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Gene Review

EPHX2  -  epoxide hydrolase 2, cytoplasmic

Homo sapiens

Synonyms: Bifunctional epoxide hydrolase 2, CEH, SEH
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Disease relevance of EPHX2

  • EPHX1 and EPHX2 genotype data were obtained from 133 idiopathic Parkinson's disease patients and 212 control subjects matched on age, gender and ethnicity [1].
  • For example, sEH expression in renal and hepatic malignant neoplasms and surrounding non-neoplastic tissues was found to be significantly decreased, whereas expression was found to be increased in seminoma as compared to normal tissues [2].
  • The Prevalence of CYP2C8, 2C9, 2J2, and soluble epoxide hydrolase polymorphisms in African Americans with hypertension [3].
  • Interestingly, the Arg287Gln polymorphism recently suggested to be involved in hypercholesterolemia was found to possess a higher isoprenoid phosphatase activity than the wild type sEH [4].
  • Allelic forms of human sEH, with markedly different enzymatic profiles, may have important physiological implications with respect to the disposition of epoxides formed from the oxidation of fatty acids, such as arachidonic acid-derived intermediates, as well in the regulation of toxicity due to xenobiotic epoxide exposures [5].

Psychiatry related information on EPHX2

  • The effects of sustained eucapnic hypoxia (SEH, 20 minutes SaO2, approximately 80%) on ventilation and supraglottic airflow resistance (Rua) plus genioglossal (gg) and diaphragmatic (di) electromyograms (EMGs) were compared during wakefulness and nonrapid eye movement (NREM) sleep in six healthy normal male subjects [6].

High impact information on EPHX2


Chemical compound and disease context of EPHX2

  • We demonstrate that a serine esterase inhibitor provides some protection from the toxicity of epoxy fatty esters to sEH expressing cells as do intercellular free sulfhydryls, but that this protection is not due to glutathione conjugation [11].
  • Conversion of 12,13-cis-epoxyoctadecenoic acid (12,13-EOA) to 12,13-dihydroxyoctadecenoic acid (12,13-DHOA) by soluble epoxide hydrolase has been suggested to be a critical step in mediating the toxicity of epoxidized linoleic acid [12].
  • Thus, the development of hypercholesterolemia with age in FEC-H might be related to alterations in the enzyme systems (ACAT, CEH) which modulate the level of cholesterol esters in the liver [13].

Biological context of EPHX2


Anatomical context of EPHX2


Associations of EPHX2 with chemical compounds


Regulatory relationships of EPHX2


Other interactions of EPHX2

  • The microsomal (EPHX1) and soluble (EPHX2) epoxide hydrolases function to regulate the oxidation status of a wide range of xenobiotic- and lipid-derived substrates; therefore, interindividual variation in these pathways may mitigate epoxide-related cellular injury [1].
  • CYP2C8 and 2J2 were also widely distributed in human tissues but were less frequently associated with sEH [22].
  • CYP2C9 was also found in almost all of these organs and tissues, suggesting that 2C9 and sEH are very similar in their tissue-specific patterns of expression [22].
  • Intrafamilial correlation analysis of the modifier effect of Glu287Arg substitution in the EPHX2 gene was carried out among 79 LDLR mutation carriers and 81 noncarriers [23].
  • Changes observed in HMGR, ACAT, and CEH mRNA levels paralleled changes in enzyme specific activities [24].

