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Gene Review

Ephx2  -  epoxide hydrolase 2, cytoplasmic

Rattus norvegicus

Synonyms: Bifunctional epoxide hydrolase 2
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Disease relevance of Ephx2


High impact information on Ephx2

  • Epoxyeicosatrienoic acids (EETs) have demonstrated antiinflammatory properties, and hydrolysis of these epoxides by sEH is known to diminish this activity [3].
  • The sEH inhibitor significantly decreased total bronchoalveolar lavage cell number by 37% in tobacco smoke-exposed rats with significant reductions noted in neutrophils, alveolar macrophages, and lymphocytes [3].
  • The mammalian soluble epoxide hydrolase (sEH) is an enzyme with multiple functions, being implicated in detoxification of xenobiotic epoxides as well as in regulation of physiological processes such as blood pressure [6].
  • Subsequently, we found rat sEH hydrolyzed 4-nitrophenyl phosphate with a rate constant of 0.8 s(-1) and a K(m) of 0.24 mM [6].
  • The expressed CEH activity was highly dependent on the presence of trihydroxy bile salts (cholate or one of its conjugates); maximum hydrolytic activity was observed in the presence of 10 mM sodium cholate [7].

Chemical compound and disease context of Ephx2


Biological context of Ephx2


Anatomical context of Ephx2

  • The most significant structure of the deduced protein is a modified peroxisomal targeting signal (Ser-Lys-Ile) at the carboxyl terminus that is regarded to be responsible for the unusual dual localization of the cytosolic epoxide hydrolase in peroxisomes as well as in the cytosol [1].
  • A catalytically active bile salt-dependent cholesteryl ester hydrolase (CEH) was expressed when Xenopus oocytes were injected with rat liver mRNA [7].
  • Polyclonal antibodies raised to TLCEH exhibited no cross-immunoreactivity with cytosolic proteins from other rat tissues and inhibited 70% of testis cytosolic CEH [13].
  • Radiation inactivation by high energy electrons, a method for determining the size of a protein without prior purification, was used to study the acid and neutral cholesteryl ester hydrolase (CEH) activities of rat liver microsomes [14].
  • In spite of significant amounts of intracellular enzyme protein demonstrated by Western blotting, in cell lysates there was a consistently low level of catalytic activity, and in cultured cells there was no evidence that CEH served as an effective intracellular cholesteryl ester hydrolase or synthase [4].

Associations of Ephx2 with chemical compounds

  • These studies demonstrate that increased sEH expression in the Ang II hypertensive kidney leads to increased EET hydration [2].
  • In additional experiments, the sEH inhibitor N-cyclohexyl-N-dodecyl urea (NCND; 3 mg/d) or vehicle (corn oil, 0.5 mL) was administered daily by intraperitoneal injection starting on day 10 [2].
  • In the presence of 10 mM sodium cholate, the CEH activity was maximal near pH 7 but was significant between pH 6 and 8 [7].
  • The expressed CEH was not activated by dihydroxy bile salts (deoxycholate and its conjugates) [7].
  • Phenylmethylsulfonyl fluoride, a serine enzyme inhibitor, was inhibitory to the expressed CEH activity, whereas p-chloromercuribenzoate (up to 5 mM), a potent thiol-blocking agent, did not significantly inhibit the expressed activity [7].

Other interactions of Ephx2


Analytical, diagnostic and therapeutic context of Ephx2

  • The obtained sequence information was used to perform PCR experiments resulting in the isolation of a 680 bp cDNA clone encoding the carboxy terminus of cEH [20].
  • The unique cDNA was sequenced and found to be similar to hepatic CEH, pI 6.1 esterase, and hydrolase A. In Northern blot analysis, the cDNA hybridized with a single band from lung messenger RNA (mRNA) [21].
  • The 1,839-base pair complementary DNA (cDNA) for rat lung carboxylesterase was cloned by reverse transcriptase polymerase chain reaction from total rat lung RNA using specific primers derived from the 5' and 3' untranslated regions of rat hepatic cholesteryl ester hydrolase (CEH) [21].
  • Gel mobility shift assays further demonstrated that NF-Y binds to the inverted CCAAT box motif and is required for the sterol-mediated regulation.These results indicate that multiple cis-elements regulate transcription of the cholesteryl ester hydrolase (CEH) gene, consistent with the reported regulation of CEH expression.-Natarajan, R., S [12].
  • A rat liver cytosolic cholesteryl ester hydrolase (CEH) was purified 12,600-fold by ammonium sulfate precipitation, cation exchange chromatography and gel permeation high-performance liquid chromatography, with an overall yield of 20% [22].


