EPHX1

EPHX1
Identifiers
AliasesEPHX1, EPHX, EPOX, HYL1, MEH, epoxide hydrolase 1
External IDsMGI: 95405 HomoloGene: 94 GeneCards: EPHX1
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
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_001299847
NP_034275

Location (UCSC)Chr 1: 225.81 – 225.85 MbChr 1: 180.98 – 181.02 Mb
PubMed search[1][2]
Wikidata
View/Edit HumanView/Edit Mouse

Epoxide hydrolase 1 is an enzyme encoded by the EPHX1 gene in humans.[3][4]

Function

Epoxide hydrolase plays an important role in both the activation and detoxification of exogenous chemicals such as polycyclic aromatic hydrocarbons.[4]

Discovery

Microsomal epoxide hydrolase 1 (EPHX1) was first isolated by Watabe and Kanehira from rabbit liver [5] and later also purified from human liver and characterized.[6] EPHX1 belongs to the family of α/β hydrolases [7] and converts epoxides to diols.[8]

Tissue distribution

EPHX1 protein can be found predominantly in 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, lung, and intestine.[9] It was found also in bronchial epithelial cells [10] and upper gastrointestinal tract.[11] EPHX1 expression is individually variable among humans [12] and it can be modestly induced by chemicals as phenobarbital, β-naphtoflavone, benzanthracene, trans-stilbene oxide, etc.[13]

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).[14][15][16] 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.[8] EPHX1 has broad substrate specificity.[17][18] EPHX1 detoxifies low molecular weight chemicals, e.g., butadiene, benzene, styrene, etc.,[19] but more complex compounds as polycyclic aromatic hydrocarbons are rather bioactivated to genotoxic species.[20][21]

EPHX1 mediates the sodium-dependent transport of bile acids into hepatocytes.[22] Androstene oxide and epoxyestratrienol have been shown as endogenous EPHX1 substrates.[23][24] EPHX1 also metabolizes endocannabinoid 2-arachidonoylglycerol to arachidonic acid[25] and may play an important role in the endocannabinoid signaling pathway.

Clinical significance

Mutations in EPHX1 have been linked with preeclampsia,[26][27] elevated blood levels of bile salts (i.e. hypercholanemia),[28] Fetal hydantoin syndrome,[29] and diphenylhydantoin toxicity. Functional single nucleotide polymorphisms (SNPs) in EPHX1 have been found and frequently studied.[30] Two SNPs - Y113H (rs1051740, T337C) and H139R (rs2234922, A416G) – seemed to influence EPHX1 activity in vitro [31] and their combination was used for deduction of EPHX1 activity.[32] However, their functional effect was not confirmed in human liver microsomes.[33]

