Microsomal epoxide hydrolase (EPHX1) is an evolutionarily highly conserved biotransformation enzyme for converting epoxides to diols. Notably, the enzyme is able to either detoxify or bioactivate a wide range of substrates. Mutations and polymorphic variants in the EPHX1 gene have been associated with susceptibility to several human diseases including cancer. This review summarizes the key knowledge concerning EPHX1 gene and protein structure, expression pattern and regulation, and substrate specificity. The relevance of EPHX1 for human pathology is especially discussed.

Centre for Systems Medicine Department of Physiology Royal College of Surgeons in Ireland Dublin 2 Ireland

Toxicogenomics Unit National Institute of Public Health Prague Czech Republic

Toxicogenomics Unit National Institute of Public Health Prague Czech Republic; Biomedical Centre Faculty of Medicine in Plzen Charles University Prague Plzen Czech Republic

Zobrazit více v PubMed

Abdull Razis AF, Bagatta M, De Nicola GR, Iori R, Ioannides C. Induction of epoxide hydrolase and glucuronosyl transferase by isothiocyanates and intact glucosinolates in precision-cut rat liver slices: importance of side-chain substituent and chirality. Arch Toxicol. 2011;85:919–927. PubMed

Agudo A, Peluso M, Sala N, Capellá G, Munnia A, Piro S, Marín F, Ibáñez R, Amiano P, Tormo MJ, Ardanaz E, Barricarte A, Chirlaque MD, Dorronsoro M, Larrañaga N, Martínez C, Navarro C, Quirós JR, Sánchez MJ, González CA. Aromatic DNA adducts and polymorphisms in metabolic genes in healthy adults: findings from the EPIC-Spain cohort. Carcinogenesis. 2009;30:968–976. PubMed

Akatsuka T, Tohmatsu J, Yoshihara N, Katsuhara N, Okamoto T, Shikata T, Odaka T. Detection of an Antigen (AN6520) Possibly Related to Non-A, Non-B Hepatitis, by Monoclonal Antibodies. I. J Med Virol. 1986;20:33–42. PubMed

Akatsuka T, Kobayashi N, Ishikawa T, Saito T, Shindo M, Yamauchi M, Kurokohchi K, Miyazawa H, Duan H, Matsunaga T, Komoda T, Morisseau C, Hammock BD. Autoantibody response to microsomal epoxide hydrolase in hepatitis C and A. J Autoimmun. 2007;28:7–18. PubMed PMC

Alves C, von Dippe P, Amoui M, Levy D. Bile acid transport into hepatocyte smooth endoplasmic reticulum vesicles is mediated by microsomal epoxide hydrolase, a membrane protein exhibiting two distinct topological orientations. J Biol Chem. 1993;268:20148–20155. PubMed

Ananthanarayanan M, von Dippe P, Levy D. Identification of the hepatocyte Na+-dependent bile acid transport protein using monoclonal antibodies. J. Biol. Chem. 1988;263:8338–8343. PubMed

Andrew AS, Gui J, Sanderson AC, Mason RA, Morlock EV, Schned AR, Kelsey KT, Marsit CJ, Moore JH, Karagas MR. Bladder cancer SNP panel predicts susceptibility and survival. Hum Genet. 2009;125:527–539. PubMed PMC

Arand M, Grant DF, Beetham JK, Friedberg T, Oesch F, Hammock BD. Sequence similarity of mammalian epoxide hydrolases to the bacterial haloalkane dehalogenase and other related proteins. FEBS Lett. 1994;338:251–256. PubMed

Armstrong RN, Kedzierski B, Levin W, Jerina DM. Enantioselectivity of microsomal epoxide hydrolase toward arene oxide substrates. J Biol Chem. 1981;256:4726–4733. PubMed

Azzato EM, Chen RA, Wacholder S, Chanock SJ, Klebanoff MA, Caporaso NE. Maternal EPHX1 polymorphisms and risk of phenytoin-induced congenital malformations. Pharmacogenet Genomics. 2010;20:58–63. PubMed

Backman JT, Siegle I, Zanger UM, Fritz P. Immunohistochemical detection of microsomal epoxide hydrolase in human synovial tissue. Histochem J. 1999;31:645–649. PubMed

Barth S, Fischer M, Schmid RD, Pleiss J. Sequence and structure of epoxide hydrolases: a systematic analysis. Proteins. 2004;55:846–855. PubMed

Bauer AK, Faiola B, Abernethy DJ, Marchan R, Pluta LJ, Wong VA, Gonzalez FJ, Butterworth BE, Borghoff SJ, Everitt JI, Recio L. Male mice deficient in microsomal epoxide hydrolase are not susceptible to benzene-induced toxicity. Toxicol Sci. 2003;72:201–209. PubMed

