Oxidative DNA and RNA damage in the livers of Sprague-Dawley rats treated with the hepatocarcinogen 2-nitropropane.
2-Nitropropane (2-NP), a widely used industrial chemical, is a mutagen in bacteria and a powerful hepatocarcinogen in Sprague-Dawley rats. In contrast, 1-nitropropane (1-NP) is not mutagenic and does not appear to be carcinogenic. Thus far, the mechanism of carcinogenicity of 2-NP has not been examined. We report in the present work that i.p. treatment of male Sprague-Dawley rats with 100 mg/kg 2-NP results in a 3.6-fold increase (P less than 0.01) in the levels of 8-hydroxydeoxyguanosine as well as in the appearance of an additional electrochemically active species, presumably a modified deoxynucleoside, in liver DNA hydrolysates 6 h after dosing. Treatment with 2-NP also induces an 11-fold increase (P less than 0.0001) in the levels of 8-hydroxyguanosine in rat liver RNA, and results in the appearance of two new electrochemically active species (RX1 and RX2), presumably modified nucleosides. Small, statistically not significant increases of 8-hydroxyguanosine in RNA and of 8-hydroxydeoxyguanosine in DNA, as well as the induction of much smaller amounts of RX2 (but apparently not RX1) in rat liver RNA, are also observed following analogous treatment with 1-NP. Since the presence of 8-hydroxyguanine, a product of the attack of hydroxyl radicals (or other reactive oxygen species) on guanine, can cause DNA misreplication [Kuchino et al., Nature (Lond.), 327: 77-79, 1987], our findings are consistent with a mechanism of hepatocarcinogenicity of 2-NP based on damage to nucleic acids from the intracellular generation of reactive forms of oxygen and/or the 2-NP free radical.
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American Health Foundation, Valhalla, New York 10595.
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D000080242:8-Hydroxy-2'-Deoxyguanosine; D000473:Alkanes / Q000633:toxicity*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000187:drug effects; D004249:DNA Damage; D003849:Deoxyguanosine / Q000032:analysis; D005609:Free Radicals; D006147:Guanine / Q000031:analogs & derivatives / Q000032:analysis; D008099:Liver / Q000187:drug effects*; D009595:Nitroparaffins / Q000633:toxicity*; D010084:Oxidation-Reduction; D011407:Propane / Q000633:toxicity / Q000031:analogs & derivatives; D012313:RNA; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D000473:Alkanes; D005609:Free Radicals; D009595:Nitroparaffins; C024829:8-hydroxyguanine; D006147:Guanine; D012313:RNA; D000080242:8-Hydroxy-2'-Deoxyguanosine; D004247:DNA; D003849:Deoxyguanosine; C016617:2-nitropropane; D011407:Propane