The objective of the research is to continue investigations on the metabolism and toxicity of halogenated hydrocarbons, which are important environmental chemicals. The studies will emphasize detailed investigations of reaction mechanisms, enzymology, and toxicology. Moreover, structure-toxicity studies will provide information about the mechanisms by which halogenated chemicals produce tissue damage and are important in enhancing the ability to predict toxic effects of chemicals.
The specific aims of the proposed research are: 1. To study the nephrotoxicity of S-conjugates of amino acids and glutathione. 2. To study the biological role and catalytic mechanism of microsomal glutathione S-transferases. 3. To study the role of episulfonium ion formation in the toxicity of vicinial-dihaloalkanes. The studies will contribute to the understanding of the mechanisms by which halogenated alkanes and alkenes produce toxicity. Biochemical and mechanistic studies with compounds that may be encountered under toxicologically relevant circumstances and with model compounds that are synthetically accessible and whose study yields much valuable information are important to establish an experimental and conceptual basis for future studies and for assessing the potential risk associated with exposure to halogenated alkanes and alkenes.
|Blackburn, Anneke C; Matthaei, Klaus I; Lim, Cindy et al. (2006) Deficiency of glutathione transferase zeta causes oxidative stress and activation of antioxidant response pathways. Mol Pharmacol 69:650-7|
|Anders, M W (2005) Formation and toxicity of anesthetic degradation products. Annu Rev Pharmacol Toxicol 45:147-76|
|Lim, Cindy E L; Matthaei, Klaus I; Blackburn, Anneke C et al. (2004) Mice deficient in glutathione transferase zeta/maleylacetoacetate isomerase exhibit a range of pathological changes and elevated expression of alpha, mu, and pi class glutathione transferases. Am J Pathol 165:679-93|
|Lantum, Hoffman B M; Iyer, Ramaswamy A; Anders, M W (2004) Acivicin-induced alterations in renal and hepatic glutathione concentrations and in gamma-glutamyltransferase activities. Biochem Pharmacol 67:1421-6|
|Anderson, Wayne B; Board, Philip G; Anders, M W (2004) Glutathione transferase zeta-catalyzed bioactivation of dichloroacetic acid: reaction of glyoxylate with amino acid nucleophiles. Chem Res Toxicol 17:650-62|
|Lantum, Hoffman B M; Cornejo, Judith; Pierce, Robert H et al. (2003) Perturbation of maleylacetoacetic acid metabolism in rats with dichloroacetic Acid-induced glutathione transferase zeta deficiency. Toxicol Sci 74:192-202|
|Jolivette, Larry J; Anders, M W (2003) Computational and experimental studies on the distribution of addition and substitution products of the microsomal glutathione transferase 1-catalyzed conjugation of glutathione with fluoroalkenes. Chem Res Toxicol 16:137-44|
|Board, Philip G; Taylor, Matthew C; Coggan, Marjorie et al. (2003) Clarification of the role of key active site residues of glutathione transferase zeta/maleylacetoacetate isomerase by a new spectrophotometric technique. Biochem J 374:731-7|
|Lantum, Hoffman B M; Baggs, Raymond B; Krenitsky, Daria M et al. (2002) Nephrotoxicity of chlorofluoroacetic acid in rats. Toxicol Sci 70:261-8|
|Anderson, Wayne B; Liebler, Daniel C; Board, Philip G et al. (2002) Mass spectral characterization of dichloroacetic acid-modified human glutathione transferase zeta. Chem Res Toxicol 15:1387-97|
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