Beetham JK, Grant D, Arand M, Garbarino J, Kiyosue T, Pinot F, Oesch F, Belknap WR, Shinozaki K, Hammock BD. Gene evolution of epoxide hydrolases and recommended nomenclature. DNA Cell Biol. 1995;14:61–71. PubMed

Benhamou S, Reinikainen M, Bouchardy C, Dayer P, Hirvonen A. Association between lung cancer and microsomal epoxide hydrolase genotypes. Cancer Res. 1998;58:5291–5293. PubMed

Bhaskar LV, Thangaraj K, Patel M, Shah AM, Gopal K, Saikrishna L, Tamang R, Singh L, Rao VR. EPHX1 gene polymorphisms in alcohol dependence and their distribution among the Indian populations. Am J Drug Alcohol Abuse. 2013;39:16–22. PubMed

Buehler BA, Delimont D, van Waes M, Finnell RH. Prenatal prediction of risk of the fetal hydantoin syndrome. New Eng J Med. 1990;322:1567–1571. PubMed

Carbonari D, Mansi A, Proietto AR, Paci E, Bonanni RC, Gherardi M, Gatto MP, Sisto R, Tranfo G. Influence of genetic polymorphisms of styrene-metabolizing enzymes on the levels of urinary biomarkers of styrene exposure. Toxicol Lett. 2015;233:156–162. PubMed

Caruso A, Bellia C, Pivetti A, Agnello L, Bazza F, Scazzone C, Bivona G, Lo Sasso B, Ciaccio M. Effects of EPHX1 and CYP3A4 polymorphisms on carbamazepine metabolism in epileptic patients. Pharmgenomics Pers Med. 2014;7:117–120. PubMed PMC

Casson AG, Zheng Z, Porter GA, Guernsey DL. Genetic polymorphisms of microsomal epoxide hydroxylase and glutathione S-transferases M1, T1 and P1, interactions with smoking, and risk for esophageal (Barrett) adenocarcinoma. Cancer Detect Prev. 2006;30:423–431. PubMed

Catsburg C, Joshi AD, Corral R, Lewinger JP, Koo J, John EM, Ingles SA, Stern MC. Polymorphisms in carcinogen metabolism enzymes, fish intake, and risk of prostate cancer. Carcinogenesis. 2012;33:1352–1359. PubMed PMC

Chen JY, Chen WN, Liu LL, Lin WS, Jiao BY, Wu YL, Lin JY, Lin X. Hepatitis B Spliced Protein (HBSP) Generated by a Spliced Hepatitis B Virus RNA Participates in Abnormality of Fibrin Formation and Functions by Binding to Fibrinogen gamma Chain. J Med Virol. 2010;82:2019–2026. PubMed

Chen JY, Chen WN, Jiao BY, Lin WS, Wu YL, Liu LL, Lin X. Hepatitis B spliced protein (HBSP) promotes the carcinogenic effects of benzo [alpha] pyrene by interacting with microsomal epoxide hydrolase and enhancing its hydrolysis activity. BMC Cancer. 2014;14:282. PubMed PMC

Cho MK, Kim SG. Differential induction of rat hepatic microsomal epoxide hydrolase and rGSTA2 by diazines: the role of cytochrome P450 2E1-mediated metabolic activation. Chem Biol Interact. 1998;116:229–245. PubMed

Coller JK, Fritz P, Zanger UM, Siegle I, Eichelbaun M, Kroemer HK, Mürdter TE. Distribution of microsomal epoxide hydrolase in humans: an immunohistochemical study in normal tissues, and benign and malignant tumours. Histochem J. 2001;33:329–336. PubMed

Costa C, Costa S, Silva S, Coelho P, Botelho M, Gaspar J, Rueff J, Laffon B, Teixeira JP. DNA damage and susceptibility assessment in industrial workers exposed to styrene. J Toxicol Environ Health A. 2012;75:735–746. PubMed

Craft JA, Baird S, Lamont M, Burchell B. Membrane topology of epoxide hydrolase. Biochim Biophys Acta. 1990;1046:32–39. PubMed

Decker M, Arand M, Cronin A. Mammalian epoxide hydrolases in xenobiotic metabolism and signaling. Arch Toxicol. 2009;83:297–318. PubMed

Duan CY, Liu MY, Li SB, Ma KS, Bie P. Lack of association of EPHX1 gene polymorphisms with risk of hepatocellular carcinoma: a meta-analysis. Tumour Biol. 2014;35:659–666. PubMed

Duan H, Takagi A, Kayano H, Koyama I, Morisseau C, Hammock BD, Akatsuka T. Monoclonal antibodies reveal multiple forms of expression of human microsomal epoxide hydrolase. Toxicol Appl Pharmacol. 2012;260:27–34. PubMed PMC

El-Sherbeni AA, El-Kadi AO. The role of epoxide hydrolases in health and disease. Arch Toxicol. 2014;88:2013–2032. PubMed

