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Gene Review

Ephx1  -  epoxide hydrolase 1, microsomal

Mus musculus

Synonyms: AI195553, Eph-1, Eph1, Epoxide hydratase, Epoxide hydrolase 1, ...
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Disease relevance of Ephx1


High impact information on Ephx1


Chemical compound and disease context of Ephx1

  • Induction of phase 2 enzymes (e.g., glutathione transferases, NAD(P)H:quinone reductase, glucuronosyltransferases, epoxide hydrolase) is a major strategy for reducing the susceptibility of animal cells to neoplasia and other forms of electrophile toxicity [9].
  • The mutated cDNAs were expressed in Escherichia coli and the resulting recombinant proteins, named [Y383F]LTA4 hydrolase, [Y383H]LTA4 hydrolase and [Y383Q]LTA4 hydrolase, were purified to homogeneity to allow assays of both the epoxide hydrolase activity, i.e. the conversion of LTA4 into leukotriene B4, and the peptidase activity [10].
  • Understanding the relationship of the metabolism of styrene to its toxicity depends upon knowing the balance between the bioactivation of styrene to the epoxide by cytochromes P-450 and the detoxication of the oxide to the glycol by microsomal epoxide hydrolase [11].
  • The efficacy of two free radical scavengers, selenium and zinc, and a microsomal epoxide hydrolase-inducing agent, cis-stilbene oxide on the acute toxicity of T-2 toxin, a potent cytotoxic trichothecene, was investigated [12].

Biological context of Ephx1

  • Genomic samples from the available AXB and BXA recombinant inbred strains were allelotyped for the SNP identified in the Ephx1 gene that distinguishes the A/J and C57BL/6J parental strains and used to map Ephx1 to Chromosome (Chr) 1 at approximately 98.5cM (LOD = 10.0) [13].
  • Genetic polymorphism of microsomal epoxide hydrolase activity in the mouse [14].
  • In cross and back-cross matings between C57BL/6J and DBA/2J mice, this phenotypic difference in epoxide hydrolase activity is inherited as a single autosomal trait, with co-dominant expression in heterozygotes [14].
  • In particular, the relative specific activity of all three enzymes decreased in the light mitochondrial (peroxisomal) cell fraction, and an increase of a mEH-like activity (benzo[a]pyrene-4,5-oxide and cis-stilbene oxide hydrolysis) in the cytosol occurred [15].
  • 6. These results provided evidence that ATB stimulated mEH and GST gene expression at early times and reduced the P4502C11 level in the absence of P4502E1 suppression [16].

Anatomical context of Ephx1

  • Embryonic fibroblast derived from the mEH-null mice were unable to produce the proximate carcinogenic metabolite of 7,12-dimethylbenz[a]anthracene (DMBA), a widely studied experimental prototype for the polycylic aromatic hydrocarbon class of chemical carcinogens [1].
  • The increase in cytosolic EH activity previously has been noted only in animals treated with peroxisome proliferators [17].
  • Using double diffusion analysis in agarose gels, we show that anti-rat liver microsomal epoxide hydrolase forms a single precipitin line with solubilized microsomes from rat and mouse liver, but no reaction is seen with the corresponding cytosolic fractions [18].
  • Using trans-stilbene oxide and styrene oxide as substrates, epoxide hydrolase activities were measured in cytosolic and microsomal fractions from liver, kidney, heart, lung and testis of male DBA/2 mice [19].
  • Distribution and nature of epoxide hydrolase activity in subcellular organelles of mouse liver [20].

Associations of Ephx1 with chemical compounds


Enzymatic interactions of Ephx1

  • However, GE may be metabolically inactivated in the body by two different enzymatic routes: conjugation of the epoxide moiety with the endogenous tripeptide glutathione (GSH) catalysed by glutathione S-transferase (GST) or hydrolysis of the epoxide moiety catalysed by epoxide hydrolase (EH) [23].
  • C10GE is chemically very stable and resistant to aqueous hydrolysis, but it was rapidly metabolized in both cytosolic and microsomal fractions of all organs by epoxide hydrolase (EH)-catalysed hydrolysis of the epoxide moiety as well as carboxylesterase (CE)-catalysed hydrolysis of the ester bond [24].

