Xenobiotic metabolism results principally in detoxication. However, in certain instances, bioactivated and highly toxic intermediates are generated. Cellular levels of epoxide moieties resulting from chemical metabolism appear to be critical initiators of toxic damage, including genetic mutation. As a case in point, polyaromatic hydrocarbons (PAHs) are products of incomplete combustion of organic matter, are widespread environmental contaminants and are considered procarcinogens because they require metabolic activation to electrophilic reactive metabolites to exert their mutagenic and tumorigenic activities. Microsomal epoxide hydrolase, EPHX1, bioactivates PAHs, contributing to the formation of highly reactive and carcinogenic bay region and fjord region diol-epoxide intermediates. Previously, we characterized the gene structure for human EPXH1 and identified two structural polymorphisms, an exon 3 polymorphism encoding Y/H substitutions at amino acid position 113, and an exon 4 H/R substitution at position 139. Results of many molecular epidemiological studies have since associated EPHX1 allelic variation as a risk factor for various diseases, most notably lung cancer. Recently, a paradigm-shifting report from our laboratory demonstrated that the expression of the human EPHX1 gene is driven by the use of alternative promoters, with a far upstream promoter, termed E1-b, preferentially driving expression EPHX1 in most human tissues. New findings demonstrate that the E1-b promoter is itself genetically polymorphic and is transcriptionally modulated by dietary chemopreventive agents, such as sulforaphane. In this research program, we have designed experiments to test several key and integrated hypotheses, including: 1) that the most common structural genetic variants of EPHX1 (Y113H;H139R) confer their association with PAH-induced cancer risk by nature of their substrate-specific catalytic activity among PAH epoxides, specifically towards fjord-region epoxides that exhibit extraordinarily high tumorigenic potential;2) that the associated transcriptional activity of the E1-b promoter region is interindividually regulated by the presence of genetic polymorphism and transposable genetic elements in tissues that are principle targets of xenobiotic-induced toxicity;and, 3) that EPHX1 expression in human tissues is differentially regulated by exposures to isothiocyanate derivatives, dietary substances under current study as chemoprevention agents. The results of these investigations will delineate critical features comprising the enzymology, transcriptional regulation and genetics of human EPXH1 and elucidate the functional roles of these processes as potential risk modifiers of human disease.

Public Health Relevance

Microsomal epoxide hydrolase is an enzyme that is present in most tissues and plays a key role in metabolizing numerous environmental chemicals. The genetics and regulation of this enzyme likely determines, in part, the nature and extent of interindividual differences in toxicity that result from chemical exposures, including cancers. This research program will characterize the critical features that account for these differences and investigate their roles as risk modifiers of human diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES016358-04
Application #
8217302
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Mcallister, Kimberly A
Project Start
2009-04-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
4
Fiscal Year
2012
Total Cost
$321,473
Indirect Cost
$100,950
Name
Pennsylvania State University
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
003403953
City
University Park
State
PA
Country
United States
Zip Code
16802
Su, Shengzhong; Yang, Xi; Omiecinski, Curtis J (2014) Intronic DNA elements regulate Nrf2 chemical responsiveness of the human microsomal epoxide hydrolase gene (EPHX1) through a far upstream alternative promoter. Biochim Biophys Acta 1839:493-505
Takeda, Shuso; Ikeda, Eriko; Su, Shengzhong et al. (2014) ?(9)-THC modulation of fatty acid 2-hydroxylase (FA2H) gene expression: possible involvement of induced levels of PPAR? in MDA-MB-231 breast cancer cells. Toxicology 326:18-24
Su, Shengzhong; Omiecinski, Curtis J (2014) Sp1 and Sp3 transcription factors regulate the basal expression of human microsomal epoxide hydrolase (EPHX1) through interaction with the E1b far upstream promoter. Gene 536:135-44
Nguyen, Hong Loan; Yang, Xi; Omiecinski, Curtis J (2013) Expression of a novel mRNA transcript for human microsomal epoxide hydrolase (EPHX1) is regulated by short open reading frames within its 5'-untranslated region. RNA 19:752-66
Takeda, Shuso; Yoshida, Kazutaka; Nishimura, Hajime et al. (2013) ?(9)-Tetrahydrocannabinol disrupts estrogen-signaling through up-regulation of estrogen receptor ? (ER?). Chem Res Toxicol 26:1073-9
Takeda, Shuso; Noguchi, Momoko; Matsuo, Kazumasa et al. (2013) (-)-Xanthatin up-regulation of the GADD45? tumor suppressor gene in MDA-MB-231 breast cancer cells: role of topoisomerase II? inhibition and reactive oxygen species. Toxicology 305:1-9
Takeda, Shuso; Harada, Mari; Su, Shengzhong et al. (2013) Induction of the fatty acid 2-hydroxylase (FA2H) gene by ?(9)-tetrahydrocannabinol in human breast cancer cells. J Toxicol Sci 38:305-8
Takeda, Shuso; Okajima, Shunsuke; Miyoshi, Hiroko et al. (2012) Cannabidiolic acid, a major cannabinoid in fiber-type cannabis, is an inhibitor of MDA-MB-231 breast cancer cell migration. Toxicol Lett 214:314-9
Takeda, Shuso; Hirayama, Akari; Urata, Shino et al. (2011) Cannabidiol-2',6'-dimethyl ether as an effective protector of 15-lipoxygenase-mediated low-density lipoprotein oxidation in vitro. Biol Pharm Bull 34:1252-6
Omiecinski, Curtis J; Vanden Heuvel, John P; Perdew, Gary H et al. (2011) Xenobiotic metabolism, disposition, and regulation by receptors: from biochemical phenomenon to predictors of major toxicities. Toxicol Sci 120 Suppl 1:S49-75

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