Esteban-Jurado C, Vila-Casadesús M, Garre P, Lozano JJ, Pristoupilova A, Beltran S, Muñoz J, Ocaña T, Balaguer F, López-Cerón M, Cuatrecasas M, Franch-Expósito S, Piqué JM, Castells A, Carracedo A, Ruiz-Ponte C, Abulí A, Bessa X, Andreu M, Bujanda L, Caldés T, Castellví-Bel S. Whole-exome sequencing identifies rare pathogenic variants in new predisposition genes for familial colorectal cancer. Genet Med. 2015;17:131–142. PubMed PMC

Farin FM, Omiecinski CJ. Regiospecific expression of cytochrome P-450s and microsomal epoxide hydrolase in human brain tissue. J Toxicol Environ Health. 1993;40:317–335. PubMed

Fathy M, Hamed M, Youssif O, Fawzy N, Ashour W. Association between environmental tobacco smoke exposure and lung cancer susceptibility: modification by antioxidant enzyme genetic polymorphisms. Mol Diagn Ther. 2014;18:55–62. PubMed

Fretland AJ, Omiecinski CJ. Epoxide hydrolases: biochemistry and molecular biology. Chem Biol Interact. 2000;129:41–59. PubMed

Fritz P, Behrle E, Zanger UM, Mürdter T, Schwarzmann P, Kroemer HK. Immunohistochemical assessment of human microsomal epoxide hydrolase in primary and secondary liver neoplasm: a quantitative approach. Xenobiotica. 1996;26:107–116. PubMed

Fritz P, Mürdter TE, Eichelbaum M, Siegle I, Weissert M, Zanger UM. Microsomal epoxide hydrolase expression as a predictor of tamoxifen response in primary breast cancer: a retrospective exploratory study with long-term follow-up. J Clin Oncol. 2001;19:3–9. PubMed

Gaedigk A, Leeder JS, Grant DM. Tissue-specific expression and alternative splicing of human microsomal epoxide hydrolase. DNA Cell Biol. 1997;16:1257–1266. PubMed

Gaedigk A, Spielberg SP, Grant DM. Characterization of the microsomal epoxide hydrolase gene in patients with anticonvulsant adverse drug reactions. Pharmacogenetics. 1994;4:142–153. PubMed

Gill SS, Ota K, Ruebner B, Hammock BD. Microsomal and cytosolic epoxide hydrolase in rhesus monkey liver, and in normal and neoplastic human liver. Life Sci. 1983;32:2693–2700. PubMed

Gilsing AM, Berndt SI, Ruder EH, Graubard BI, Ferrucci LM, Burdett L, Weissfeld JL, Cross AJ, Sinha R. Meat-related mutagen exposure, xenobiotic metabolizing gene polymorphisms and the risk of advanced colorectal adenoma and cancer. Carcinogenesis. 2012;33:1332–1339. PubMed PMC

Goode EL, White KL, Vierkant RA, Phelan CM, Cunningham JM, Schildkraut JM, Berchuck A, Larson MC, Fridley BL, Olson JE, Webb PM, Chen X, Beesley J, Chenevix-Trench G, Sellers TA. Xenobiotic-Metabolizing gene polymorphisms and ovarian cancer risk. Mol Carcinog. 2011;50:397–402. PubMed PMC

Hammock BD, Storms DH, Grant DF. Epoxide hydrolases. In: Guengerich FP, editor. Comprehensive toxicology. Vol. 3. Pergamon; Oxford: 1997. pp. 283–305.

Hardwick JP, Gonzalez FJ, Kasper CB. Transcriptional regulation of rat liver epoxide hydratase, NADPH-Cytochrome P-450 oxidoreductase, and cytochrome P-450b genes by phenobarbital. J Biol Chem. 1983;258:8081–8085. PubMed

Harris TR, Hammock BD. Soluble epoxide hydrolase: gene structure, expression and deletion. Gene. 2013;526:61–74. PubMed PMC

Hartsfield JK, Jr, Sutcliffe MJ, Everett ET, Hassett C, Omiecinski CJ, Saari JA. Assignment of microsomal epoxide hydrolase (EPHX1) to human chromosome 1q42. 1 by in situ hybridization. Cytogenet Cell Genet. 1998;83:44–45. PubMed

Hassett C, Robinson KB, Beck NB, Omiecinski CJ. The human microsomal epoxide hydrolase gene (EPHX1): complete nucleotide sequence and structural characterization. Genomics. 1994a;23:433–442. PubMed

Hassett C, Aicher L, Sidhu JS, Omiecinski CJ. Human microsomal epoxide hydrolase: genetic polymorphism and functional expression in vitro of amino acid variants. Hum Mol Genet. 1994b;3:421–428. PubMed PMC

