Epoxide hydrolases convert epoxides to 1,2-dihydrodiols and determine the disposition of reactive epoxide intermediates. Since these epoxides are often the ultimate toxic or carcinogenic form of a protoxin or procarcinogen, the understanding of the nature of epoxide hydrolases and their participation in the deactivation of epoxide intermediates is essential to our ultimate understanding of mechanisms of chemical toxicity and carcinogenesis. Most studies of the role of epoxide hydrolases in xenobiotic metabolism have assumed that a single membrane-bound form of the enzyme exists. We have recently obtained evidence, however, that at least a second membrane-bound epoxide hydrolase exists which has biochemical properties very different from those of the hydrolase previously described. The purpose of the proposed studies is to examine this and other """"""""alternative"""""""" epoxide hydrolases, and to assess their involvement in the metabolism and ultimate expression of toxic and/or carcinogenic compounds. The biochemical properties and genetic control of this second epoxide hydrolase will be studied. Its participation in the conversion of active epoxide intermediates of several toxic and carcinogenic compounds will also be studied. We expect ultimately to be able to assess the toxicological importance of this heretofore overlooked enzyme. A second set of experiments will use immunological assays to determine the degree of polymorphism of epoxide hydrolase in man. If, in fact, epoxide hydrolase exists as multiple enzyme forms in man, this may have important toxicological significance, since it would imply genetically determined differences in the capacity of individuals for metabolizing active intermediates of some chemical toxins and carcinogens.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA034455-03
Application #
3172146
Study Section
Toxicology Study Section (TOX)
Project Start
1983-05-01
Project End
1986-04-30
Budget Start
1985-05-01
Budget End
1986-04-30
Support Year
3
Fiscal Year
1985
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Type
Overall Medical
DUNS #
121911077
City
Chicago
State
IL
Country
United States
Zip Code
60612
Luo, G; Guenthner, T M (1996) Covalent binding to DNA in vitro of 2',3'-oxides derived from allylbenzene analogs. Drug Metab Dispos 24:1020-7
Qato, M K; Guenthner, T M (1995) 32P-postlabeling analysis of adducts formed between DNA and safrole 2',3'-epoxide: absence of adduct formation in vivo. Toxicol Lett 75:201-7
Pirmohamed, M; Kitteringham, N R; Guenthner, T M et al. (1992) An investigation of the formation of cytotoxic, protein-reactive and stable metabolites from carbamazepine in vitro. Biochem Pharmacol 43:1675-82
Luo, G; Qato, M K; Guenthner, T M (1992) Hydrolysis of the 2',3'-allylic epoxides of allylbenzene, estragole, eugenol, and safrole by both microsomal and cytosolic epoxide hydrolases. Drug Metab Dispos 20:440-5
Hjelle, J T; Guenthner, T M; Bell, K et al. (1990) Inhibition of catalase and epoxide hydrolase by the renal cystogen 2-amino-4,5-diphenylthiazole and its metabolites. Toxicology 60:211-22
Qato, M K; Reinmund, S G; Guenthner, T M (1990) Production of monospecific antiserum to a cytosolic epoxide hydrolase from human liver. Biochem Pharmacol 39:293-300
Guenthner, T M; Hjelle, J T; Whalen, R (1989) Selective inhibition of cytosolic epoxide hydrolase activity in vitro by compounds that inhibit catalase. J Biochem Toxicol 4:241-9
Guenthner, T M; Qato, M; Whalen, R et al. (1989) Similarities between catalase and cytosolic epoxide hydrolase. Drug Metab Rev 20:733-48
Pezzuto, J M; Nanayakkara, N P; Compadre, C M et al. (1986) Characterization of bacterial mutagenicity mediated by 13-hydroxy-ent-kaurenoic acid (steviol) and several structurally-related derivatives and evaluation of potential to induce glutathione S-transferase in mice. Mutat Res 169:93-103
Guenthner, T M; Karnezis, T A (1986) Immunochemical characterization of human lung epoxide hydrolases. J Biochem Toxicol 1:67-81

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