EPHX1

Epoxide hydrolase 1 is an enzyme encoded by the EPHX1 gene in humans.[5][6]

EPHX1
Identifiers
Aliases	EPHX1, EPHX, EPOX, HYL1, MEH, epoxide hydrolase 1
External IDs	OMIM: 132810 MGI: 95405 HomoloGene: 94 GeneCards: EPHX1
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1q42.12 Start 225,810,092 bp[1] End 225,845,563 bp[1]
Gene location (Mouse) Chr. Chromosome 1 (mouse)[2] Band 1 H4|1 84.48 cM Start 180,976,210 bp[2] End 181,020,904 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • catalytic activity • hydrolase activity • cis-stilbene-oxide hydrolase activity • epoxide hydrolase activity • enzyme binding Cellular component • integral component of membrane • organelle membrane • endoplasmic reticulum membrane • endoplasmic reticulum • membrane • intracellular membrane-bounded organelle • cell membrane Biological process • cellular aromatic compound metabolic process • xenobiotic metabolic process • aromatic compound catabolic process • response to organic cyclic compound • response to toxic substance • epoxide metabolic process • liver development • diol biosynthetic process • cellular response to organic substance • cellular response to glucocorticoid stimulus Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	2052	13849
Ensembl	ENSG00000143819	ENSMUSG00000038776
UniProt	P07099	Q9D379
RefSeq (mRNA)	NM_001291163 NM_000120 NM_001136018	NM_010145 NM_001312918
RefSeq (protein)	NP_000111 NP_001129490 NP_001278092 NP_001365355 NP_001365356 NP_001365357 NP_001365358 NP_001365359 NP_001365360 NP_001365361	NP_001299847 NP_034275
Location (UCSC)	Chr 1: 225.81 – 225.85 Mb	Chr 1: 180.98 – 181.02 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Function

Epoxide hydrolase plays an important role in both the activation and detoxification of exogenous chemicals such as polycyclic aromatic hydrocarbons.[6]

Discovery

Microsomal epoxide hydrolase 1 (EPHX1) was first isolated by Watabe and Kanehira from rabbit liver [7] and later also purified from human liver and characterized.[8] EPHX1 belongs to the family of α/β hydrolases [9] and converts epoxides to diols.[10]

Tissue distribution

EPHX1 protein can be found predominantly in the membrane fraction of the endoplasmic reticulum of eucaryotic cells. Its expression in mammals is generally the highest in the liver, followed by adrenal gland, lung, kidney, and intestine.[11] It was found also in bronchial epithelial cells [12] and upper gastrointestinal tract.[13] EPHX1 expression is individually variable among humans [14] and it can be modestly induced by chemicals as phenobarbital, β-naphtoflavone, benzanthracene, trans-stilbene oxide, etc.[15]

Gene structure and ontology

Human EPHX1 orthologues were found in 127 organisms. Human microsomal epoxide hydrolase is coded by EPHX1 gene located on chromosome 1 (1q42.12).[16][17][18] Three transcription variants differing in the 5´-untranslated region have been identified with length of 455 amino acids.

Function

Conversion of epoxides to trans-dihydrodiols presents prototypical EPHX1 reaction.[10] EPHX1 has broad substrate specificity.[19][20] EPHX1 detoxifies low molecular weight chemicals, e.g., butadiene, benzene, styrene, etc.,[21] but more complex compounds as polycyclic aromatic hydrocarbons are rather bioactivated to genotoxic species.[22][23]

EPHX1 mediates the sodium-dependent transport of bile acids into hepatocytes.[24] Androstene oxide and epoxyestratrienol have been shown as endogenous EPHX1 substrates.[25][26] EPHX1 also metabolizes endocannabinoid 2-arachidonoylglycerol to arachidonic acid[27] and may play an important role in the endocannabinoid signaling pathway.