Hassett C, Lin J, Carty CL, Laurenzana EM, Omiecinski CJ. Human hepatic microsomal epoxide hydrolase: comparative analysis of polymorphic expression. Arch Biochem Biophys. 1997;337:275–283. PubMed

Hassett C, Laurenzana EM, Sidhu JS, Omiecinski CJ. Effects of chemical inducers on human microsomal epoxide hydrolase in primary hepatocyte cultures. Biochem Pharmacol. 1998;55:1059–1069. PubMed

Heininger K. A unifying hypothesis of Alzheimer’s disease. III. Risk factors. Hum Psychopharmacol. 2000;15:1–70. PubMed

Hemminki K, Frank C, Försti A, Musak L, Kazimirova A, Barancokova M, Horska A, Vymetalkova V, Smerhovsky Z, Naccarati A, Soucek P, Vodickova L, Buchancova J, Smolkova B, Dusinska M, Vodicka P. Metabolic gene variants associated with chromosomal aberrations in healthy humans. Genes Chromosomes Cancer. 2015;54:260–266. PubMed

Hlavata I, Vrana D, Smerhovsky Z, Pardini B, Naccarati A, Vodicka P, Novotny J, Mohelnikova-Duchonova B, Soucek P. Association between exposure-relevant polymorphisms in CYP1B1, EPHX1, NQO1, GSTM1, GSTP1 and GSTT1 and risk of colorectal cancer in a Czech population. Oncol Rep. 2010;24:1347–1353. PubMed

Honscha W, Oesch F, Friedberg T. Tissue-specific expression and differential inducibility of several microsomal epoxide hydrolase mRNAs which are formed by alternative splicing. Arch Biochem Biophys. 1991;287:380–385. PubMed

Hosagrahara VP, Rettie AE, Hassett C, Omiecinski CJ. Functional analysis of human microsomal epoxide hydrolase genetic variants. Chem Biol Interact. 2004;150:149–159. PubMed PMC

Hu JJ, Wang ZT, Li B. Meta-analysis demonstrates lack of an association of microsomal epoxide hydrolase 1 polymorphisms with esophageal cancer risk. Genet Mol Res. 2013;12:4540–4548. PubMed

Jackson MR, Craft JA, Burchell B. Nucleotide and deduced amino acid sequence of human liver microsomal epoxide hydrolase. Nucleic Acids Res. 1987;15:7188. PubMed PMC

Jourenkova-Mironova N, Mitrunen K, Bouchardy C, Dayer P, Benhamou S, Hirvonen A. High-activity microsomal epoxide hydrolase genotypes and the risk of oral, pharynx, and larynx cancers. Cancer Res. 2000;60:534–536. PubMed

Kessler R, Hamou MF, Albertoni M, de Tribolet N, Arand M, Van Meir EG. Identification of the putative brain tumor antigen BF7/GE2 as the (de)toxifying enzyme microsomal epoxide hydrolase. Cancer Res. 2000;60:1403–1409. PubMed

Khedhaier A, Hassen E, Bouaouina N, Gabbouj S, Ahmed SB, Chouchane L. Implication of Xenobiotic Metabolizing Enzyme gene (CYP2E1, CYP2C19, CYP2D6, mEH and NAT2) polymorphisms in breast carcinoma. BMC Cancer. 2008;8:109. PubMed PMC

Kim S, Lan Q, Waidyanatha S, Chanock S, Johnson BA, Vermeulen R, Smith MT, Zhang L, Li G, Shen M, Yin S, Rothman N, Rappaport SM. Genetic polymorphisms and benzene metabolism in humans exposed to a wide range of air concentrations. Pharmacogenet Genomics. 2007;17:789–801. PubMed

Kim SK, Woodcroft KJ, Kim SG, Novak RF. Insulin and glucagon signaling in regulation of microsomal epoxide hydrolase expression in primary cultured rat hepatocytes. Drug Metab Dispos. 2003;31:1260–1268. PubMed

Kitteringham NR, Davis C, Howard N, Pirmohamed M, Park BK. Interindividual and interspecies variation in hepatic microsomal epoxide hydrolase activity: studies with cis-stilbene oxide, carbamazepine 10, 11-epoxide and naphthalene. J Pharmacol Exp Ther. 1996;278:1018–1027. PubMed

Laasanen J, Romppanen EL, Hiltunen M, Helisalmi S, Mannermaa A, Punnonen K, Heinonen S. Two exonic single nucleotide polymorphisms in the microsomal epoxide hydrolase gene are jointly associated with preeclampsia. Eur J Hum Genet. 2002;10:569–573. PubMed

Laffon B, Pérez-Cadahía B, Pásaro E, Méndez J. Effect of epoxide hydrolase and glutathione S-tranferase genotypes on the induction of micronuclei and DNA damage by styrene-7,8-oxide in vitro. Mutat Res. 2003;536:49–59. PubMed

