EPHX1

Epoxide hydrolase 1, microsomal (xenobiotic)
Identifiers
Symbols EPHX1 ; EPHX; EPOX; HYL1; MEH
External IDs OMIM: 132810 MGI: 95405 HomoloGene: 94 ChEMBL: 1968 GeneCards: EPHX1 Gene
EC number 3.3.2.9
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 2052 13849
Ensembl ENSG00000143819 ENSMUSG00000038776
UniProt P07099 Q9D379
RefSeq (mRNA) NM_000120 NM_010145
RefSeq (protein) NP_000111 NP_034275
Location (UCSC) Chr 1:
225.81 – 225.85 Mb		 Chr 1:
180.98 – 181.02 Mb
PubMed search

Epoxide hydrolase 1 is an enzyme encoded by the EPHX1 gene in humans.[1][2]

Function

Epoxide hydrolase plays an important role in both the activation and detoxification of exogenous chemicals such as polycyclic aromatic hydrocarbons.[2]

Discovery

Microsomal epoxide hydrolase 1 (EPHX1) was first isolated by Watabe and Kanehira from rabbit liver [3] and later also purified from human liver and characterized.[4] EPHX1 belongs to the family of α/β hydrolases [5] and converts epoxides to diols.[6]

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.[7] It was found also in bronchial epithelial cells [8] and upper gastrointestinal tract.[9] EPHX1 expression is individually variable among humans [10] and it can be modestly induced by chemicals as phenobarbital, β-naphtoflavone, benzanthracene, trans-stilbene oxide, etc.[11]

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).[12][13][14] 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.[6] EPHX1 has broad substrate specificity.[15][16] EPHX1 detoxifies low molecular weight chemicals, e.g., butadiene, benzene, styrene, etc.,[17] but more complex compounds as polycyclic aromatic hydrocarbons are rather bioactivated to genotoxic species.[18][19]

EPHX1 mediates the sodium-dependent transport of bile acids into hepatocytes.[20] Androstene oxide and epoxyestratrienol have been shown as endogenous EPHX1 substrates.[21][22] EPHX1 also metabolizes endocannabinoid 2-arachidonoylglycerol to arachidonic acid[23] and may play an important role in the endocannabinoid signaling pathway.

Clinical significance

Mutations in EPHX1 have been linked with preeclampsia,[24][25] elevated blood levels of bile salts (i.e. hypercholanemia),[26] Fetal hydantoin syndrome,[27] and diphenylhydantoin toxicity. Functional single nucleotide polymorphisms (SNPs) in EPHX1 have been found and frequently studied.[28] Two SNPs - Y113H (rs1051740, T337C) and H139R (rs2234922, A416G) – seemed to influence EPHX1 activity in vitro [29] and their combination was used for deduction of EPHX1 activity.[30] However, their functional effect was not confirmed in human liver microsomes.[31]

