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Gene Review

EPHX1  -  epoxide hydrolase 1, microsomal (xenobiotic)

Homo sapiens

Synonyms: EPHX, EPOX, Epoxide hydratase, Epoxide hydrolase 1, HYL1, ...
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Disease relevance of EPHX1

  • We investigated the effect of exon 3 and 4 polymorphisms of the EPHX1 gene in 121 patients with cancers of the oral cavity/pharynx, 129 patients with cancer of the larynx, and 172 non-cancer controls, all Caucasian regular smokers [1].
  • In this investigation, we examined the potential association between the risk of Parkinson's disease and genetic variation within the EPHX1 and EPHX2 genes [2].
  • Combinations of either GSTM1null or GSTP1*2 with low activity of EPHX1 presented significant risk of breast cancer (OR = 1.88, CI = 1.00-3.52, P = 0.049 and OR = 2.40, CI = 1.15-5.00, P = 0.019, respectively) as well [3].
  • We performed a case-control study among Northwestern Mediterranean Caucasians to investigate a possible association between these EPHX1 variants and lung cancer risk [4].
  • Combinations of the Y113H and H139R polymorphic EPHX1 variants have been assumed to alter the enzyme activity and thus the risk of squamous cell head and neck cancer (SCCHN) [5].

Psychiatry related information on EPHX1


High impact information on EPHX1


Chemical compound and disease context of EPHX1


Biological context of EPHX1


Anatomical context of EPHX1


Associations of EPHX1 with chemical compounds

  • Lack of increased genetic damage in 1,3-butadiene-exposed Chinese workers studied in relation to EPHX1 and GST genotypes [26].
  • When the combined influence of the CYP2B6 genotype and the predicted activity of EPHX1 were examined, urinary metabolites in subjects with low enzyme activity were lower than in those with medium or high activity after high styrene exposure (>or=50 ppm) [27].
  • Genetic polymorphism of epoxide hydrolase and glutathione S-transferase in COPD [14].
  • Using the purified protein preparations, rates of cSO and BaPO hydrolysis for the reference protein, Y113/H139, were approximately 2-fold greater than those measured with the other EPHX1 allelic variants [28].
  • Microsomal epoxide hydrolase (mEH) plays a central role in xenobiotic metabolism as well as mediating the sodium-dependent uptake of bile acids into the liver, where these compounds regulate numerous biological processes such as cholesterol metabolism and hepatocyte signaling pathways [19].

Physical interactions of EPHX1

  • In previous studies we have established that GATA-4 binding to the EPHX1 core promoter is critical for EPHX1 expression [19].

Regulatory relationships of EPHX1

  • Coexpression of GATA-4 stimulated EPHX1 promoter activity up to 7.5-fold in a dose-dependent manner [29].
  • Furthermore, this work showed that EH is expressed in CYP2E1-null and wild-type mice [30].
  • Soluble epoxide hydrolase (sEH) is highly expressed in human liver and contains a C-terminal epoxide hydrolase activity and an N-terminal phosphatase activity [31].
  • Activation of benzo[a]pyrene to genotoxic products that cause induction of umu gene expression in Salmonella typhimurium NM2009 by P450 1A1 and P450 1B1 enzymes was found to be enhanced by inclusion of purified epoxide hydrolase (isolated from rat or human livers) with the reaction mixture [32].

Other interactions of EPHX1

  • 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 [2].
  • No elevated proportion of LOH was observed for genotypes at CYP1A1 (12% for the 1/2 genotype vs 10% for the 1/1 genotype) or EH (11% for the 1/1 genotype vs 10% for the 1/2 genotype) [33].
  • In contrast, the GSTM1 null genotype or polymorphisms within the p450-cyp2E1 and mEh genes was not significantly different in patients and controls [34].
  • The distribution of EPHX1 and GSTP1 gene genotypes was similar in the control and patient groups [35].
  • Two coding-region mEH variants (Tyr113His, His139Arg) and CYP2C9 variants (Arg144Cys, Ile359Leu) have been described and affect enzyme specific activity [36].

