreas or from the carcinogen target tissue, the urinary bladder epithelium. The N-OH-ABP sulfotransferase activities of liver and colon cytosols from different individuals were highly correlated with their thermostable phenol sulfotransferase (TS-PST) activity (liver, r = 0.99, P < 0.01; colon, r = 0.88, P < 0.01), but not with activities for the thermolabile phenol sulfotransferase (TL-PST; liver, r = 0.29; colon, r = 0.53), or for the dehydroepiandrosterone sulfotransferase (DHEA-ST; liver, r = 0.32; colon, negligible activity). N-OH-ABP sulfotransferase activity was highly sensitive to inhibition by a selective TS-PST inhibitor, 2,6-dichloro-4-nitrophenol (IC50 = 0.7 microM), and by p-nitrophenol, but was unaffected by competitive inhibitors of TL-PST (dopamine) or DHEA-ST (DHEA, DHEA-sulfate). The N-OH-ABP sulfotransferase activity also exhibited thermostability properties similar to that of the TS-PST. From these data, we conclude that human liver TS-PST but not TL-PST or DHEA-ST can metabolically activate the proximate human carcinogen N-OH-ABP to a reactive sulfuric acid ester intermediate that binds covalently to DNA. In addition, in view of the putative role of N-OH-ABP as a major transport form of the carcinogen to the urinary bladder and of the absence of sulfotransferase activity in this tissue, we hypothesize that sulfotransferase activation in the liver may actually decrease the bioavailability of N-OH-ABP toward extrahepatic tissues and thus serve as an important overall detoxification mechanism for the urinary bladder.