Landi S, Gemignani F, Moreno V, Gioia-Patricola L, Chabrier A, Guino E, Navarro M, de Oca J, Capellà G, Canzian F Bellvitge Colorectal Cancer Study Group. A comprehensive analysis of phase I and phase II metabolism gene polymorphisms and risk of colorectal cancer. Pharmacogenet Genomics. 2005;15:535–546. PubMed

Lee J, Dahl M, Nordestgaard BG. Genetically lowered microsomal epoxide hydrolase activity and tobacco-related cancer in 47,000 individuals. Cancer Epidemiol Biomarkers Prev. 2011;20:1673–1682. PubMed

Lewis DF, Lake BG, Bird MG. Molecular modelling of human microsomal epoxide hydrolase (EH) by homology with a fungal (Aspergillus niger) EH crystal structure of 1.8 A resolution: structure-activity relationships in epoxides inhibiting EH activity. Toxicol In Vitro. 2005;19:517–522. PubMed

Li H, Fu WP, Hong ZH. Microsomal epoxide hydrolase gene polymorphisms and risk of chronic obstructive pulmonary disease: a comprehensive meta-analysis. Oncol Lett. 2013;5:1022–1030. PubMed PMC

Liang SH, Hassett C, Omiecinski CJ. Alternative promoters determine tissue-specific expression profiles of the human microsomal epoxide hydrolase gene (EPHX1) Mol Pharmacol. 2005;67:220–230. PubMed PMC

Liu M, Sun A, Shin EJ, Liu X, Kim SG, Runyons CR, Markesbery W, Kim HC, Bing G. Expression of microsomal epoxide hydrolase is elevated in Alzheimer’s hippocampus and induced by exogenous beta-amyloid and trimethyl-tin. Eur J Neurosci. 2006;23:2027–2034. PubMed

Liu F, Yuan D, Wei Y, Wang W, Yan L, Wen T, Xu M, Yang J, Li B. Systematic review and meta-analysis of the relationship between EPHX1 polymorphisms and colorectal cancer risk. PLoS One. 2012;7:e43821. PubMed PMC

Liu HQ, Zhang CP, Zhang CZ, Liu XC, Liu ZJ. Influence of two common polymorphisms in the EPHX1 gene on warfarin maintenance dosage: a meta-analysis. Biomed Res Int. 2015;2015:564149. PubMed PMC

Lu AY, Thomas PE, Ryan D, Jerina DM, Levin W. Purification of human liver microsomal epoxide hydrase. Differences in the properties of the human and rat enzymes. J Biol Chem. 1979;254:5878–5781. PubMed

Marowsky A, Burgener J, Falck JR, Fritschy JM, Arand M. Distribution of soluble and microsomal epoxide hydrolase in the mouse brain and its contribution to cerebral epoxyeicosatrienoic acid metabolism. Neuroscience. 2009;163:646–661. PubMed

Masoodi TA, Rao Talluri V, Shaik NA, Al-Aama JY, Hasan Q. Functional genomics based prioritization of potential nsSNPs in EPHX1, GSTT1, GSTM1 and GSTP1 genes for breast cancer susceptibility studies. Genomics. 2012;99:330–339. PubMed

Mertes I, Fleischmann R, Glatt HR, Oesch F. Interindividual variations in the activities of cytosolic and microsomal epoxide hydrolase in human liver. Carcinogenesis. 1985;6:219–223. PubMed

Mitrou PN, Watson MA, Loktionov AS, Cardwell C, Gunter MJ, Atkin WS, Macklin CP, Cecil T, Bishop DT, Primrose J, Bingham SA. Role of NQO1C609T and EPHX1 gene polymorphisms in the association of smoking and alcohol with sporadic distal colorectal adenomas: results from the UKFSS Study. Carcinogenesis. 2007;28:875–882. PubMed

Miyata M, Kudo G, Lee YH, Yang TJ, Gelboin HV, Fernandez-Salguero P, Kimura S, Gonzalez FJ. Targeted disruption of the microsomal epoxide hydrolase gene. Microsomal epoxide hydrolase is required for the carcinogenic activity of 7,12-dimethylbenz[a]anthracene. J Biol Chem. 1999;274:23963–23968. PubMed

Morisseau C, Newman JW, Wheelock CE, Hill T, III, Morin D, Buckpitt AR, Hammock BD. Development of metabolically stable inhibitors of Mammalian microsomal epoxide hydrolase. Chem Res Toxicol. 2008;21:951–957. PubMed

Murray GI, Weaver RJ, Paterson PJ, Ewen SW, Melvin WT, Burke MD. Expression of xenobiotic metabolizing enzymes in breast cancer. J Pathol. 1993;169:347–353. PubMed

