Activation of propane 2-nitronate to a genotoxicant in V79-derived cell lines engineered for the expression of rat hepatic sulfotransferases

2-Nitropropane (2-NP) is a genotoxic hepatocarcinogen in rats. The genotoxi city of the compound has been attributed to a sulfotransferase-mediated for mation of DNA-reactive species from the anionic farm of 2-NP, propane 3-nit ronate (P2N). Several observations have suggested that sulfotransferases (S ULTs) 1A1 and/or 1C1 may be important in the activation of P2N to a genotox icant in rat liver, but a definite proof is lacking. In order to identify t he sulfotransferase(s) of rat liver that are capable of activating P2N, we have investigated the genotoxicity of P2N in various V79-derived cell lines engineered for expression of individual forms of rat hepatic sulfotransfer ases. Genotoxicity was assessed by measuring the induction of DNA repair sy nthesis, 1-Hydroxymethylpyrene (HMP), which is metabolically activated by m ost sulfotransferases, served as a positive control. Neither P2N nor HMP in duced DNA repair in the parental V79-MZ cells, which do not show any sulfot ransferase activity. P2N was also inactive in V79-rHSTa and V79-rHST20 cell s, which express specific hydroxysteroid sulfotransferases. By contrast, a clear and concentration-dependent induction of repair synthesis by P2N was observed in V79-rPST-IV and V79-rST1C1 cells, which express rat SULT1A1 and SULT1C1, respectively. HMP was genotoxic in all sulfotransferase-expressin g cell lines. Acetone oxime (AO), the tautomeric form of the first reductio n product of 2-NP, 2-nitrosopropane, was inactive in all cell lines. The re sults corroborate the essential role of sulfotransferases in the metabolic activation of P2N to genotoxic products and identify two rat sulfotransfera ses which are capable of catalyzing the activation step. (C) 1999 Elsevier Science B.V. All rights reserved.