15-Hydroxyeicosatetraenoic acid

15(S)-HETE.svg (5Z,8Z,11Z,13E,15S)-15-Hydroxyicosa-5,8,11,13-tetraenoic acid 15-HETE, 15(S)-HETE, 15(S)-HETE 3401 54845-95-3 correct CAS correct FDA 44JHK6G39Q 5280724 CCCCC[C@@H](/C=C/C=C\C/C=C\C/C=C\CCCC(=O)O)O 4444307 1S/C20H32O3/c1-2-3-13-16-19(21)17-14-11-9-7-5-4-6-8-10-12-15-18-20(22)23/h4-5,8-11,14,17,19,21H,2-3,6-7,12-13,15-16,18H2,1H3,(H,22,23)/b5-4-,10-8-,11-9-,17-14+/t19-/m0/s1 JSFATNQSLKRBCI-VAEKSGALSA-N 20 32 3 15-Hydroxyeicosatetraenoic acid (also termed 15-HETE, 15(S)-HETE, and 15S-HETE) is an eicosanoid, i.e. a metabolite of arachidonic acid. Various cell types metabolize arachidonic acid to 15(S)-hydroperoxyeicosatetraenoic acid (15(S)-HpETE). This initial hydroperoxide product is extremely short-lived in cells: if not otherwise metabolized, it is rapidly reduced to 15(S)-HETE. Both of these metabolites, depending on the cell type which forms them, can be further metabolized to 15-oxo-eicosatetraenoic acid (15-oxo-ETE), 5(S),15(S)-dihydroxy-eicosatetraenoic acid (5(S),15(S)-diHETE), 5-oxo-15(S)-hydroxyeicosatetraenoic acid (5-oxo-15(S)-HETE), a subset of specialized pro-resolving mediators viz., the lipoxins, a class of pro-inflammatory mediators, the eoxins, and other products that have less well-defined activities and functions. Thus, 15(S)-HETE and 15(S)-HpETE, in addition to having intrinsic biological activities, are key precursors to numerous biologically active derivatives. 18761324 2009 Moreno J. J. New aspects of the role of hydroxyeicosatetraenoic acids in cell growth and cancer development Biochemical Pharmacology 77 1 1–10 10.1016/j.bcp.2008.07.033 22002716 3798028 2011 Schneider C Cyclooxygenases and lipoxygenases in cancer Cancer and Metastasis Reviews 30 3–4 277–294 Pozzi A 10.1007/s10555-011-9310-3 Some cell types (e.g. platelets) metabolize arachidonic acid to the stereoisomer of 15(S)-HpETE, 15(R)-HpETE. Both stereoisomers may also be formed as result of the metabolism of arachidonic acid by cellular microsomes or as a result of arachidonic acid auto-oxidation. Similar to 15(S)-HpETEs, 15(R)-HpETE may be rapidly reduced to 15(R)-HETE. These R,S stereoisomers differ only in having their hydroxy residue in opposite orientations. While the two R stereoisomers are sometimes referred to as 15-HpETE and 15-HETE, proper usage should identify them as R stereoisomers. 15(R)-HpETE and 15(R)-HETE lack some of the activity attributed to their S stereoisomers but can be further metabolized to bioactive products viz., the 15(R) class of lipoxins (also termed epi-lipoxins). 24656045 4004957 2014 Buckley C. D. Proresolving lipid mediators and mechanisms in the resolution of acute inflammation Immunity 40 3 315–327 Gilroy D. W. Serhan C. N. 10.1016/j.immuni.2014.02.009 15(S)-HETE, 15(S)-HpETE, and many of their derivative metabolites are thought to have physiologically important functions. They appear to act as hormone-like autocrine and paracrine signaling agents that are involved in regulating inflammatory and perhaps other responses. 22331435 2012 Zhu D Role of 15-lipoxygenase/15-hydroxyeicosatetraenoic acid in hypoxia-induced pulmonary hypertension The Journal of Physiological Sciences 62 3 163–172 Ran Y 10.1007/s12576-012-0196-9 2723454 free 10717549 Clinically, drugs that are stable analogs, and therefore mimic the anti-inflammatory actions of the lipoxins and drugs that block the production or actions of the pro-inflammatory eoxins may prove useful for treating acute and chronic inflammatory disorders. Leeper KV Diagnosis and treatment of pulmonary infections in adult respiratory distress syndrome New Horizons (Baltimore, Md.) 1 4 550–562 1993 8087575 Nomenclature and stereoisomers 15(S)-HETE is unambiguously designated by a shortened version of its IUPAC name viz., 15(S)-hydroxy-5Z,8Z,11Z,13E-eicosatetraenoic acid. In this terminology S refers to the absolute configuration of the chirality of the hydroxy functional group at carbon position 15. Its 15(R) enantiomer is designated 15(R)-hydroxy-5Z,8Z,11Z,13E-eicosatetraenoic acid. Z and E give the cis–trans isomerism about each double bond at carbon positions 5, 8, 11, and 13 with Z indicating cis and E indicating trans isomerism. Both stereoisomers are produced from their corresponding S and R 15-HpETE stereoisomers, i.e. 15(S)-hydroperoxy-5Z,8Z,11Z,13E-eicosatetraenoic acid (15(S)-HpETE) and 15(R)-hydroperoxy-5Z,8Z,11Z,13E-eicosatetraenoic acid (15(R)-HpETE). Production Human cells release arachidonic acid (i.e. 5Z,8Z,11Z,14Z-eicosatetraenoic acid) from its storage site in phospholipids by reactions that involve phospholipase C and/or lipase enzymes. This release is stimulated or enhanced by cell stimulation. The freed arachidonic acid is then converted to 15-hydroperoxy/hydroxy products by one or more of the following five pathways. 