Nakajima Y, Saito Y, Shiseki K, Fukushima-Uesaka H, Hasegawa R, Ozawa S, Sugai K, Katoh M, Saitoh O, Ohnuma T, Kawai M, Ohtsuki T, Suzuki C, Minami N, Kimura H, Goto Y, Kamatani N, Kaniwa N, Sawada J. Haplotype structures of EPHX1 and their effects on the metabolism of carbamazepine-10, 11-epoxide in Japanese epileptic patients. Eur J Clin Pharmacol. 2005;61:25–34. PubMed

Newman JW, Morisseau C, Hammock BD. Epoxide hydrolases: their roles and interactions with lipid metabolism. Prog Lipid Res. 2005;44:1–51. PubMed

Nguyen HL, Yang X, Omiecinski CJ. 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. 2013;19:752–766. PubMed PMC

Nithipatikom K, Endsley MP, Pfeiffer AW, Falck JR, Campbell WB. A novel activity of microsomal epoxide hydrolase: metabolism of the endocannabinoid 2-arachidonoylglycerol. J Lipid Res. 2014;55:2093–102. PubMed PMC

Oesch F, Jerina DM, Daly JW. Substrate specificity of hepatic epoxide hydrase in microsomes and in a purified preparation: evidence for homologous enzymes. Arch Biochem Biophys. 1971a;144:253–261. PubMed

Oesch F, Kaubisch N, Jerina DM, Daly JW. Hepatic Epoxide Hydrase. Structure-Activity Relationships for Substrates and Inhibitors Biochemistry. 1971b;10:4858–4866. PubMed

Oesch F. Purification and specificity of a human microsomal epoxide hydratase. Biochem J. 1974;139:77–88. PubMed PMC

Oesch F, Raphael D, Schwind H, Glatt HR. Species differences in activating and inactivating enzymes related to the control of mutagenic metabolites. Arch Toxicol. 1977;39:97–108. PubMed

Oesch F, Herrero ME, Hengstler JG, Lohmann M, Arand M. Metabolic detoxification: implications for thresholds. Toxicol Pathol. 2000;28:382–387. PubMed

Ollis DL, Cheah E, Cygler M, Dijkstra B, Frolow F, Franken SM, Harel M, Remington SJ, Silman I, Schrag J, Sussman JL, Verschueren KHG, Goldman A. The α/β hydrolase fold. Protein Eng. 1992;5:197–211. PubMed

Peluso ME, Munnia A, Srivatanakul P, Jedpiyawongse A, Sangrajrang S, Ceppi M, Godschalk RW, van Schooten FJ, Boffetta P. DNA adducts and combinations of multiple lung cancer at-risk alleles in environmentally exposed and smoking subjects. Environ Mol Mutagen. 2013;54:375–383. PubMed

Peng DR, Pacifici GM, Rane A. Human fetal liver cultures: basal activities and inducibility of epoxide hydrolases and aryl hydrocarbon hydroxylase. Biochem Pharmacol. 1984;33:71–77. PubMed

Peng H, Zhu QS, Zhong S, Levy D. Transcription of the human microsomal epoxide hydrolase gene (EPHX1) is regulated by an HNF-4α/CAR/RXR/PSF complex. Biochim Biophys Acta. 2013;1829:1000–1009. PubMed

Pérez-Morales R, Méndez-Ramírez I, Moreno-Macias H, Mendoza-Posadas AD, Martínez-Ramírez OC, Castro-Hernández C, Gonsebatt ME, Rubio J. Genetic susceptibility to lung cancer based on candidate genes in a sample from the Mexican Mestizo population: a case-control study. Lung. 2014;192:167–173. PubMed

Popp SL, Abele IS, Buck MB, Stope MB, Blok LJ, Hanifi-Moghaddam P, Burger CW, Fritz P, Knabbe C. Microsomal epoxide hydrolase expression in the endometrial uterine corpus is regulated by progesterone during the menstrual cycle. J Mol Histol. 2010;41:111–119. PubMed

Puranik YG, Birnbaum AK, Marino SE, Ahmed G, Cloyd JC, Remmel RP, Leppik IE, Lamba JK. Association of carbamazepine major metabolism and transport pathway gene polymorphisms and pharmacokinetics in patients with epilepsy. Pharmacogenomics. 2013;14:35–45. PubMed PMC

Pushparajah DS, Umachandran M, Plant KE, Plant N, Ioannides C. Differential response of human and rat epoxide hydrolase to polycyclic aromatic hydrocarbon exposure: studies using precision-cut tissue slices. Mutat Res. 2008;640:153–161. PubMed

Rawal S, Morisseau C, Hammock BD, Shivachar AC. Differential subcellular distribution and colocalization of the microsomal and soluble epoxide hydrolases in cultured neonatal rat brain cortical astrocytes. J Neurosci Res. 2009;87:218–227. PubMed PMC

