Oxime, and Related Compounds Cyclopentanone Primary Nitroalkanes, Secondary Nitroalkanes, Comparison of Oxidative Damage to Rat Liver DNA and RNA by Updated Version

The hepatocarcinogen 2-nitropropane causes oxidative damage to liver DNA and RNA after administration to rats; increases in 8-hydroxydeoxyguanosine and formation of an unknown moiety (DM ) in DNA, plus increases in 8-hydroxyguanosine and the appearance of two unidentified peaks (KM and R\2) in RNA were observed by high-performance liquid chromatography of nucleosides from 2-nitropropane-treated rats using electrochemical detection (E. S. Fiala et al.. Cancer Res., 49:5518-5522, 1989). In the present study, damage to Sprague-Dawley rat liver RNA and DNA was assessed to determine whether the characteristic pattern of oxidative nucleic acid damage caused by 2-nitropropane also occurred after i.p. administration of primary nitroalkanes, other secondary nitroalkanes, 2-methyl-2-nitropropane (a tertiary nitroalkane), and cyclopentanone oxime. All of the secondary nitroalkanes and cyclopentanone oxime significantly increased levels of 8-hydroxyguanine in both DNA and RNA and caused the appearance of DX1, RX1, and RX2. The primary nitroal kanes and the tertiary nitroalkane 2-methyl-2-nitropropane did not cause a similar pattern of nucleic acid damage. The rates of reprotonation of nitronates of the secondary nitroalkanes to the respective un-ionized neutral forms at pH 7.7 were more than 20-fold less than the rates of reprotonation of primary nitroalkane nitronates, suggesting that the anionic nitronates, rather than neutral compounds, are more immediately responsible for the DNA and RNA damage observed in vivo. Since 8hydroxyguanine is a miscoding lesion in DNA, these results suggest the possibility, still to be rigorously tested, that hepatocarcinogenicity may be associated not only with 2-nitropropane but also with other secondary nitroalkanes as well as with those ketoximes that are capable of being converted to secondary nitroalkanes in vivo.