Other interactions of Ephx1


Analytical, diagnostic and therapeutic context of Ephx1

  • In a complete carcinogenesis bioassay, the mEH mice were totally resistant to tumorigenesis [1].
  • These data establish in an intact animal model that mEH is a key genetic determinant in DMBA carcinogenesis through its role in production of the ultimate carcinogenic metabolite of DMBA, the 3,4-diol-1,2-epoxide [1].
  • Furthermore, Ouchterlony immunodiffusion using antibodies raised in rabbits towards the control form of cytosolic epoxide hydrolase revealed identity between the two forms of cytosolic epoxide hydrolase, but no reaction with the microsomal epoxide hydrolase was observed [28].
  • 3. Treatment of rat with a single dose of ATB resulted in 2-21-fold increases in mEH mRNA levels at 24 h with an ED50 = 60 mg/kg. mEH mRNA level was elevated 9- and 21-fold at 12 and 24 h after treatment at 200 mg/kg respectively as compared with control [16].
  • Western blot analysis revealed that ATB induced mEH protein levels by 2-fold relative to control [16].


  1. Targeted disruption of the microsomal epoxide hydrolase gene. Microsomal epoxide hydrolase is required for the carcinogenic activity of 7,12-dimethylbenz[a]anthracene. Miyata, M., Kudo, G., Lee, Y.H., Yang, T.J., Gelboin, H.V., Fernandez-Salguero, P., Kimura, S., Gonzalez, F.J. J. Biol. Chem. (1999) [Pubmed]
  2. Comparison of mouse and human colon tumors with regard to phase I and phase II drug-metabolizing enzyme systems. Massaad, L., de Waziers, I., Ribrag, V., Janot, F., Beaune, P.H., Morizet, J., Gouyette, A., Chabot, G.G. Cancer Res. (1992) [Pubmed]
  3. Monooxygenase, epoxide hydrolase, and glutathione-S-transferase activities in human lung. Variation between groups of bronchogenic carcinoma and non-cancer patients and interindividual differences. Oesch, F., Schmassmann, H., Ohnhaus, E., Althaus, U., Lorenz, J. Carcinogenesis (1980) [Pubmed]
  4. Altered patterns of cutaneous xenobiotic metabolism in UVB-induced squamous cell carcinoma in SKH-1 hairless mice. Das, M., Bickers, D.R., Santella, R.M., Mukhtar, H. J. Invest. Dermatol. (1985) [Pubmed]
  5. Hepatotoxicity of germander in mice. Loeper, J., Descatoire, V., Letteron, P., Moulis, C., Degott, C., Dansette, P., Fau, D., Pessayre, D. Gastroenterology (1994) [Pubmed]
  6. Epoxide hydrolase activity in the mitochondrial fraction of mouse liver. Gill, S.S., Hammock, B.D. Nature (1981) [Pubmed]
  7. Rapid purification of cytosolic epoxide hydrolase from normal and clofibrate-treated animals by affinity chromatography. Prestwich, G.D., Hammock, B.D. Proc. Natl. Acad. Sci. U.S.A. (1985) [Pubmed]
  8. Accelerated ovarian failure induced by 4-vinyl cyclohexene diepoxide in Nrf2 null mice. Hu, X., Roberts, J.R., Apopa, P.L., Kan, Y.W., Ma, Q. Mol. Cell. Biol. (2006) [Pubmed]
  9. Chemoprotective properties of phenylpropenoids, bis(benzylidene)cycloalkanones, and related Michael reaction acceptors: correlation of potencies as phase 2 enzyme inducers and radical scavengers. Dinkova-Kostova, A.T., Abeygunawardana, C., Talalay, P. J. Med. Chem. (1998) [Pubmed]
  10. Evidence for a catalytic role of tyrosine 383 in the peptidase reaction of leukotriene A4 hydrolase. Blomster, M., Wetterholm, A., Mueller, M.J., Haeggström, J.Z. Eur. J. Biochem. (1995) [Pubmed]
  11. Metabolism of styrene oxide to styrene glycol by mouse liver and lung. Carlson, G.P. J. Toxicol. Environ. Health Part A (1998) [Pubmed]
  12. Assessment of possible protective roles of selenium, zinc, and cis-stilbene oxide against acute T-2 toxin poisoning: a preliminary report. Yazdanpanah, H., Roshanzamir, F., Shafaghi, B., Faizi, M., Elhami, M., Rasekh, H.R. Nat. Toxins (1997) [Pubmed]