Clinical significance

Mutations in EPHX1 have been linked with preeclampsia,[28][29] elevated blood levels of bile salts (i.e. hypercholanemia),[30] Fetal hydantoin syndrome,[31] and diphenylhydantoin toxicity. Functional single nucleotide polymorphisms (SNPs) in EPHX1 have been found and frequently studied.[32] Two SNPs - Y113H (rs1051740, T337C) and H139R (rs2234922, A416G) – seemed to influence EPHX1 activity in vitro [33] and their combination was used for deduction of EPHX1 activity.[34] However, their functional effect was not confirmed in human liver microsomes.[35]

Due to the EPHX1 role in metabolism of procarcinogens and existence of gene variations with functional effect a number of association studies has been conducted. Significant associations between EPHX1 SNPs and risk of lung, upper aerodigestive tract, breast, and ovarian cancers have been observed in various populations.[36][37][38][39][40] Meta-analyses confirmed associations of rs1051740 and rs2234922 SNPs with the risk of lung cancer.[41][42][43] Meta-analyses reporting no association of these SNPs with esophageal and hepatocellular cancer risk have been reported as well [44][45]). Genetically predicted low EPHX1 activity was associated with increased risk of developing tobacco-related cancer in smokers from 47089 Danish individuals .[46] Recent meta-analysis comprising 8,259 patients with chronic obstructive pulmonary disease (COPD) and 42,883 controls reported that the predicted slow activity EPHX1 phenotype is a significant risk factor for COPD in Caucasian, but not in Asian population.[47] Role of EPHX1 expression in pathogenesis of neurodegeneration as Alzheimer´s disease,[48] methamphetamine-induced drug dependence,[49] and cerebral metabolism of epoxyeicosatrienoic acids [50] was suggested. Modulation of metabolism of epoxyeicosatrienoic acids by EPHX1 may interfere with, e.g., signal transmission of neurons, vasodilation, cardiovascular homeostasis, and inflammation. Transformation of the current knowledge about EPHX1 into clinical applications is, however, limited by the lack of crystal structure of the enzyme and by the complex relations between its genotype and phenotype.

