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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES003257-08
Application #
3250433
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1984-01-01
Project End
1995-06-30
Budget Start
1992-07-01
Budget End
1993-06-30
Support Year
8
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Institute for Cancer Prevention
Department
Type
DUNS #
City
Valhalla
State
NY
Country
United States
Zip Code
10595
Sodum, R S; Fiala, E S (2001) Analysis of peroxynitrite reactions with guanine, xanthine, and adenine nucleosides by high-pressure liquid chromatography with electrochemical detection: C8-nitration and -oxidation. Chem Res Toxicol 14:438-50
Sodum, R S; Akerkar, S A; Fiala, E S (2000) Determination of 3-nitrotyrosine by high-pressure liquid chromatography with a dual-mode electrochemical detector. Anal Biochem 280:278-85
Sohn, O S; Fiala, E S (2000) Analysis of nitrite/nitrate in biological fluids: denitrification of 2-nitropropane in F344 rats. Anal Biochem 279:202-8
Sodum, R S; Fiala, E S (1998) N2-amination of guanine to 2-hydrazinohypoxanthine, a novel in vivo nucleic acid modification produced by the hepatocarcinogen 2-nitropropane. Chem Res Toxicol 11:1453-9
Fiala, E S; Sohn, O S; Li, H et al. (1997) Inhibition of 2-nitropropane-induced rat liver DNA and RNA damage by benzyl selenocyanate. Carcinogenesis 18:1809-15
Sodum, R S; Fiala, E S (1997) Amination of tyrosine in liver cytosol protein of male F344 rats treated with 2-nitropropane, 2-nitrobutane, 3-nitropentane, or acetoxime. Chem Res Toxicol 10:1420-6
Fiala, E S; Sodum, R S; Hussain, N S et al. (1995) Secondary nitroalkanes: induction of DNA repair in rat hepatocytes, activation by aryl sulfotransferase and hepatocarcinogenicity of 2-nitrobutane and 3-nitropentane in male F344 rats. Toxicology 99:89-97
Sodum, R S; Sohn, O S; Nie, G et al. (1994) Activation of the liver carcinogen 2-nitropropane by aryl sulfotransferase. Chem Res Toxicol 7:344-51
Sodum, R S; Nie, G; Fiala, E S (1993) 8-Aminoguanine: a base modification produced in rat liver nucleic acids by the hepatocarcinogen 2-nitropropane. Chem Res Toxicol 6:269-76
Swenson, D H; el-Bayoumy, K; Shuie, G H et al. (1993) Synthesis of N-(purin-8-yl)arylamines. Chem Res Toxicol 6:480-5

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