Analytical, diagnostic and therapeutic context of EPHX1


  1. High-activity microsomal epoxide hydrolase genotypes and the risk of oral, pharynx, and larynx cancers. Jourenkova-Mironova, N., Mitrunen, K., Bouchardy, C., Dayer, P., Benhamou, S., Hirvonen, A. Cancer Res. (2000) [Pubmed]
  2. 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]
  3. Breast cancer: role of polymorphisms in biotransformation enzymes. Sarmanová, J., Sůsová, S., Gut, I., Mrhalová, M., Kodet, R., Adámek, J., Roth, Z., Soucek, P. Eur. J. Hum. Genet. (2004) [Pubmed]
  4. Lung cancer susceptibility in relation to combined polymorphisms of microsomal epoxide hydrolase and glutathione S-transferase P1. To-Figueras, J., Gené, M., Gómez-Catalán, J., Piqué, E., Borrego, N., Corbella, J. Cancer Lett. (2001) [Pubmed]
  5. Association between head and neck cancer and microsomal epoxide hydrolase genotypes. Wenghoefer, M., Pesch, B., Harth, V., Broede, P., Fronhoffs, S., Landt, O., Brüning, T., Abel, J., Bolt, H.M., Herberhold, C., Vetter, H., Ko, Y.D. Arch. Toxicol. (2003) [Pubmed]
  6. Regio- and enantioselectivity of soybean fatty acid epoxide hydrolase. Blée, E., Schuber, F. J. Biol. Chem. (1992) [Pubmed]
  7. Two exonic single nucleotide polymorphisms in the microsomal epoxide hydrolase gene are jointly associated with preeclampsia. Laasanen, J., Romppanen, E.L., Hiltunen, M., Helisalmi, S., Mannermaa, A., Punnonen, K., Heinonen, S. Eur. J. Hum. Genet. (2002) [Pubmed]
  8. Cytochrome P-450 isozyme pattern is related to individual susceptibility to diethylnitrosamine-induced liver cancer in rats. Aitio, A., Aitio, M.L., Camus, A.M., Cardis, E., Bartsch, H. Jpn. J. Cancer Res. (1991) [Pubmed]
  9. Human peripheral lymphocytes as indicators of microsomal epoxide hydrolase activity in liver and lung. Omiecinski, C.J., Aicher, L., Holubkov, R., Checkoway, H. Pharmacogenetics (1993) [Pubmed]
  10. Expression of microsomal epoxide hydrolase is elevated in Alzheimer's hippocampus and induced by exogenous beta-amyloid and trimethyl-tin. Liu, M., Sun, A., Shin, E.J., Liu, X., Kim, S.G., Runyons, C.R., Markesbery, W., Kim, H.C., Bing, G. Eur. J. Neurosci. (2006) [Pubmed]
  11. Prenatal prediction of risk of the fetal hydantoin syndrome. Buehler, B.A., Delimont, D., van Waes, M., Finnell, R.H. N. Engl. J. Med. (1990) [Pubmed]
  12. Halothane hepatitis. Detection of a constitutional susceptibility factor. Farrell, G., Prendergast, D., Murray, M. N. Engl. J. Med. (1985) [Pubmed]
  13. Glutathione S-transferase and epoxide hydrolase activity in human leukocytes in relation to risk of lung cancer and other smoking-related cancers. Heckbert, S.R., Weiss, N.S., Hornung, S.K., Eaton, D.L., Motulsky, A.G. J. Natl. Cancer Inst. (1992) [Pubmed]
  14. Genetic polymorphism of epoxide hydrolase and glutathione S-transferase in COPD. Cheng, S.L., Yu, C.J., Chen, C.J., Yang, P.C. Eur. Respir. J. (2004) [Pubmed]
  15. Analysis of the EPHX1 113 polymorphism and GSTM1 homozygous null polymorphism and oral clefting associated with maternal smoking. Hartsfield, J.K., Hickman, T.A., Everett, E.T., Shaw, G.M., Lammer, E.J., Finnell, R.A. Am. J. Med. Genet. (2001) [Pubmed]
