Abstract

In support of the long range goals of this project, to explore the toxicological importance of aliphatic epoxides in the metabolism of alkene compounds, we will continue to study structure-mutagenicity relationships for such epoxides and attempt to develop QSAR equations to describe the mutagenicity of series of related epoxides. Compounds of interest are (a) aryl alkene oxides, b) cyclohexene oxide derivatives and their bicyclic analogues, c) aliphatic epoxide metabolites of drugs and environmental contaminants, d) methylenecyclo oxides, and e) epoxides related to fecapentaene. Mutagenicity will be measured by the plate-incorporation and liquid-preincubation procedures of the Ames test. The liquid test will also be used to study detoxification by using the Ames test in the presence of S9 liver fractions and their subfractions. These tests will be followed by HPLC for the detection of diol and glutathione detoxification products. For selective epoxides and their alkene precursors, it is planned to test the correlations and predictions gained from the Ames bacterial testing with in vivo testing using alkaline DNA unwinding assays and sister chromatid exchange as the end points. Specific-site alkylation studies of nucleosides and DNA will be extended by a comparison of N versus O alkylations as a function of SN1 or borderline SN2 versus SN2 reactions.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES003345-08
Application #
3250566
Study Section
Toxicology Study Section (TOX)
Project Start
1983-09-28
Project End
1989-08-31
Budget Start
1987-09-01
Budget End
1988-08-31
Support Year
8
Fiscal Year
1987
Total Cost
Indirect Cost

  Institution

Name
University of Michigan Ann Arbor
Department
Type
Schools of Pharmacy
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109

  Publications

Sinsheimer, J E; Chen, R; Das, S K et al. (1993) The genotoxicity of enantiomeric aliphatic epoxides. Mutat Res 298:197-206
Tan, R S; Chu, E H; Sinsheimer, J E (1993) Molecular analysis of hypoxanthine phosphoribosyl transferase mutants induced by glycidyl 1-naphthyl ether in mouse spleen cells in vivo. Environ Mol Mutagen 22:71-7
Einisto, P; Hooberman, B H; Sinsheimer, J E (1993) Base-pair mutations caused by six aliphatic epoxides in Salmonella typhimurium TA100, TA104, TA4001, and TA4006. Environ Mol Mutagen 21:253-7
Hooberman, B H; Chakraborty, P K; Sinsheimer, J E (1993) Quantitative structure-activity relationships for the mutagenicity of propylene oxides with Salmonella. Mutat Res 299:85-93
Das, L; Das, S K; Chu, E H et al. (1993) Chromosomal aberrations in mouse lymphocytes exposed in vivo and in vitro to aliphatic epoxides. Mutat Res 299:19-24
Chen, R; Nguyen, P; You, Z et al. (1993) Enantioselective detoxication of optical isomers of glycidyl ethers. Chirality 5:501-4
Sinsheimer, J E; Hooberman, B H; Das, S K et al. (1992) Genotoxicity of chryseno[4,5-bcd]thiophene and its sulfone derivative. Environ Mol Mutagen 19:259-64
van den Eeckhout, E; Coene, J; Claereboudt, J et al. (1991) Comparison of the isolation of adducts of 2'-deoxycytidine and 2'-deoxyguanosine with phenylglycidyl ether by high-performance liquid chromatography on a reversed-phase column and a polystyrene-divinylbenzene column. J Chromatogr 541:317-31
Sinsheimer, J E; Giri, A K; Hooberman, B H et al. (1991) Mutagenicity in Salmonella and sister chromatid exchange in mice for 1,4-, 1,3-, 2,4-, and 3,4-dimethylphenanthrenes. Environ Mol Mutagen 17:93-7
Giri, A K; Messerly, E A; Chakraborty, P K et al. (1990) DNA strand breaks in liver for four aliphatic epoxides in mice. Mutat Res 242:187-94

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