The broad objectives of the proposed research are to explore the chemical basis of the bioactivation and biotransformation of halogen- and sulfur-containing xenobiotics and environmental chemicals and their metabolites, the enzymology of bioactivation, and the development of in vitro expression systems to study haloalkene bioactivation. There are four Specific Aims:
Specific Aim 1 : The objective of this aim is to study the glutathione- and cysteine-conjugate beta-lyase-dependent bioactivation of haloalkenes. The goals include (a) the investigation of the activation of the microsomal glutathione transferase with haloalkenes as substrates, (b) investigation of the fate of 3H-labeled cysteine S-conjugates, of 13C-labeled cysteine S-conjugates by 13C-NMR spectroscopy, and of cysteine S-conjugates by Fourier-transform ion cyclotron resonance mass spectrometry, (c) the development of expression systems for studying the biosynthesis and bioactivation of glutathione- and cysteine S-conjugates of haloalkenes, and (d) the enzymology and molecular biology of aminoacylases that process haloalkene-derived mercapturic acids.
Specific Aim 2 : The objective of these studies is to map the tissue and organ distribution of mRNAs and enzymes of the beta-lyase pathway by immunohistochemistry, in situ hybridization, and in situ reverse-transcriptase polymerase chain reaction.
Specific Aim 3 : The objective of these studies is to investigate the bioactivation of dichloroacetic acid, which is a terminal product of the beta-lyase-dependent bioactivation of haloalkenes, as well as a drinking-water contaminant and a rodent carcinogen.
Specific Aim 4 : The objective of these studies is to investigate the bioactivation, biotransformation, and mutagenicity (Ames test) of the methionine-derived, food mutagen 2-chloro-4-methylthiobutanoic acid, which has been identified in processed fish. The proposed studies address an important human health issue: many of the halogen-and sulfur-containing compounds or classes of compounds are important environmental contaminants. Haloalkanes and haloalkenes, particularly chloroalkanes and chloroalkenes, are among the most common environmental chemicals, and several are carcinogenic in rodent bioassays. Because of widespread environmental contamination and occupational exposure, some, e.g., trichloroethene and tetrachloroethene, are listed as EPA Priority Chemicals. A thorough understanding of the bioactivation mechanisms of toxic halogen- and sulfur-containing compounds is important for assessing the hazards associated with human exposure and for the design of experiments to test the biological effects of such compounds in long-term animal studies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES003127-18
Application #
2909969
Study Section
Toxicology Subcommittee 2 (TOX)
Project Start
1982-07-01
Project End
2001-04-30
Budget Start
1999-05-01
Budget End
2000-04-30
Support Year
18
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Rochester
Department
Pharmacology
Type
Schools of Dentistry
DUNS #
208469486
City
Rochester
State
NY
Country
United States
Zip Code
14627
Board, Philip G; Anders, M W (2007) Glutathione transferase omega 1 catalyzes the reduction of S-(phenacyl)glutathiones to acetophenones. Chem Res Toxicol 20:149-54
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

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