  16. The biotransformation of isoprene and the two isoprene monoepoxides by human cytochrome P450 enzymes, compared to mouse and rat liver microsomes. Bogaards, J.J., Venekamp, J.C., van Bladeren, P.J. Chem. Biol. Interact. (1996) [Pubmed]
  17. Microsomal epoxide hydrolase expression as a predictor of tamoxifen response in primary breast cancer: a retrospective exploratory study with long-term follow-up. Fritz, P., Mürdter, T.E., Eichelbaum, M., Siegle, I., Weissert, M., Zanger, U.M. J. Clin. Oncol. (2001) [Pubmed]
  18. An investigation of the formation of cytotoxic, protein-reactive and stable metabolites from carbamazepine in vitro. Pirmohamed, M., Kitteringham, N.R., Guenthner, T.M., Breckenridge, A.M., Park, B.K. Biochem. Pharmacol. (1992) [Pubmed]
  19. CCAAT/enhancer-binding protein alpha (C/EBPalpha) activates transcription of the human microsomal epoxide hydrolase gene (EPHX1) through the interaction with DNA-bound NF-Y. Zhu, Q.S., Qian, B., Levy, D. J. Biol. Chem. (2004) [Pubmed]
  20. Role of epoxide hydrolase, NAD(P)H:quinone oxidoreductase, cytochrome P450 2E1 or alcohol dehydrogenase genotypes in susceptibility to colorectal cancer. van der Logt, E.M., Bergevoet, S.M., Roelofs, H.M., Te Morsche, R.H., Dijk, Y., Wobbes, T., Nagengast, F.M., Peters, W.H. Mutat. Res. (2006) [Pubmed]
  21. Dose-dependent influence of genetic polymorphisms on DNA damage induced by styrene oxide, ethylene oxide and gamma-radiation. Godderis, L., Aka, P., Mateuca, R., Kirsch-Volders, M., Lison, D., Veulemans, H. Toxicology (2006) [Pubmed]
  22. Interest of genotyping and phenotyping of drug-metabolizing enzymes for the interpretation of biological monitoring of exposure to styrene. Haufroid, V., Jakubowski, M., Janasik, B., Ligocka, D., Buchet, J.P., Bergamaschi, E., Manini, P., Mutti, A., Ghittori, S., Arand, M., Hangen, N., Oesch, F., Hirvonen, A., Lison, D. Pharmacogenetics (2002) [Pubmed]
  23. Expression of cytochrome P450 and microsomal epoxide hydrolase in cervical and oral epithelial cells immortalized by human papillomavirus type 16 E6/E7 genes. Farin, F.M., Bigler, L.G., Oda, D., McDougall, J.K., Omiecinski, C.J. Carcinogenesis (1995) [Pubmed]
  24. Fingerprinting of cytochrome P450 and microsomal epoxide hydrolase gene expression in human blood cells. Krovat, B.C., Tracy, J.H., Omiecinski, C.J. Toxicol. Sci. (2000) [Pubmed]
  25. Micronucleus assays using cytochalasin-blocked MCL-5 cells, a proprietary human cell line expressing five human cytochromes P-450 and microsomal epoxide hydrolase. Crofton-Sleigh, C., Doherty, A., Ellard, S., Parry, E.M., Venitt, S. Mutagenesis (1993) [Pubmed]
  26. Lack of increased genetic damage in 1,3-butadiene-exposed Chinese workers studied in relation to EPHX1 and GST genotypes. Zhang, L., Hayes, R.B., Guo, W., McHale, C.M., Yin, S., Wiencke, J.K., Patrick O'Neill, J., Rothman, N., Li, G.L., Smith, M.T. Mutat. Res. (2004) [Pubmed]
