Secondary nitroalkanes such as 2-nitropropane (2-NP), and ketozimes such as acetone oxime and cyclohexanone oxime, are important industrial chemicals produced in quantities of millions of pounds per year. 2-NP and acetone oxime are known to be hepatocarcinogenic in rats, but the mechanism of their carcinogenicity has not yet been clarified. In the previous phase of this program we have obtained evidence that the nitronate of 2-NP is a more proximate mutagen in Salmonella than is the neutral form of the nitroalkane. Furthermore, 2-NP, as well as other 2o nitroalkanes including 3-nitropentane and nitrocyclopentane, induces the formation of increased levels of 8-hydroxyguainine, and of other, as yet unidentified specific base damage not only in DNA but also in RNA of rat liver. Acetone oxime, which can presumably by metabolically N-oxidized to 2-NP nitronate, produces a pattern of DNA and RNA damage in rat liver qualitatively identical to that produced by 2o nitroalkanes. These findings indicate a commonality between the biological effect of 2o nitroalkanes and ketoximes, and suggest that industrially important 2o nitroalkanse and ketoximes may represent hitherto unacknowledged classes of chemical carcinogens whose activity depends on increased production of reactive forms of oxygen and/or of nitroalkane free radicals. The goals of this program are to test the validity of these conclusions by 1) submitting representative 2o nitroalkanes and ketoximes to bioassay in F344 rats; 2) further characterizing the specific base damage other than 8-additional oxidative nucleic acid damage, such as the formation of thymine glycol, is induced by 2o nitroalkanes and ketoximes; 4) determining if nitroalkane nitrates and derived free radical forms of 2o nitroalkanse form direct adducts with nucleic acid bases in vitro and in vivo; and 5) determining the persistence of the nucleic acid base lesions induced by 2o nitroalkanes and ketoximes. The results of these studies are expected to lead to increased knowledge of the role of reactive forms of oxygen in the initiation of carcinogenesis, and to provide important information on possible carcinogenic hazards associated with two very widely used classes of industrial chemicals.
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