Kreis P, Brandner S, Coughtrie M W, Pabel U, Meinl W, Glatt H, Andrae U
GSF-National Research Center for Environment and Health, Institute of Toxicology, D-85764 Neuherberg, Germany.
Carcinogenesis. 2000 Feb;21(2):295-9. doi: 10.1093/carcin/21.2.295.
The industrial solvent 2-nitropropane (2-NP) is a genotoxic hepatocarcinogen in rats. The genotoxicity of the compound in rats has been attributed to sulfotransferase-mediated formation of DNA-reactive nitrenium ions from the anionic form of 2-NP, propane 2-nitronate (P2N). Whether human sulfotransferases are capable of activating P2N is unknown. In the present study we have addressed this question by investigating the genotoxicity of P2N in various V79-derived cell lines engineered for expression of individual forms of human sulfotransferases, the phenol-sulfating and the monoamine-sulfating phenol sulfotransferases (hP-PST and hM-PST) and the human hydroxysteroid sulfotransferase (hHST). Genotoxicity was assessed by measuring the induction of DNA repair synthesis and by analyzing the formation of DNA modifications. P2N induced repair synthesis in V79-hP-PST and V79-hM-PST cells, whereas induction of repair synthesis in V79-hHST cells was negligible. P2N also resulted in the formation of 8-aminodeoxyguanosine and increased the level of 8-oxodeoxyguanosine in V79-hP-PST cells, but not in the parental V79-MZ cells, which do not show any sulfotransferase activity. Acetone oxime, the tautomeric form of the first reduction product of 2-NP, 2-nitrosopropane, was inactive in all cell lines. The results show that the human phenol sulfotransferases P-PST and M-PST are capable of metabolically activating P2N (P-PST >> M-PST) and that the underlying mechanism is apparently identical to that resulting in the activation of P2N in rat liver, where 2-NP causes carcinomas. These results support the notion that 2-NP should be regarded as a potential human carcinogen.
工业溶剂2-硝基丙烷（2-NP）是大鼠中的一种基因毒性致癌物。该化合物在大鼠中的基因毒性归因于磺基转移酶介导的从2-NP的阴离子形式丙烷2-硝基酸盐（P2N）形成DNA反应性氮鎓离子。人类磺基转移酶是否能够激活P2N尚不清楚。在本研究中，我们通过研究P2N在为表达各种人类磺基转移酶、酚硫酸化和单胺硫酸化酚磺基转移酶（hP-PST和hM-PST）以及人类羟基类固醇磺基转移酶（hHST）而构建的各种V79衍生细胞系中的基因毒性来解决这个问题。通过测量DNA修复合成的诱导并分析DNA修饰的形成来评估基因毒性。P2N在V79-hP-PST和V79-hM-PST细胞中诱导修复合成，而在V79-hHST细胞中修复合成的诱导可忽略不计。P2N还导致V79-hP-PST细胞中8-氨基脱氧鸟苷的形成并增加8-氧代脱氧鸟苷的水平，但在不显示任何磺基转移酶活性的亲本V79-MZ细胞中则没有。丙酮肟是2-NP的第一个还原产物2-亚硝基丙烷的互变异构体，在所有细胞系中均无活性。结果表明，人类酚磺基转移酶P-PST和M-PST能够代谢激活P2N（P-PST >> M-PST），并且潜在机制显然与导致大鼠肝脏中P2N激活的机制相同，在大鼠肝脏中2-NP会导致癌症。这些结果支持2-NP应被视为潜在人类致癌物的观点。