  27. Influence of genetic polymorphisms of styrene-metabolizing enzymes and smoking habits on levels of urinary metabolites after occupational exposure to styrene. Ma, M., Umemura, T., Mori, Y., Gong, Y., Saijo, Y., Sata, F., Kawai, T., Kishi, R. Toxicol. Lett. (2005) [Pubmed]
  28. Functional analysis of human microsomal epoxide hydrolase genetic variants. Hosagrahara, V.P., Rettie, A.E., Hassett, C., Omiecinski, C.J. Chem. Biol. Interact. (2004) [Pubmed]
  29. Regulation of human microsomal epoxide hydrolase gene (EPHX1) expression by the transcription factor GATA-4. Zhu, Q.S., Qian, B., Levy, D. Biochim. Biophys. Acta (2004) [Pubmed]
  30. Cytochrome P450 2E1 (CYP2E1) is essential for acrylonitrile metabolism to cyanide: comparative studies using CYP2E1-null and wild-type mice. Wang, H., Chanas, B., Ghanayem, B.I. Drug Metab. Dispos. (2002) [Pubmed]
  31. Effects of human soluble epoxide hydrolase polymorphisms on isoprenoid phosphate hydrolysis. Enayetallah, A.E., Grant, D.F. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  32. Metabolism of benzo[a]pyrene to trans-7,8-dihydroxy-7, 8-dihydrobenzo[a]pyrene by recombinant human cytochrome P450 1B1 and purified liver epoxide hydrolase. Shimada, T., Gillam, E.M., Oda, Y., Tsumura, F., Sutter, T.R., Guengerich, F.P., Inoue, K. Chem. Res. Toxicol. (1999) [Pubmed]
  33. Variability in loss of constitutional heterozygosity across loci and among individuals: association with candidate genes in ductal breast carcinoma. Rebbeck, T.R., Godwin, A.K., Buetow, K.H. Mol. Carcinog. (1996) [Pubmed]
  34. Glutathione S transferase theta 1 gene (GSTT1) null genotype is associated with an increased risk for acquired aplastic anemia in children. Dirksen, U., Moghadam, K.A., Mambetova, C., Esser, C., Fuhrer, M., Burdach, S. Pediatr. Res. (2004) [Pubmed]
  35. Genetic polymorphisms in the cytochromes P-450 (1A1, 2E1), microsomal epoxide hydrolase and glutathione S-transferase M1, T1, and P1 genes, and their relationship with chronic bronchitis and relapsing pneumonia in children. Korytina, G.F., Yanbaeva, D.G., Babenkova, L.I., Etkina, E.I., Victorova, T.V. J. Mol. Med. (2005) [Pubmed]
  36. Epoxide hydrolase and CYP2C9 polymorphisms, cigarette smoking, and risk of colorectal carcinoma in the Nurses' Health Study and the Physicians' Health Study. Tranah, G.J., Chan, A.T., Giovannucci, E., Ma, J., Fuchs, C., Hunter, D.J. Mol. Carcinog. (2005) [Pubmed]
  37. Combined analysis of polymorphisms in glutathione S-transferase M1 and microsomal epoxide hydrolase in lung cancer patients. Habalová, V., Salagovic, J., Kalina, I., Stubna, J. Neoplasma (2004) [Pubmed]
  38. Assignment1 of microsomal epoxide hydrolase (EPHX1) to human chromosome 1q42.1 by in situ hybridization. Hartsfield, J.K., Sutcliffe, M.J., Everett, E.T., Hassett, C., Omiecinski, C.J., Saari, J.A. Cytogenet. Cell Genet. (1998) [Pubmed]
  39. Inhibition of human m-epoxide hydrolase gene expression in a case of hypercholanemia. Zhu, Q.S., Xing, W., Qian, B., von Dippe, P., Shneider, B.L., Fox, V.L., Levy, D. Biochim. Biophys. Acta (2003) [Pubmed]
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