Arachidonate Epoxygenase / Epoxide Hydrolase (Homo sapiens)

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1-4, 6-9, 11...ProductProductArachidonic acidCatalystCYP2J214,15-DiHETrEGlutathionyl-HETrEsCOXCOX5,6-DiH-PGF1a8(9)-EpETrECYP2C85(6)-EpETrEEPHX2Phosphotidyl-EpETrEs11(12)-EpETrE8,9-DiHETrE11,12-DiHETrE5,6-DiHETrEGST314(15)-EpETrE5(6)-Epoxy-PGE1EPHX2EPHX2EPHX2CYP2C991, 5, 10, 131161329, 119, 112, 102, 6


The cytochrome P450-dependent formation of polyunsaturated fatty acid epoxides is an important biochemical pathway creating mediators of inflammation and blood pressure regulation. Once formed these compounds can be incorperated into phospholipid membrance, and released by the action of phospholipase A2. The epoxides of arachidonic acid, i.e. the epoxyeicosatrieneoic acid or EETs, are putative endothelial derived hyperpolarization factors which increase the open state probability of Ca++ sensitive K+ channels, leading to vasodilation in arteriolar beds. The 11(12)-EET in particular appears to have potent functions in vasodilation, and are inhibitors of NFKb dependent inflammatory signalling, and PAI-1 activity. The 5(6)-EET appears unique, in that its metabolic transformation through cyclooxygenase activities produces potent vasoconstrictors. With the exception of the 5(6)-EET, these epoxy fatty acids are good substrates for the soluble epoxide hydrolase. Hydrolytic tranformation to vicinal diols eliminates vasoactive actions, however these vicinal diols have been reported to have other biological activites, including PPAR-alpha activation. Recent development of inhibitors of the soluble epoxide hydrolase are proving to have potent anti-inflammatory, anti-hypertensive, and anti-nociceptive properties. Reports of enzyme catalyzed glutathione-conjugates of the epoxy fatty acids have been reported, but the activity and relavance of these potential metabolic products are unknown to date.


Fatty Acid Epoxygenase
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  1. Oliw EH, Benthin G; ''On the metabolism of epoxyeicosatrienoic acids by ram seminal vesicles: isolation of 5(6)epoxy-prostaglandin F1 alpha.''; Biochem Biophys Res Commun, 1985 PubMed Europe PMC Scholia
  2. Larsen BT, Miura H, Hatoum OA, Campbell WB, Hammock BD, Zeldin DC, Falck JR, Gutterman DD; ''Epoxyeicosatrienoic and dihydroxyeicosatrienoic acids dilate human coronary arterioles via BK(Ca) channels: implications for soluble epoxide hydrolase inhibition.''; Am J Physiol Heart Circ Physiol, 2006 PubMed Europe PMC Scholia
  3. Spector AA, Fang X, Snyder GD, Weintraub NL; ''Epoxyeicosatrienoic acids (EETs): metabolism and biochemical function.''; Prog Lipid Res, 2004 PubMed Europe PMC Scholia
  4. Harder DR, Roman RJ, Gebremedhin D; ''Molecular mechanisms controlling nutritive blood flow: role of cytochrome P450 enzymes.''; Acta Physiol Scand, 2000 PubMed Europe PMC Scholia
  5. N�sing RM, Schweer H, Fleming I, Zeldin DC, Wegmann M; ''Epoxyeicosatrienoic acids affect electrolyte transport in renal tubular epithelial cells: dependence on cyclooxygenase and cell polarity.''; Am J Physiol Renal Physiol, 2007 PubMed Europe PMC Scholia
  6. Zhang L, Ding H, Yan J, Hui R, Wang W, Kissling GE, Zeldin DC, Wang DW; ''Genetic variation in cytochrome P450 2J2 and soluble epoxide hydrolase and risk of ischemic stroke in a Chinese population.''; Pharmacogenet Genomics, 2008 PubMed Europe PMC Scholia
  7. Larsen BT, Gutterman DD, Sato A, Toyama K, Campbell WB, Zeldin DC, Manthati VL, Falck JR, Miura H; ''Hydrogen peroxide inhibits cytochrome p450 epoxygenases: interaction between two endothelium-derived hyperpolarizing factors.''; Circ Res, 2008 PubMed Europe PMC Scholia
  8. Carroll MA, Schwartzman M, Sacerdoti D, McGiff JC; ''Novel renal arachidonate metabolites.''; Am J Med Sci, 1988 PubMed Europe PMC Scholia
  9. Newman JW, Morisseau C, Hammock BD; ''Epoxide hydrolases: their roles and interactions with lipid metabolism.''; Prog Lipid Res, 2005 PubMed Europe PMC Scholia
  10. Vriens J, Owsianik G, Fisslthaler B, Suzuki M, Janssens A, Voets T, Morisseau C, Hammock BD, Fleming I, Busse R, Nilius B; ''Modulation of the Ca2 permeable cation channel TRPV4 by cytochrome P450 epoxygenases in vascular endothelium.''; Circ Res, 2005 PubMed Europe PMC Scholia
  11. Inceoglu B, Schmelzer KR, Morisseau C, Jinks SL, Hammock BD; ''Soluble epoxide hydrolase inhibition reveals novel biological functions of epoxyeicosatrienoic acids (EETs).''; Prostaglandins Other Lipid Mediat, 2007 PubMed Europe PMC Scholia
  12. Sacerdoti D, Gatta A, McGiff JC; ''Role of cytochrome P450-dependent arachidonic acid metabolites in liver physiology and pathophysiology.''; Prostaglandins Other Lipid Mediat, 2003 PubMed Europe PMC Scholia
  13. Oliw EH; ''Biosynthesis of 5,6-dihydroxyprostaglandin E1 and F1 alpha from 5,6-dihydroxyeicosatrienoic acid by ram seminal vesicles.''; Biochim Biophys Acta, 1984 PubMed Europe PMC Scholia
  14. Sarkis A, Roman RJ; ''Role of cytochrome P450 metabolites of arachidonic acid in hypertension.''; Curr Drug Metab, 2004 PubMed Europe PMC Scholia
  15. Capdevila JH, Kishore V, Dishman E, Blair IA, Falck JR; ''A novel pool of rat liver inositol and ethanolamine phospholipids contains epoxyeicosatrienoic acids (EETs).''; Biochem Biophys Res Commun, 1987 PubMed Europe PMC Scholia
  16. Mannervik B, Board PG, Hayes JD, Listowsky I, Pearson WR; ''Nomenclature for mammalian soluble glutathione transferases.''; Methods Enzymol, 2005 PubMed Europe PMC Scholia
  17. Morisseau C, Hammock BD; ''Gerry Brooks and epoxide hydrolases: four decades to a pharmaceutical.''; Pest Manag Sci, 2008 PubMed Europe PMC Scholia
  18. Spearman ME, Prough RA, Estabrook RW, Falck JR, Manna S, Leibman KC, Murphy RC, Capdevila J; ''Novel glutathione conjugates formed from epoxyeicosatrienoic acids (EETs).''; Arch Biochem Biophys, 1985 PubMed Europe PMC Scholia