  13. The Ephx1(d) allele encoding an Arg338Cys substitution is associated with heat lability. Hartsfield, J.K., Everett, E.T. Mamm. Genome (2000) [Pubmed]
  14. Genetic polymorphism of microsomal epoxide hydrolase activity in the mouse. Lyman, S.D., Poland, A., Taylor, B.A. J. Biol. Chem. (1980) [Pubmed]
  15. Epoxide metabolism in the liver of mice treated with clofibrate (ethyl-alpha-(p-chlorophenoxyisobutyrate], a peroxisome proliferator. Moody, D.E., Loury, D.N., Hammock, B.D. Toxicol. Appl. Pharmacol. (1985) [Pubmed]
  16. Partial hepatoprotective effects of allylthiobenzimidazole in the absence of cytochrome P4502E1 suppression: effects on epoxide hydrolase, rGSTA2, rGSTA3/5, rGSTM1 and rGSTM2 expression. Kim, S.G., Lee, A.K., Kim, N.D. Xenobiotica (1998) [Pubmed]
  17. The effect of tridiphane (2-(3,5-dichlorophenyl)-2-(2,2,2-trichloroethyl)oxirane) on hepatic epoxide-metabolizing enzymes: indications of peroxisome proliferation. Moody, D.E., Hammock, B.D. Toxicol. Appl. Pharmacol. (1987) [Pubmed]
  18. Cytosolic and microsomal epoxide hydrolases are immunologically distinguishable from each other in the rat and mouse. Guenthner, T.M., Hammock, B.D., Vogel, U., Oesch, F. J. Biol. Chem. (1981) [Pubmed]
  19. Organ distribution of epoxide hydrolases in cytosolic and microsomal fractions of normal and nafenopin-treated male DBA/2 mice. Waechter, F., Bentley, P., Bieri, F., Muakkassah-Kelly, S., Stäubli, W., Villermain, M. Biochem. Pharmacol. (1988) [Pubmed]
  20. Distribution and nature of epoxide hydrolase activity in subcellular organelles of mouse liver. Kaur, S., Gill, S.S. Biochem. Pharmacol. (1986) [Pubmed]
  21. Selective inhibition of cytosolic epoxide hydrolase activity in vitro by compounds that inhibit catalase. Guenthner, T.M., Hjelle, J.T., Whalen, R. J. Biochem. Toxicol. (1989) [Pubmed]
  22. Effects of hepatic inducers on testicular epoxide-metabolizing enzymes in the rat and mouse. DiBiasio, K.W., Silva, M.H., Hammock, B.D., Shull, L.R. Fundamental and applied toxicology : official journal of the Society of Toxicology. (1989) [Pubmed]
  23. Metabolic inactivation of five glycidyl ethers in lung and liver of humans, rats and mice in vitro. Boogaard, P.J., de Kloe, K.P., Bierau, J., Kuiken, G., Borkulo, P.E., Watson, W.P., van Sittert, N.J. Xenobiotica (2000) [Pubmed]
  24. Metabolic inactivation of 2-oxiranylmethyl 2-ethyl-2,5-dimethylhexanoate (C10GE) in skin, lung and liver of human, rat and mouse. Boogaard, P.J., van Elburg, P.A., de Kloe, K.P., Watson, W.P., van Sittert, N.J. Xenobiotica (1999) [Pubmed]
  25. Mutation of tyrosine 383 in leukotriene A4 hydrolase allows conversion of leukotriene A4 into 5S,6S-dihydroxy-7,9-trans-11,14-cis-eicosatetraenoic acid. Implications for the epoxide hydrolase mechanism. Andberg, M.B., Hamberg, M., Haeggström, J.Z. J. Biol. Chem. (1997) [Pubmed]
  26. Effects of perfluoro fatty acids on xenobiotic-metabolizing enzymes, enzymes which detoxify reactive forms of oxygen and lipid peroxidation in mouse liver. Permadi, H., Lundgren, B., Andersson, K., DePierre, J.W. Biochem. Pharmacol. (1992) [Pubmed]
  27. Spectrophotometric substrates for cytosolic epoxide hydrolase. Dietze, E.C., Kuwano, E., Hammock, B.D. Anal. Biochem. (1994) [Pubmed]
  28. Properties of cytosolic epoxide hydrolase purified from the liver of untreated and clofibrate-treated mice. Purification procedure and physiochemical characterization of the pure enzymes. Meijer, J., Depierre, J.W. Eur. J. Biochem. (1985) [Pubmed]
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