  1. Isolation and characterization of a cDNA encoding rat liver cytosolic epoxide hydrolase and its functional expression in Escherichia coli. Knehr, M., Thomas, H., Arand, M., Gebel, T., Zeller, H.D., Oesch, F. J. Biol. Chem. (1993) [Pubmed]
  2. Soluble epoxide hydrolase inhibition lowers arterial blood pressure in angiotensin II hypertension. Imig, J.D., Zhao, X., Capdevila, J.H., Morisseau, C., Hammock, B.D. Hypertension (2002) [Pubmed]
  3. Attenuation of tobacco smoke-induced lung inflammation by treatment with a soluble epoxide hydrolase inhibitor. Smith, K.R., Pinkerton, K.E., Watanabe, T., Pedersen, T.L., Ma, S.J., Hammock, B.D. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  4. The effects of varying the expression of a neutral cholesteryl ester hydrolase on the turnover of cholesteryl ester in rat hepatoma cells. Zolfaghari, R., Glick, J.M., Fisher, E.A. J. Biol. Chem. (1993) [Pubmed]
  5. Cholesterol metabolism in rat adrenal gland during reversible endotoxic shock. Abarca, S., García, R. Eur. J. Biochem. (1993) [Pubmed]
  6. The N-terminal domain of mammalian soluble epoxide hydrolase is a phosphatase. Cronin, A., Mowbray, S., Dürk, H., Homburg, S., Fleming, I., Fisslthaler, B., Oesch, F., Arand, M. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  7. Expression in Xenopus oocytes of rat liver mRNA coding for a bile salt-dependent cholesteryl ester hydrolase. Zolfaghari, R., Harrison, E.H., Ross, A.C., Fisher, E.A. Proc. Natl. Acad. Sci. U.S.A. (1989) [Pubmed]
  8. Age- and gender-related changes in the hepatic metabolism of 2-methylpropene and relationship to epoxide metabolizing enzymes. Cornet, M., Mertens, K., Callaerts, A., Sonck, W., Vercruysse, A., Rogiers, V. Mech. Ageing Dev. (1994) [Pubmed]
  9. Difference of gene expression profiles in spontaneous hypertensive rats and Wistar-Kyoto rats from two sources. Okuda, T., Sumiya, T., Iwai, N., Miyata, T. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  10. Polymorphism in soluble epoxide hydrolase and blood pressure in spontaneously hypertensive rats. Fornage, M., Hinojos, C.A., Nurowska, B.W., Boerwinkle, E., Hammock, B.D., Morisseau, C.H., Doris, P.A. Hypertension (2002) [Pubmed]
  11. Coordinate induction of peroxisomal beta-oxidation activity and cytosolic epoxide hydrolase activity. Oesch, F., Schladt, L. Pharmacol. Ther. (1987) [Pubmed]
  12. Regulation of the rat neutral cytosolic cholesteryl ester hydrolase promoter by hormones and sterols: a role for nuclear factor-Y in the sterol-mediated response. Natarajan, R., Ghosh, S., Grogan, W.M. J. Lipid Res. (1999) [Pubmed]
  13. Testicular temperature-labile cholesteryl ester hydrolase. Relationship to isoenzymes from other tissues, correlation with spermatogenesis, and inhibition by physiological concentrations of divalent cations. Wee, S., Grogan, W.M. J. Biol. Chem. (1993) [Pubmed]
  14. Analysis of microsomal cholesteryl ester hydrolases by radiation inactivation. Harrison, E.H., Rojas, C.J., Gad, M.Z., Kempner, E.S. J. Biol. Chem. (1993) [Pubmed]
  15. Structure and organization of the microsomal xenobiotic epoxide hydrolase gene. Falany, C.N., McQuiddy, P., Kasper, C.B. J. Biol. Chem. (1987) [Pubmed]
  16. Microsomal and cytosolic epoxide hydrolases, the peroxisomal fatty acid beta-oxidation system and catalase. Activities, distribution and induction in rat liver parenchymal and non-parenchymal cells. Steinberg, P., Schladt, L., Dienes, H.P., Timms, C., Oesch, F. Eur. J. Biochem. (1988) [Pubmed]
  17. Xenobiotic metabolizing enzyme activities and viability are well preserved in EDTA-isolated rat liver parenchymal cells after cryopreservation. Diener, B., Abdel-Latif, H., Arand, M., Oesch, F. Toxicol. Appl. Pharmacol. (1995) [Pubmed]
  18. Determination of DNA single strand breaks and selective DNA amplification by N-nitrodimethylamine and analogs, and estimation of the indicator cells' metabolic capacities. Frei, E., Pool, B.L., Glatt, H.R., Gemperlein-Mertes, I., Oesch, F., Schlehofer, J.R., Schmezer, P., Weber, H., Wiessler, M. J. Cancer Res. Clin. Oncol. (1986) [Pubmed]
  19. Protein expression changes in the Sprague Dawley rat liver proteome following administration of peroxisome proliferator activated receptor alpha and gamma ligands. White, I.R., Man, W.J., Bryant, D., Bugelski, P., Camilleri, P., Cutler, P., Hayes, W., Holbrook, J.D., Kramer, K., Lord, P.G., Wood, J. Proteomics (2003) [Pubmed]
  20. An impaired peroxisomal targeting sequence leading to an unusual bicompartmental distribution of cytosolic epoxide hydrolase. Arand, M., Knehr, M., Thomas, H., Zeller, H.D., Oesch, F. FEBS Lett. (1991) [Pubmed]
  21. Molecular cloning and expression of rat lung carboxylesterase and its potential role in the detoxification of organophosphorus compounds. Wallace, T.J., Ghosh, S., McLean Grogan, W. Am. J. Respir. Cell Mol. Biol. (1999) [Pubmed]
  22. Rapid three-step purification of a hepatic neutral cholesteryl ester hydrolase which is not the pancreatic enzyme. Ghosh, S., Grogan, W.M. Lipids (1991) [Pubmed]
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