Notes

References

1. GRCh38: Ensembl release 89: ENSG00000143819 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000038776 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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6. "Entrez Gene: EPHX1 epoxide hydrolase 1, microsomal (xenobiotic)".
7. Watabe, T; Kanehira, S (1970). "Solubilization of epoxide hydrolase from liver microsomes". Chem Pharm Bull. 18 (6): 1295–1296. doi:10.1248/cpb.18.1295. PMID 5465293.
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10. Oesch F, Kaubisch N, Jerina DM, Daly JW (1971). "Hepatic epoxide hydrase. Structure-activity relationships for substrates and inhibitors". Biochemistry. 10 (26): 4858–66. doi:10.1021/bi00802a005. PMID 5134533.
11. Oesch F, Raphael D, Schwind H, Glatt HR (1977). "Species differences in activating and inactivating enzymes related to the control of mutagenic metabolites". Arch. Toxicol. 39 (1–2): 97–108. doi:10.1007/BF00343279. PMID 341853.
12. Coller JK, Fritz P, Zanger UM, Siegle I, Eichelbaum M, Kroemer HK, Mürdter TE (2001). "Distribution of microsomal epoxide hydrolase in humans: an immunohistochemical study in normal tissues, and benign and malignant tumours". Histochem. J. 33 (6): 329–36. doi:10.1023/A:1012414806166. PMID 11758809.
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17. Hassett C, Robinson KB, Beck NB, Omiecinski CJ (1994). "The human microsomal epoxide hydrolase gene (EPHX1): complete nucleotide sequence and structural characterization". Genomics. 23 (2): 433–42. doi:10.1006/geno.1994.1520. PMID 7835893.
18. Hartsfield JK, Sutcliffe MJ, Everett ET, Hassett C, Omiecinski CJ, Saari JA (1998). "Assignment1 of microsomal epoxide hydrolase (EPHX1) to human chromosome 1q42.1 by in situ hybridization". Cytogenet. Cell Genet. 83 (1–2): 44–5. doi:10.1159/000015164. PMID 9925921.
19. Lu AY, Thomas PE, Ryan D, Jerina DM, Levin W (1979). "Purification of human liver microsomal epoxide hydrase. Differences in the properties of the human and rat enzymes". J. Biol. Chem. 254 (13): 5878–81. PMID 109443.
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22. Shou M, Gonzalez FJ, Gelboin HV (1996). "Stereoselective epoxidation and hydration at the K-region of polycyclic aromatic hydrocarbons by cDNA-expressed cytochromes P450 1A1, 1A2, and epoxide hydrolase". Biochemistry. 35 (49): 15807–13. doi:10.1021/bi962042z. PMID 8961944.
23. Casson AG, Zheng Z, Porter GA, Guernsey DL (2006). "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. 30 (5): 423–31. doi:10.1016/j.cdp.2006.09.005. PMID 17064856.
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27. Nithipatikom K, Endsley MP, Pfeiffer AW, Falck JR, Campbell WB (2014). "A novel activity of microsomal epoxide hydrolase: metabolism of the endocannabinoid 2-arachidonoylglycerol". J. Lipid Res. 55 (10): 2093–102. doi:10.1194/jlr.M051284. PMC 4174002. PMID 24958911.
28. Zusterzeel PL, Peters WH, Visser W, Hermsen KJ, Roelofs HM, Steegers EA (2001). "A polymorphism in the gene for microsomal epoxide hydrolase is associated with pre-eclampsia". J. Med. Genet. 38 (4): 234–7. doi:10.1136/jmg.38.4.234. PMC 1734856. PMID 11283205.
29. Laasanen J, Romppanen EL, Hiltunen M, Helisalmi S, Mannermaa A, Punnonen K, Heinonen S (2002). "Two exonic single nucleotide polymorphisms in the microsomal epoxide hydrolase gene are jointly associated with preeclampsia". Eur. J. Hum. Genet. 10 (9): 569–73. doi:10.1038/sj.ejhg.5200849. PMID 12173035.
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35. Hosagrahara, VP; Rettie, AE; Hassett, C; Omiecinski, CJ (2004). "Functional analysis of human microsomal epoxide hydrolase genetic variants". Chem Biol Interact. 150 (2): 149–159. doi:10.1016/j.cbi.2004.07.004. PMC 4091877. PMID 15535985.
36. Jourenkova-Mironova N, Mitrunen K, Bouchardy C, Dayer P, Benhamou S, Hirvonen A (2000). "High-activity microsomal epoxide hydrolase genotypes and the risk of oral, pharynx, and larynx cancers". Cancer Res. 60 (3): 534–6. PMID 10676631.
37. Sarmanová J, Sůsová S, Gut I, Mrhalová M, Kodet R, Adámek J, Roth Z, Soucek P (2004). "Breast cancer: role of polymorphisms in biotransformation enzymes". Eur. J. Hum. Genet. 12 (10): 848–54. doi:10.1038/sj.ejhg.5201249. PMID 15280903.
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40. Tan X, He WW, Wang YY, Shi LJ, Chen MW (2014). "EPHX1 Tyr113His and His139Arg polymorphisms in esophageal cancer risk: a meta-analysis". Genet. Mol. Res. 13 (1): 649–59. doi:10.4238/2014.January.28.10. PMID 24615030.
41. Kiyohara C, Yoshimasu K, Takayama K, Nakanishi Y (2006). "EPHX1 polymorphisms and the risk of lung cancer: a HuGE review". Epidemiology. 17 (1): 89–99. doi:10.1097/01.ede.0000187627.70026.23. PMID 16357600.
42. Liu H, Li HY, Chen HJ, Huang YJ, Zhang S, Wang J (2013). "EPHX1 A139G polymorphism and lung cancer risk: a meta-analysis". Tumour Biol. 34 (1): 155–63. doi:10.1007/s13277-012-0523-z. PMID 23055191.
43. Wang S, Zhu J, Zhang R, Wang S, Gu Z (2013). "Association between microsomal epoxide hydrolase 1 T113C polymorphism and susceptibility to lung cancer". Tumour Biol. 34 (2): 1045–52. doi:10.1007/s13277-012-0644-4. PMID 23378225.
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45. Duan CY, Liu MY, Li SB, Ma KS, Bie P (2014). "Lack of association of EPHX1 gene polymorphisms with risk of hepatocellular carcinoma: a meta-analysis". Tumour Biol. 35 (1): 659–66. doi:10.1007/s13277-013-1090-7. PMID 23955801.
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47. Li H, Fu WP, Hong ZH (2013). "Microsomal epoxide hydrolase gene polymorphisms and risk of chronic obstructive pulmonary disease: A comprehensive meta-analysis". Oncol Lett. 5 (3): 1022–1030. doi:10.3892/ol.2012.1099. PMC 3576314. PMID 23426996.
48. Liu, M; Sun, A; Shin, EJ; Liu, X; Kim, SG; Runyons, CR; Markesbery, W; Kim, HC; Bing, G (2006). "Expression of microsomal epoxide hydrolase is elevated in Alzheimer's hippocampus and induced by exogenous beta-amyloid and trimethyl-tin". Eur J Neurosci. 23 (8): 2027–2034. doi:10.1111/j.1460-9568.2006.04724.x. PMID 16630050.
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Further reading