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106822view13:30, 17 September 2019MaintBotHMDB identifier normalization
94200view14:48, 25 August 2017DeSlAdded ID for 5(6)-Epoxy-PGE1
71506view19:21, 17 October 2013MaintBotremoved data source from nodes without identifier
67058view10:00, 26 June 2013Christine ChichesterOntology Term : 'arachidonic acid metabolic pathway' added !
63166view20:24, 8 May 2013MaintBotUpdating GPML version
59189view19:02, 22 February 2013MaintBotUpdated Ensembl data source
44962view12:48, 6 October 2011MartijnVanIerselOntology Term : 'metabolic pathway of secondary metabolites' added !
41165view23:41, 1 March 2011MaintBotRemoved redundant pathway information and comments
38950view00:05, 25 September 2010KhanspersChanged layout
38949view00:02, 25 September 2010Khanspers
33404view14:48, 30 November 2009MaintBotRemoved group label
30254view04:39, 25 July 2009AlexanderPicoModified categories
29908view12:13, 9 June 2009Thomasupdated ensembl references
29111view05:25, 3 April 2009JwnewmanModified description
29110view05:12, 3 April 2009JwnewmanPeriodical save, work in progress
28979view15:33, 19 March 2009EveloCorrecte COX annotation to something that *might* be right
28976view13:22, 19 March 2009EveloSpecify description
28975view13:18, 19 March 2009EveloPeriodical save, work in progress
28974view13:08, 19 March 2009EveloPeriodical save, work in progress
28973view12:45, 19 March 2009MartijnVanIerselNew pathway

External references


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NameTypeDatabase referenceComment
11(12)-EpETrEMetaboliteHMDB0010409 (HMDB)
11,12-DiHETrEMetaboliteHMDB0002314 (HMDB)
14(15)-EpETrEMetaboliteHMDB0004264 (HMDB)
14,15-DiHETrEMetaboliteHMDB0002265 (HMDB)
5(6)-EpETrEMetaboliteHMDB0002190 (HMDB)
5(6)-Epoxy-PGE1Metabolite53481368 (PubChem-compound)
5,6-DiH-PGF1aMetabolitefull name = 5,6-Dihydro-Prostaglandin F1a
5,6-DiHETrEMetaboliteHMDB0002343 (HMDB)
8(9)-EpETrEMetaboliteHMDB0002232 (HMDB)
8,9-DiHETrEMetaboliteHMDB0002311 (HMDB)
Arachidonic acidMetaboliteHMDB0001043 (HMDB)
COXGeneProduct1351 (Entrez Gene)
COXGeneProduct9377 (Entrez Gene)
CYP2C8GeneProduct1558 (Entrez Gene)
CYP2C9GeneProduct1559 (Entrez Gene)
CYP2J2GeneProductENSG00000134716 (Ensembl)
EPHX2GeneProduct2053 (Entrez Gene)
  • 5(6)-EpETrE is a poor sEH substrate
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GST3GeneProduct2950 (Entrez Gene)

Annotated Interactions

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