Activation of the liver carcinogen 2-nitropropane by aryl sulfotransferase.
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.
Sodum
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Division of Biochemical Pharmacology, American Health Foundation, Valhalla, New York 10595.
Sohn
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Nie
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Fiala
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D000818:Animals; D015239:Arylsulfotransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000187:drug effects; D006151:Guanosine / Q000031:analogs & derivatives / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced; D008297:Male; D009595:Nitroparaffins / Q000378:metabolism*; D009596:Nitrophenols / Q000494:pharmacology; D010416:Pentachlorophenol / Q000494:pharmacology; D011407:Propane / Q000031:analogs & derivatives* / Q000378:metabolism; D012313:RNA / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344
D002273:Carcinogens; D009595:Nitroparaffins; D009596:Nitrophenols; D006151:Guanosine; C032533:8-aminoguanosine; C015802:2,6-dichloro-4-nitrophenol; D012313:RNA; D004247:DNA; D010416:Pentachlorophenol; D015239:Arylsulfotransferase; C016617:2-nitropropane; D011407:Propane