Analytical, diagnostic and therapeutic context of EPHX2


  1. Genetic polymorphisms of microsomal and soluble epoxide hydrolase and the risk of Parkinson's disease. Farin, F.M., Janssen, P., Quigley, S., Abbott, D., Hassett, C., Smith-Weller, T., Franklin, G.M., Swanson, P.D., Longstreth, W.T., Omiecinski, C.J., Checkoway, H. Pharmacogenetics (2001) [Pubmed]
  2. Distribution of soluble epoxide hydrolase, cytochrome P450 2C8, 2C9 and 2J2 in human malignant neoplasms. Enayetallah, A.E., French, R.A., Grant, D.F. J. Mol. Histol. (2006) [Pubmed]
  3. The Prevalence of CYP2C8, 2C9, 2J2, and soluble epoxide hydrolase polymorphisms in African Americans with hypertension. Dreisbach, A.W., Japa, S., Sigel, A., Parenti, M.B., Hess, A.E., Srinouanprachanh, S.L., Rettie, A.E., Kim, H., Farin, F.M., Hamm, L.L., Lertora, J.J. Am. J. Hypertens. (2005) [Pubmed]
  4. Effects of human soluble epoxide hydrolase polymorphisms on isoprenoid phosphate hydrolysis. Enayetallah, A.E., Grant, D.F. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  5. Identification and functional characterization of human soluble epoxide hydrolase genetic polymorphisms. Sandberg, M., Hassett, C., Adman, E.T., Meijer, J., Omiecinski, C.J. J. Biol. Chem. (2000) [Pubmed]
  6. Ventilatory responses to sustained eucapnic hypoxia in healthy males during wakefulness and NREM sleep. McEvoy, R.D., Popovic, R.M., Saunders, N.A., White, D.P. Sleep. (1997) [Pubmed]
  7. Genetic and environmental factors that regulate cytosolic epoxide hydrolase activity in normal human lymphocytes. Norris, K.K., DeAngelo, T.M., Vesell, E.S. J. Clin. Invest. (1989) [Pubmed]
  8. Beyond vasodilatation: non-vasomotor roles of epoxyeicosatrienoic acids in the cardiovascular system. Larsen, B.T., Campbell, W.B., Gutterman, D.D. Trends Pharmacol. Sci. (2007) [Pubmed]
  9. Prevention and reversal of cardiac hypertrophy by soluble epoxide hydrolase inhibitors. Xu, D., Li, N., He, Y., Timofeyev, V., Lu, L., Tsai, H.J., Kim, I.H., Tuteja, D., Mateo, R.K., Singapuri, A., Davis, B.B., Low, R., Hammock, B.D., Chiamvimonvat, N. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  10. Inhibitors of soluble epoxide hydrolase attenuate vascular smooth muscle cell proliferation. Davis, B.B., Thompson, D.A., Howard, L.L., Morisseau, C., Hammock, B.D., Weiss, R.H. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  11. Metabolism of monoepoxides of methyl linoleate: bioactivation and detoxification. Greene, J.F., Williamson, K.C., Newman, J.W., Morisseau, C., Hammock, B.D. Arch. Biochem. Biophys. (2000) [Pubmed]
  12. Linoleic acid, cis-epoxyoctadecenoic acids, and dihydroxyoctadecadienoic acids are toxic to Sf-21 cells in the absence of albumin. Mitchell, L.A., Moran, J.H., Grant, D.F. Toxicol. Lett. (2002) [Pubmed]
  13. Reduced synthesis and rapid esterification of cholesterol in the liver of hamsters with spontaneous hypercholesterolemia. Sablé-Amplis, R., Sicart, R., Farré, G. Comp. Biochem. Physiol., B (1987) [Pubmed]
  14. The soluble epoxide hydrolase gene harbors sequence variation associated with susceptibility to and protection from incident ischemic stroke. Fornage, M., Lee, C.R., Doris, P.A., Bray, M.S., Heiss, G., Zeldin, D.C., Boerwinkle, E. Hum. Mol. Genet. (2005) [Pubmed]
  15. Identification of radiation-specific responses from gene expression profile. Park, W.Y., Hwang, C.I., Im, C.N., Kang, M.J., Woo, J.H., Kim, J.H., Kim, Y.S., Kim, J.H., Kim, H., Kim, K.A., Yu, H.J., Lee, S.J., Lee, Y.S., Seo, J.S. Oncogene (2002) [Pubmed]
  16. Sequence variation in the soluble epoxide hydrolase gene and subclinical coronary atherosclerosis: Interaction with cigarette smoking. Wei, Q., Doris, P.A., Pollizotto, M.V., Boerwinkle, E., Jacobs, D.R., Siscovick, D.S., Fornage, M. Atherosclerosis (2007) [Pubmed]
  17. Enzymatic hydration of leukotriene A4. Purification and characterization of a novel epoxide hydrolase from human erythrocytes. McGee, J., Fitzpatrick, F. J. Biol. Chem. (1985) [Pubmed]
  18. Similarities between catalase and cytosolic epoxide hydrolase. Guenthner, T.M., Qato, M., Whalen, R., Glomb, S. Drug Metab. Rev. (1989) [Pubmed]
  19. Profile of drug-metabolizing enzymes in human ileum and colon. Pacifici, G.M., Franchi, M., Gervasi, P.G., Longo, V., di Simplicio, P., Temellini, A., Giuliani, L. Pharmacology (1989) [Pubmed]
  20. Regio- and enantioselectivity of soybean fatty acid epoxide hydrolase. Blée, E., Schuber, F. J. Biol. Chem. (1992) [Pubmed]
  21. Metabolism of epoxyeicosatrienoic acids by cytosolic epoxide hydrolase: substrate structural determinants of asymmetric catalysis. Zeldin, D.C., Wei, S., Falck, J.R., Hammock, B.D., Snapper, J.R., Capdevila, J.H. Arch. Biochem. Biophys. (1995) [Pubmed]
  22. Distribution of soluble epoxide hydrolase and of cytochrome P450 2C8, 2C9, and 2J2 in human tissues. Enayetallah, A.E., French, R.A., Thibodeau, M.S., Grant, D.F. J. Histochem. Cytochem. (2004) [Pubmed]
  23. Soluble epoxide hydrolase variant (Glu287Arg) modifies plasma total cholesterol and triglyceride phenotype in familial hypercholesterolemia: intrafamilial association study in an eight-generation hyperlipidemic kindred. Sato, K., Emi, M., Ezura, Y., Fujita, Y., Takada, D., Ishigami, T., Umemura, S., Xin, Y., Wu, L.L., Larrinaga-Shum, S., Stephenson, S.H., Hunt, S.C., Hopkins, P.N. J. Hum. Genet. (2004) [Pubmed]
  24. Effects of CYP7A1 overexpression on cholesterol and bile acid homeostasis. Pandak, W.M., Schwarz, C., Hylemon, P.B., Mallonee, D., Valerie, K., Heuman, D.M., Fisher, R.A., Redford, K., Vlahcevic, Z.R. Am. J. Physiol. Gastrointest. Liver Physiol. (2001) [Pubmed]
  25. Microsomal and soluble epoxide hydrolases are members of the same family of C-X bond hydrolase enzymes. Lacourciere, G.M., Armstrong, R.N. Chem. Res. Toxicol. (1994) [Pubmed]
  26. Localization of the human soluble epoxide hydrolase gene (EPHX2) to chromosomal region 8p21-p12. Larsson, C., White, I., Johansson, C., Stark, A., Meijer, J. Hum. Genet. (1995) [Pubmed]
  27. Structural characterization of the human soluble epoxide hydrolase gene (EPHX2). Sandberg, M., Meijer, J. Biochem. Biophys. Res. Commun. (1996) [Pubmed]
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