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.[34][35][36][37][38] Meta-analyses confirmed associations of rs1051740 and rs2234922 SNPs with the risk of lung cancer.[39][40][41] Meta-analyses reporting no association of these SNPs with esophageal and hepatocellular cancer risk have been reported as well [42][43]). Genetically predicted low EPHX1 activity was associated with increased risk of developing tobacco-related cancer in smokers from 47089 Danish individuals .[44] 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.[45] Role of EPHX1 expression in pathogenesis of neurodegeneration as Alzheimer´s disease,[46] methamphetamine-induced drug dependence,[47] and cerebral metabolism of epoxyeicosatrienoic acids [48] 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. "Human PubMed Reference:".
  2. "Mouse PubMed Reference:".
  3. 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. PMID 9925921. doi:10.1159/000015164.
  4. 1 2 "Entrez Gene: EPHX1 epoxide hydrolase 1, microsomal (xenobiotic)".
  5. Watabe, T; Kanehira, S (1970). "Solubilization of epoxide hydrolase from liver microsomes.". Chem Pharm Bull (Tokyo). 18 (6): 1295–1296. PMID 5465293. doi:10.1248/cpb.18.1295.
  6. Oesch F (1974). "Purification and specificity of a human microsomal epoxide hydratase". Biochem. J. 139 (1): 77–88. PMC 1166253Freely accessible. PMID 4463951. doi:10.1042/bj1390077.
  7. Ollis DL, Cheah E, Cygler M, Dijkstra B, Frolow F, Franken SM, Harel M, Remington SJ, Silman I, Schrag J (1992). "The alpha/beta hydrolase fold". Protein Eng. 5 (3): 197–211. PMID 1409539. doi:10.1093/protein/5.3.197.
  8. 1 2 Oesch F, Kaubisch N, Jerina DM, Daly JW (1971). "Hepatic epoxide hydrase. Structure-activity relationships for substrates and inhibitors". Biochemistry. 10 (26): 4858–66. PMID 5134533. doi:10.1021/bi00802a005.
  9. 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. PMID 341853.
  10. 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. PMID 11758809.
  11. Voho A, Metsola K, Anttila S, Impivaara O, Järvisalo J, Vainio H, Husgafvel-Pursiainen K, Hirvonen A (2006). "EPHX1 gene polymorphisms and individual susceptibility to lung cancer". Cancer Lett. 237 (1): 102–8. PMID 16005144. doi:10.1016/j.canlet.2005.05.029.
  12. Mertes I, Fleischmann R, Glatt HR, Oesch F (1985). "Interindividual variations in the activities of cytosolic and microsomal epoxide hydrolase in human liver". Carcinogenesis. 6 (2): 219–23. PMID 3971488. doi:10.1093/carcin/6.2.219.
  13. Peng DR, Pacifici GM, Rane A (1984). "Human fetal liver cultures: basal activities and inducibility of epoxide hydrolases and aryl hydrocarbon hydroxylase". Biochem. Pharmacol. 33 (1): 71–7. PMID 6538414. doi:10.1016/0006-2952(84)90371-x.
  14. Skoda RC, Demierre A, McBride OW, Gonzalez FJ, Meyer UA (1988). "Human microsomal xenobiotic epoxide hydrolase. Complementary DNA sequence, complementary DNA-directed expression in COS-1 cells, and chromosomal localization". J. Biol. Chem. 263 (3): 1549–54. PMID 2891713.
  15. 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. PMID 7835893. doi:10.1006/geno.1994.1520.
  16. 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. PMID 9925921. doi:10.1159/000015164.
  17. 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.
  18. Fretland AJ, Omiecinski CJ (2000). "Epoxide hydrolases: biochemistry and molecular biology". Chem. Biol. Interact. 129 (1–2): 41–59. PMID 11154734. doi:10.1016/s0009-2797(00)00197-6.
  19. Decker M, Arand M, Cronin A (2009). "Mammalian epoxide hydrolases in xenobiotic metabolism and signalling". Arch. Toxicol. 83 (4): 297–318. PMID 19340413. doi:10.1007/s00204-009-0416-0.
  20. 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. PMID 8961944. doi:10.1021/bi962042z.
  21. 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. PMID 17064856. doi:10.1016/j.cdp.2006.09.005.
  22. Ananthanarayanan M, von Dippe P, Levy D (1988). "Identification of the hepatocyte Na+-dependent bile acid transport protein using monoclonal antibodies". J. Biol. Chem. 263 (17): 8338–43. PMID 3372528.
  23. 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. PMID 7128597. doi:10.1111/j.1432-1033.1982.tb06797.x.
  24. Newman JW, Morisseau C, Hammock BD (2005). "Epoxide hydrolases: their roles and interactions with lipid metabolism". Prog. Lipid Res. 44 (1): 1–51. PMID 15748653. doi:10.1016/j.plipres.2004.10.001.
  25. 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. PMC 4174002Freely accessible. PMID 24958911. doi:10.1194/jlr.M051284.
  26. 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. PMC 1734856Freely accessible. PMID 11283205. doi:10.1136/jmg.38.4.234.
  27. 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. PMID 12173035. doi:10.1038/sj.ejhg.5200849.
  28. Zhu QS, Xing W, Qian B, von Dippe P, Shneider BL, Fox VL, Levy D (2003). "Inhibition of human m-epoxide hydrolase gene expression in a case of hypercholanemia". Biochim. Biophys. Acta. 1638 (3): 208–16. PMID 12878321. doi:10.1016/s0925-4439(03)00085-1.
  29. Buehler BA, Delimont D, van Waes M, Finnell RH (1990). "Prenatal prediction of risk of the fetal hydantoin syndrome". N. Engl. J. Med. 322 (22): 1567–72. PMID 2336087. doi:10.1056/NEJM199005313222204.
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  33. 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. PMC 4091877Freely accessible. PMID 15535985. doi:10.1016/j.cbi.2004.07.004.
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  38. 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. PMID 24615030. doi:10.4238/2014.January.28.10.
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  40. 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. PMID 23055191. doi:10.1007/s13277-012-0523-z.
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  42. Hu JJ, Wang ZT, Li B (2013). "Meta-analysis demonstrates lack of an association of microsomal epoxide hydrolase 1 polymorphisms with esophageal cancer risk". Genet. Mol. Res. 12 (4): 4540–8. PMID 24222229. doi:10.4238/2013.October.15.2.
  43. 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. PMID 23955801. doi:10.1007/s13277-013-1090-7.
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  46. 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. PMID 16630050. doi:10.1111/j.1460-9568.2006.04724.x.
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