SULFOTRANSFERASE-MEDIATED GENOTOXICITY OF PROPANE 2-NITRONATE IN CULTURED OVINE SEMINAL-VESICLE CELLS

2-Nitropropane (?2-NP) is: a well-known genotoxin and carcinogen in ra t liver. Several metabolic pathways, particularly cytochrome P450-, pe roxidase- and sulfotransferase-dependent ones, have been suggested to lead to the formation of DNA-reactive species from 2-NP. Because rat l iver cells express most types of xenobiotic-metabolizing enzymes, the role of specific pathways in the metabolic activation of 2-NP is diffi cult to assess in these cells. We have therefore investigated the geno toxicity of 2-NP and its anionic form, propane ?,2-nitronate (P2N), in cultured ovine seminal vesicle (OSV) cells. OSV cells lack cytochrome P450-dependent monooxygenase activity, but express prostaglandin-H-sy nthase (PHS) and, as we found out, phenol sulfotransferase. The induct ion of DNA, repair synthesis and specific DNA modifications served as indicators for the genotoxicity of 2-NP and P2N. Both forms strongly i nduced repair, P2N being more active than 2-NP. The secondary nitroalk anes nitrocyclopentane and nitrocyclohexane also induced repair, where as 1-nitropropane and the reduction product of 2-NP, acetone oxime, di d not. P2N also elicited the formation of the characteristic DNA modif ications 'DXI' and 8-aminodeoxyguanosine and increased the level of 8- oxodeoxyguanosine residues in the DNA. Pretreatment of OSV cells with indomethacin, an inhibitor of PHS, affected neither the induction of r epair nor the formation of the DNA modifications, and P2N was not a re ducing substrate for the PHS-peroxidase activity. In contrast, the sul fotransferase inhibitor pentachlorophenol strongly reduced genotoxicit y. The results show that cytochrome P450-dependent monooxygenases are not required for the metabolic conversion of secondary nitroalkanes or their nitronates into DNA-damaging products, nor is Pi-IS involved in the metabolic activation. instead, the data corroborate an essential role of sulfotransferase(s) in the genotoxicity and carcinogenicity of secondary nitroalkanes. Moreover, it is demonstrated for the first ti me that these compounds can be genotoxic in cells other than hepatocyt es ol hepatoma cells. This implies that in species other than the rat, organs other than the liver can be targets for the genotoxicity, and possibly carcinogenicity, of secondary nitroalkanes. (C) 1998 Elsevier Science B.V.