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.[32][33][34][35][36] Meta-analyses confirmed associations of rs1051740 and rs2234922 SNPs with the risk of lung cancer.[37][38][39] Meta-analyses reporting no association of these SNPs with esophageal and hepatocellular cancer risk have been reported as well [40][41]). Genetically predicted low EPHX1 activity was associated with increased risk of developing tobacco-related cancer in smokers from 47089 Danish individuals .[42] 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.[43] Role of EPHX1 expression in pathogenesis of neurodegeneration as Alzheimer´s disease,[44] methamphetamine-induced drug dependence,[45] and cerebral metabolism of epoxyeicosatrienoic acids [46] 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. ↑ 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.
  2. 1 2 "Entrez Gene: EPHX1 epoxide hydrolase 1, microsomal (xenobiotic)".
  3. ↑ Watabe, T; Kanehira, S (1970). "Solubilization of epoxide hydrolase from liver microsomes.". Chem Pharm Bull (Tokyo). 18 (6): 1295–1296. doi:10.1248/cpb.18.1295. PMID 5465293.
  4. ↑ Oesch F (1974). "Purification and specificity of a human microsomal epoxide hydratase". Biochem. J. 139 (1): 77–88. doi:10.1042/bj1390077. PMC 1166253. PMID 4463951.
  5. ↑ 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. doi:10.1093/protein/5.3.197. PMID 1409539.
  6. 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. doi:10.1021/bi00802a005. PMID 5134533.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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. doi:10.1016/j.canlet.2005.05.029. PMID 16005144.
  10. ↑ 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. doi:10.1093/carcin/6.2.219. PMID 3971488.
  11. ↑ 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. doi:10.1016/0006-2952(84)90371-x. PMID 6538414.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ Fretland AJ, Omiecinski CJ (2000). "Epoxide hydrolases: biochemistry and molecular biology". Chem. Biol. Interact. 129 (1-2): 41–59. doi:10.1016/s0009-2797(00)00197-6. PMID 11154734.
  17. ↑ Decker M, Arand M, Cronin A (2009). "Mammalian epoxide hydrolases in xenobiotic metabolism and signalling". Arch. Toxicol. 83 (4): 297–318. doi:10.1007/s00204-009-0416-0. PMID 19340413.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ Newman JW, Morisseau C, Hammock BD (2005). "Epoxide hydrolases: their roles and interactions with lipid metabolism". Prog. Lipid Res. 44 (1): 1–51. doi:10.1016/j.plipres.2004.10.001. PMID 15748653.
  23. ↑ 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.
  24. ↑ 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.
  25. ↑ 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.
  26. ↑ 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. doi:10.1016/s0925-4439(03)00085-1. PMID 12878321.
  27. ↑ 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. doi:10.1056/NEJM199005313222204. PMID 2336087.
  28. ↑ "dbSNP". Retrieved 29 December 2014.
  29. ↑ Hassett C, Aicher L, Sidhu JS, Omiecinski CJ (1994). "Human microsomal epoxide hydrolase: genetic polymorphism and functional expression in vitro of amino acid variants". Hum. Mol. Genet. 3 (3): 421–8. doi:10.1093/hmg/3.3.421. PMID 7516776.
  30. ↑ 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.
  31. ↑ 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. PMID 15535985.
  32. ↑ 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.
  33. ↑ 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.
  34. ↑ 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 (2011). "Xenobiotic-Metabolizing gene polymorphisms and ovarian cancer risk". Mol. Carcinog. 50 (5): 397–402. doi:10.1002/mc.20714. PMC 3115705. PMID 21480392.
  35. ↑ Pérez-Morales R, Méndez-Ramírez I, Moreno-Macias H, Mendoza-Posadas AD, Martínez-Ramírez OC, Castro-Hernández C, Gonsebatt ME, Rubio J (2014). "Genetic susceptibility to lung cancer based on candidate genes in a sample from the Mexican Mestizo population: a case-control study". Lung 192 (1): 167–73. doi:10.1007/s00408-013-9536-7. PMID 24357096.
  36. ↑ 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.
  37. ↑ 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.
  38. ↑ 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.
  39. ↑ 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.
  40. ↑ 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. doi:10.4238/2013.October.15.2. PMID 24222229.
  41. ↑ 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.
  42. ↑ Lee J, Dahl M, Nordestgaard BG (2011). "Genetically lowered microsomal epoxide hydrolase activity and tobacco-related cancer in 47,000 individuals". Cancer Epidemiol. Biomarkers Prev. 20 (8): 1673–82. doi:10.1158/1055-9965.EPI-10-1165. PMID 21653646.
  43. ↑ 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.
  44. ↑ 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.
  45. ↑ Shin, EJ; Bing, G; Chae, JS; Kim, TW; Bach, JH; Park, DH; Yamada, K; Nabeshima, T; Kim, HC (2009). "Role of microsomal epoxide hydrolase in methamphetamine-induced drug dependence in mice.". J Neurosci Res 87 (16): 3679–3686. doi:10.1002/jnr.22166. PMID 19598248.
  46. ↑ 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.

Further reading

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