Rotunno M, Yu K, Lubin JH, Consonni D, Pesatori AC, Goldstein AM, Goldin LR, Wacholder S, Welch R, Burdette L, Chanock SJ, Bertazzi PA, Tucker MA, Caporaso NE, Chatterjee N, Bergen AW, Landi MT. Phase I metabolic genes and risk of lung cancer: multiple polymorphisms and mRNA expression. PLoS One. 2009;4:e5652. PubMed PMC

Sarmanová J, Benesová K, Gut I, Nedelcheva-Kristensen V, Tynková L, Soucek P. Genetic polymorphisms of biotransformation enzymes in patients with Hodgkin’s and non-Hodgkin’s lymphomas. Hum Mol Genet. 2001;10:1265–1273. PubMed

Sarmanová J, Sůsová S, Gut I, Mrhalová M, Kodet R, Adámek J, Roth Z, Soucek P. Breast cancer: role of polymorphisms in biotransformation enzymes. Eur J Hum Genet. 2004;12:848–854. PubMed

Shin EJ, Bing G, Chae JS, Kim TW, Bach JH, Park DH, Yamada K, Nabeshima T, Kim HC. Role of microsomal epoxide hydrolase in methamphetamine-induced drug dependence in mice. J Neurosci Res. 2009;87:3679–3686. PubMed

Shou M, Gonzalez FJ, Gelboin HV. Stereoselective epoxidation and hydration at the K-region of polycyclic aromatic hydrocarbons by cDNA-expressed cytochromes P450 1A1, 1A2, and epoxide hydrolase. Biochemistry. 1996;35:15807–15813. PubMed

daSilveira VS, Canalle R, Scrideli CA, Queiroz RG, Tone LG. Role of the CYP2D6, EPHX1, MPO, and NQO1 genes in the susceptibility to acute lymphoblastic leukemia in Brazilian children. Environ Mol Mutagen. 2010;51:48–56. PubMed

Skoda RC, Demierre A, McBride OW, Gonzalez FJ, Meyer UA. Human microsomal xenobiotic epoxide hydrolase. Complementary DNA sequence, complementary DNA-directed expression in COS-1 cells, and chromosomal localization. J Biol Chem. 1988;263:1549–1554. PubMed

Spurdle AB, Chang JH, Byrnes GB, Chen X, Dite GS, McCredie MR, Giles GG, Southey MC, Chenevix-Trench G, Hopper JL. A systematic approach to analysing gene-gene interactions: polymorphisms at the microsomal epoxide hydrolase EPHX and glutathione S-transferase GSTM1, GSTT1, and GSTP1 loci and breast cancer risk. Cancer Epidemiol Biomarkers Prev. 2007;16:769–774. PubMed

Su S, Omiecinski CJ. Sp1 and Sp3 transcription factors regulate the basal expression of human microsomal epoxide hydrolase (EPHX1) through interaction with the E1b far upstream promoter. Gene. 2014;536:135–144. PubMed PMC

Su S, Yang X, Omiecinski CJ. Intronic DNA elements regulate Nrf2 chemical responsiveness of the human microsomal epoxide hydrolase gene (EPHX1) through a far upstream alternative promoter. Biochim Biophys Acta. 2014;1839:493–505. PubMed PMC

Tacconelli S, Patrignani P. Inside epoxyeicosatrienoic acids and cardiovascular disease. Front Pharmacol. 2014;5:239. PubMed PMC

Tan X, Wang YY, Chen XY, Xian L, Guo JJ, Liang GB, Chen MW. Quantitative assessment of the effects of the EPHX1 Tyr113His polymorphism on lung and breast cancer. Genet Mol Res. 2014;13:7437–7446. PubMed

Tumer TB, Sahin G, Arinç E. Association between polymorphisms of EPHX1 and XRCC1 genes and the risk of childhood acute lymphoblastic leukemia. Arch Toxicol. 2012;86:431–439. PubMed

van der Logt EM, Bergevoet SM, Roelofs HM, Te Morsche RH, Dijk Yv, Wobbes T, Nagengast FM, Peters WH. Role of epoxide hydrolase, NAD(P)H:quinone oxidoreductase, cytochrome P450 2E1 or alcohol dehydrogenase genotypes in susceptibility to colorectal cancer. Mutat Res. 2006;593:39–49. PubMed

van Loo B, Kingma J, Arand M, Wubbolts MG, Janssen DB. Diversity and biocatalytic potential of epoxide hydrolases identified by genome analysis. Appl Environ Microbiol. 2006;72:2905–2917. PubMed PMC

Vodicka P, Soucek P, Tates AD, Dusinska M, Sarmanova J, Zamecnikova M, Vodickova L, Koskinen M, de Zwart FA, Natarajan AT, Hemminki K. Association between genetic polymorphisms and biomarkers in styrene-exposed workers. Mutat Res. 2001;482:89–103. PubMed

