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Oxidative DNA and RNA Damage in the Livers of Sprague-Dawley Rats Treated with the Hepatocarcinogen 2-Nitropropane¹

American Health Foundation, Valhalla, New York 10595

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 < 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 < 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.

¹ This investigation was supported in part by National Institute of Environmental Health Sciences Grant ES03257 and National Cancer Institute Grant CA17613.

² To whom requests for reprints should be addressed, at Division of Biochemical Pharmacology, American Health Foundation, Dana Road, Valhalla, NY 10595.

Received 5/23/88. Revised 8/ 4/88. Revised 5/ 2/89. Revised 7/ 5/89. Accepted 7/14/89.

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