• Seidegård J, Ekström G (1997). "The role of human glutathione transferases and epoxide hydrolases in the metabolism of xenobiotics". Environ. Health Perspect. 105 Suppl 4: 791–9. doi:10.2307/3433285. JSTOR 3433285. PMC 1470052. PMID 9255563.
• Wormhoudt LW, Commandeur JN, Vermeulen NP (1999). "Genetic polymorphisms of human N-acetyltransferase, cytochrome P450, glutathione-S-transferase, and epoxide hydrolase enzymes: relevance to xenobiotic metabolism and toxicity". Crit. Rev. Toxicol. 29 (1): 59–124. doi:10.1080/10408449991349186. PMID 10066160.
• Wilson NM, Omiecinski CJ (1989). "Xenobiotic microsomal epoxide hydrolase: 5' sequence of the human gene". Biochim. Biophys. Acta. 1008 (3): 357–8. doi:10.1016/0167-4781(89)90029-8. PMID 2758034.
• Strickler SM, Dansky LV, Miller MA, Seni MH, Andermann E, Spielberg SP (1985). "Genetic predisposition to phenytoin-induced birth defects". Lancet. 2 (8458): 746–9. doi:10.1016/S0140-6736(85)90629-4. PMID 2864485.
• Jackson MR, Craft JA, Burchell B (1987). "Nucleotide and deduced amino acid sequence of human liver microsomal epoxide hydrolase". Nucleic Acids Res. 15 (17): 7188. doi:10.1093/nar/15.17.7188. PMC 306212. PMID 3502697.
• Hassett C, Robinson KB, Beck NB, Omiecinski CJ (1994). "The human microsomal epoxide hydrolase gene (EPHX1): complete nucleotide sequence and structural characterization". Genomics. 23 (2): 433–42. doi:10.1006/geno.1994.1520. PMID 7835893.
• McGlynn KA, Rosvold EA, Lustbader ED, Hu Y, Clapper ML, Zhou T, Wild CP, Xia XL, Baffoe-Bonnie A, Ofori-Adjei D (1995). "Susceptibility to hepatocellular carcinoma is associated with genetic variation in the enzymatic detoxification of aflatoxin B1". Proc. Natl. Acad. Sci. U.S.A. 92 (6): 2384–7. doi:10.1073/pnas.92.6.2384. PMC 42488. PMID 7892276.
• Gaedigk A, Spielberg SP, Grant DM (1994). "Characterization of the microsomal epoxide hydrolase gene in patients with anticonvulsant adverse drug reactions". Pharmacogenetics. 4 (3): 142–53. doi:10.1097/00008571-199406000-00005. PMID 7920694.
• Krovat BC, Tracy JH, Omiecinski CJ (2000). "Fingerprinting of cytochrome P450 and microsomal epoxide hydrolase gene expression in human blood cells". Toxicol. Sci. 55 (2): 352–60. doi:10.1093/toxsci/55.2.352. PMID 10828267.
• Hattori N, Fujiwara H, Maeda M, Fujii S, Ueda M (2000). "Epoxide hydrolase affects estrogen production in the human ovary". Endocrinology. 141 (9): 3353–65. doi:10.1210/endo.141.9.7682. PMID 10965908.
• Belmahdi F, Chevalier D, Lo-Guidice JM, Allorge D, Cauffiez C, Lafitte JJ, Broly F (2000). "Identification of 6 new polymorphisms, g.11177G>A, g.14622C>T (R49C), g.17540T>C, g.17639T>C, g.30929T>C, g.31074G>A (R454Q), in the human microsomal epoxide hydrolase gene (EPHX1) in a French population". Hum. Mutat. 16 (5): 450. doi:10.1002/1098-1004(200011)16:5<450::AID-HUMU28>3.0.CO;2-1. PMID 11058921.
• Sarmanová J, Benesová K, Gut I, Nedelcheva-Kristensen V, Tynková L, Soucek P (2001). "Genetic polymorphisms of biotransformation enzymes in patients with Hodgkin's and non-Hodgkin's lymphomas". Hum. Mol. Genet. 10 (12): 1265–73. doi:10.1093/hmg/10.12.1265. PMID 11406608.
• Farin FM, Janssen P, Quigley S, Abbott D, Hassett C, Smith-Weller T, Franklin GM, Swanson PD, Longstreth WT, Omiecinski CJ, Checkoway H (2001). "Genetic polymorphisms of microsomal and soluble epoxide hydrolase and the risk of Parkinson's disease". Pharmacogenetics. 11 (8): 703–8. doi:10.1097/00008571-200111000-00009. PMID 11692079.