Vodicka P, Kumar R, Stetina R, Musak L, Soucek P, Haufroid V, Sasiadek M, Vodickova L, Naccarati A, Sedikova J, Sanyal S, Kuricova M, Brsiak V, Norppa H, Buchancova J, Hemminki K. Markers of individual susceptibility and DNA repair rate in workers exposed to xenobiotics in a tire plant. Environ Mol Mutagen. 2004;44:283–292. PubMed

Vodicka P, Polivkova Z, Sytarova S, Demova H, Kucerova M, Vodickova L, Polakova V, Naccarati A, Smerhovsky Z, Ambrus M, Cerna M, Hemminki K. Chromosomal damage in peripheral blood lymphocytes of newly diagnosed cancer patients and healthy controls. Carcinogenesis. 2010;31:1238–1241. PubMed

Vogel-Bindel U, Bentley P, Oesch F. Endogenous role of microsomal epoxide hydrolase. Ontogenesis, induction inhibition, tissue distribution, immunological behaviour and purification of microsomal epoxide hydrolase with 16alpha, 17alpha-epoxyandrostene-3-one as substrate. Eur J Biochem. 1982;126:425–31. PubMed

Walsh J, Jenkins RE, Wong M, Olayanju A, Powell H, Copple I, O’Neill PM, Goldring CE, Kitteringham NR, Park BK. Identification and quantification of the basal and inducible Nrf2-dependent proteomes in mouse liver: biochemical, pharmacological and toxicological implications. J Proteomics. 2014;108:171–187. PubMed PMC

Wang S, Zhu J, Zhang R, Wang S, Gu Z. Association between microsomal epoxide hydrolase 1 T113C polymorphism and susceptibility to lung cancer. Tumour Biol. 2013;34:1045–1052. PubMed

Watabe T, Kanehira S. Solubilization of epoxide hydrolase from liver microsomes. Chem Pharm Bull (Tokyo) 1970;18:1295–1296. PubMed

Willey JC, Coy E, Brolly C, Utell MJ, Frampton MW, Hammersley J, Thilly WG, Olson D, Cairns K. Xenobiotic metabolism enzyme gene expression in human bronchial epithelial and alveolar macrophage cells. Am J Respir Cell Mol Biol. 1996;14:262–271. PubMed

Wong NA, Rae F, Bathgate A, Smith CA, Harrison DJ. Polymorphisms of the gene for microsomal epoxide hydrolase and susceptibility to alcoholic liver disease and hepatocellular carcinoma in a Caucasian population. Toxicol Lett. 2000;115:17–22. PubMed

Xing C, Chen Q, Li G, Zhang L, Zheng M, Zou Z, Hou L, Wang QF, Liu X, Guo X. Microsomal epoxide hydrolase (EPHX1) polymorphisms are associated with aberrant promoter methylation of ERCC3 and hematotoxicity in benzene-exposed workers. Environ Mol Mutagen. 2013;54:397–405. PubMed

Yamada T, Morisseau C, Maxwell JE, Argiriadi MA, Christianson DW, Hammock BD. Biochemical evidence for the involvement of tyrosine in epoxide activation during the catalytic cycle of epoxide hydrolase. J Biol Chem. 2000;275:23082–23088. PubMed

Yang X, Liang SH, Weyant DM, Lazarus P, Gallagher CJ, Omiecinski CJ. The expression of human microsomal epoxide hydrolase is predominantly driven by a genetically polymorphic far upstream promoter. J Pharmacol Exp Ther. 2009;330:23–30. PubMed PMC

Zhao ZQ, Guan QK, Yang FY, Zhao P, Zhou B, Chen ZJ. System review and metaanalysis of the relationships between five metabolic gene polymorphisms and colorectal adenoma risk. Tumour Biol. 2012;33:523–535. PubMed

Zhu Q, Xing W, Qian B, von Dippe P, Shneider BL, Fox VL, Levy D. Inhibition of human m-epoxide hydrolase gene expression in a case of hypercholanemia. Biochim Biophys Acta. 2003;1638:208–216. PubMed

Zhu QS, Qian B, Levy D. 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. J Biol Chem. 2004;279:29902–29910. PubMed

Zou J, Hallberg BM, Bergfors T, Oesch F, Arand M, Mowbray SL, Jones TA. Structure of Agergillus niger epoxide hydrolase at 1. 8 Å resolution: implications for the structure and function of the mammalian microsomal class of epoxide hydrolases. Structure with Folding and Design. 2000;8:111–122. PubMed

Zusterzeel PLM, Peters WHM, Visser W, Hermsen KJM, Roelofs HMJ, Steegers EAP. A polymorphism in the gene for microsomal epoxide hydrolase is associated with pre-eclampsia. J Med Genet. 2001;38:234–237. PubMed PMC

Frequency of Gene Polymorphisms in Admixed Venezuelan Women with Recurrent Pregnancy Loss: Microsomal Epoxy Hydroxylase (rs1051740) and Enos (rs1799983)