Activation of the Liver Carcinogen 2-Nitropropane by Aryl Sulfotransferase

Abstract

8-Aminoguanine had previously been identified as one of the nucleic acid base modifications produced in livers of rats by treatment with the hepatocarcinogen 2-nitropropane (2-NP), and a hypothetical mechanism of activation of 2-NP to hydroxylamine-O-sulfonate or acetate that would lead to NH2+, an aminating species, was proposed [Sodum et al. (1993) Chem. Res. Toxicol. 6, 269-276]. We now present in vivo and in vitro experimental evidence for the activation of 2-NP to an aminating species by rat liver aryl sulfotransferase. Pretreatment of rats with the aryl sulfotransferase inhibitors pentachlorophenol or 2,6-dichloro-4-nitrophenol significantly decreased the levels of liver nucleic acid modifications produced by 2-NP treatment. Furthermore, partially purified rat liver aryl sulfotransferase was shown to activate 2-NP and 2-NP nitronate in vitro at neutral pH and 37 degrees C, to a reactive species that aminated guanosine at the C8 position. This activation was dependent on the presence of the enzyme, its specific cofactor adenosine 3'-phosphate 5'-phosphosulfate, and mercaptoethanol. As in the case of the in vitro studies, pentachlorophenol and 2,6-dichloro-4-nitrophenol inhibited the in vitro formation of 8-aminoguanosine and 8-oxoguanosine. The corresponding primary nitroalkane, 1-nitropropane, which is not mutagenic and does not appear to be carcinogenic, was not a substrate for aryl sulfotransferase in the in vitro amination of guanosine.

Dietary lycopene decreases the initiation of liver preneoplastic foci by diethylnitrosamine in the rat

“…However, β-carotene did not prevent the 2-NP-induced increase of 8-oxoguanine in rat liver DNA (54), and none of the carotenoids tested was able to decrease 2-NP hepatocarcinogenicity (this study). Our result suggests that carotenoids are not efficient in vivo scavengers of free radicals (OH·, NO 2 -, or NO·) or that the role of these radicals in 2-NP activation is less important than initially supposed, in accordance with a recent work showing the involvement of aryl sulfotransferase in the activation of 2-NP to NHJ, an aminating species that adds to guanine to form 8-aminoguanine (56). Lastly, liver DNA damage has been found to be increased by pretreatment of the rats with CYP 2B or CYP 1A inducers such as phenobarbital or β-naphthoflavone, respectively, suggesting a role for these cytochrome P-450 subfamilies in the activation of 2-NP (51).…”

Inhibition of Sulfotransferases by Xenobiotics

“…2-nitropropane (2-NP) is a constituent of cigarette smoke and a widely used industrial solvent that is reported to be a potent hepatocarcinogen in rats [196][197][198]. It has been proved that hepatic SULT activity is required for the metabolic activation of 2-NP and its anionic form, propane 2-nitronate, and also other secondary nitroalkanes, to reactive species that are capable of inducing genotoxic effects [199][200][201][202]. It has been found that PCP strongly reduced the genotoxic effects of 2-NP and other secondary nitroalkanes [203].…”

Derivation of cancer no significant risk levels and screening safety assessment for 2‐nitropropane in spray products

“…In an earlier assessment, Health Canada () attributed the genotoxicity of 2‐NP in rats to sulfotransferase‐mediated formation of DNA‐reactive nitrenium ions produced from the anionic form of 2‐NP, propane 2‐nitronate (Sodum & Fiala, ; Sodum, Nie, & Fiala, ; Sodum, Sohn, Nie, & Fiala, ). Health Canada also noted that studies showed that human sulfotransferase is also capable of causing 2‐NP to form DNA‐reactive nitrenium.…”