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-hy droxy (N-OH) metabolite of the human bladder carcinogen 4-aminobipheny l (ABP) was investigated in vitro with human tissue cytosols. Using an enzymatic assay consisting of a PAPS-regenerating system, [H-3]N-OH-A BP, 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 prep ared from human pancreas or from the carcinogen target tissue, the uri nary bladder epithelium. The N-OH-ABP sulfotransferase activities of l iver and colon cytosols from different individuals were highly correla ted 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 a ctivities for the thermolabile phenol sulfotransferase (TL-PST; liver, r = 0.29; colon, r = 0.53), or for the dehydroepiandrosterone sulfotr ansferase 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 mu M), and by p-nitrophenol, but was unaffected by competitive inhibitors of TL-PST (dopamine) or DHEA-ST (DHEA, DHEA-sulfate). The N-OH-ABP su lfotransferase activity also exhibited thermostability properties simi lar to that of the TS-PST. From these data, we conclude that human liv er TS-PST but not TL-PST or DHEA-ST can metabolically activate the pro ximate human carcinogen N-OH-ABP to a reactive sulfuric acid ester int ermediate that binds covalently to DNA. In addition, in view of the pu tative role of N-OH-ABP as a major transport form of the carcinogen to the urinary bladder and of the absence of sulfotransferase activity i n this tissue, we hypothesize that sulfotransferase activation in the liver may actually decrease the bioavailability of N-OH-ABP toward ext rahepatic tissues and thus serve as an important overall detoxificatio n mechanism for the urinary bladder.