EPHX1

EPHX1
Identifiers
Aliases	EPHX1 , EPHX, EPOX, HYL1, MEH, epoxide hydrolase 1
External IDs	OMIM: 132810; MGI: 95405; HomoloGene: 94; GeneCards: EPHX1; OMA:EPHX1 - orthologs
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 180,803,775 bp [2] End 180,848,469 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right adrenal cortex left adrenal gland left adrenal cortex right lobe of liver left ovary right ovary olfactory zone of nasal mucosa right uterine tube bronchial epithelial cell nasal epithelium Top expressed in choroid plexus of fourth ventricle left lobe of liver stroma of bone marrow nasal epithelium olfactory epithelium Epithelium of choroid plexus vestibular membrane of cochlear duct right lung lobe iris adrenal gland More reference expression data BioGPS 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 plasma 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: 180.8 – 180.85 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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

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.

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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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. S2CID   42482323.
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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.
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25. Vogel-Bindel U, Bentley P, Oesch F (1982). "Endogenous role of microsomal epoxide hydrolase. Ontogenesis, induction inhibition, tissue distribution, immunological behaviour and purification of microsomal epoxide hydrolase with 16 alpha, 17 alpha-epoxyandrostene-3-one as substrate". Eur. J. Biochem. 126 (2): 425–31. doi: 10.1111/j.1432-1033.1982.tb06797.x . PMID   7128597.
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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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34. Benhamou S, Reinikainen M, Bouchardy C, Dayer P, Hirvonen A (1998). "Association between lung cancer and microsomal epoxide hydrolase genotypes". Cancer Res. 58 (23): 5291–3. PMID   9850050.
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. Bibcode:2004CBI...150..149H. 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.
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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. S2CID   14846609.
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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. S2CID   5969583.
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50. Marowsky A, Burgener J, Falck JR, Fritschy JM, Arand M (2009). "Distribution of soluble and microsomal epoxide hydrolase in the mouse brain and its contribution to cerebral epoxyeicosatrienoic acid metabolism". Neuroscience. 163 (2): 646–661. doi:10.1016/j.neuroscience.2009.06.033. PMID   19540314. S2CID   25808698.

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. S2CID   1073260.
• 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. Bibcode:1995PNAS...92.2384M. 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 . hdl: 2433/150184 . 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. S2CID   26515784.
• 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.