15-Lipoxygenase-1: Cells metabolize arachidonic acid with 15-lipoxygenase-1 (i.e., 15-LO-1, ALOX15) to form 15(S)-HpETE as a major product and 12(S)-hydroperoxy-5Z,8Z,10E,15Z-eicosatetraenoic acid (12(S)-HpETE) and 14(S),15(S)-trans-oxido-5Z,8Z,11Z-14,15-leukotriene A4 as minor products; 15(S)-HpETE and 12(S)-HpETE are rapidly converted to 15(S)-HETE and 12(S)-hydroxy-5Z,8Z,10E,15Z-eicosatetraenoic acid (12(S)-hydroxyeicosatetraenoic acid), (i.e. 12(S)-HETE), respectively, or further metabolized through other enzyme pathways; 14(S),15(S)-trans-oxido-5Z,8Z,11Z-14,15-leukotriene A4 is metabolized by 15-LO-1 to various isomers of 8,15(S)-dihydroxy-5S,8S,11Z,13S-eicosatetraenoic acids, e.g. 8,15(S)-LTB4's. 6318 1975 Schewe T A lipoxygenase in rabbit reticulocytes which attacks phospholipids and intact mitochondria FEBS Letters 60 1 149–152 Halangk W Hiebsch C Rapoport S. M. 10.1016/0014-5793(75)80439-x 46488283 free 1975FEBSL..60..149S 6895224 256 Metabolism of leukotriene D by porcine kidney 1981 J Biol Chem 9579–9582 Bernström K, Hammarström S 18 10.1016/S0021-9258(19)68801-0 free 6438089 1984 Hopkins N. K. Biosynthesis and metabolism of 15-hydroperoxy-5,8,11,13-eicosatetraenoic acid by human umbilical vein endothelial cells The Journal of Biological Chemistry 259 22 14048–14053 Oglesby T. D. Bundy G. L. Gorman R. R. 10.1016/S0021-9258(18)89853-2 free 1566855 1992 Sigal E Cloning of human airway 15-lipoxygenase: Identity to the reticulocyte enzyme and expression in epithelium The American Journal of Physiology 262 4 Pt 1 L392–L398 Dicharry S Highland E Finkbeiner W. E. 10.1152/ajplung.1992.262.4.L392 9177185 21017 1997 Brash A. R. Discovery of a second 15S-lipoxygenase in humans Proceedings of the National Academy of Sciences of the United States of America 94 12 6148–6152 Boeglin W. E. Chang M. S. 1997PNAS...94.6148B 10.1073/pnas.94.12.6148 free 15-Lipoxygenase-2: Cells also used 15-lipoxygenase 2 (i.e. 15-LOX-2 or ALOX15B) to make 15(S)-HpETE and 15(S)-HETE. However this enzyme has a preference for metabolizing linoleic acid rather than arachidonic acid. It therefore forms linoleic acid metabolites (e.g. 13-hydoxyperoxy/hydroxy-octadecadienoic and 9-hydroperoxy/hydroxyl-octadecadienoic acids) in greater amounts than 15(S)-HpETE and 15(S)-HETE. 15-LOX-2 also differs from 15-LOX-1 in that it does not make 12(S)-HpETE or the leukotriene A4 isomer cited above. Cyclooxygenase: Cells can use prostaglandin-endoperoxide synthase 1 (i.e. cyclooxygenenase-1 or COX-1) and prostaglandin-endoperoxide synthase 2 (COX-2) to metabolize arachidonic acid primarily to prostaglandins but also to small amounts of 11(R)-HETE and a racemic mixture of 15-HETEs composed of ~22% 15(R)-HETE and ~78% 15(S)-HETE. 19752399 2817587 2010 Mulugeta S Identification and absolute configuration of dihydroxy-arachidonic acids formed by oxygenation of 5S-HETE by native and aspirin-acetylated COX-2 The Journal of Lipid Research 51 3 575–585 Suzuki T Hernandez N. T. Griesser M Boeglin W. E. Schneider C 10.1194/jlr.M001719 free When pretreated with aspirin, however, COX-1 is inactive while COX-2 attacks arachidonic acid to produce almost exclusively 15(R)-HETE along with its presumed precursor 15(R)-HpETE. 10086190 1999 Serhan C. N. 447 133–149 Takano T Maddox J. F. Lipoxygenases and their Metabolites Aspirin-Triggered 15-Epi-Lipoxin A4 and Stable Analogs of Lipoxin A4 are Potent Inhibitors of Acute Inflammation: Receptors and Pathways Advances in Experimental Medicine and Biology 10.1007/978-1-4615-4861-4_13 978-0-306-46044-9 10692466 2000 Rowlinson S. W. Spatial requirements for 15-(R)-hydroxy-5Z,8Z,11Z,13E-eicosatetraenoic acid synthesis within the cyclooxygenase active site of murine COX-2. Why acetylated COX-1 does not synthesize 15-(R)-hete The Journal of Biological Chemistry 275 9 6586–6591 Crews B. C. Goodwin D. C. Schneider C Gierse J. K. Marnett L. J. 10.1074/jbc.275.9.6586 free Microsome metabolism: Human and rat microsomal cytochrome P450s, e.g. CYP2C19, metabolize arachidonic acid to a racemic mixture of 15-HETEs, i.e., 15(R,S)-HETEs, >90% of which is the 15(R) stereoisomer. 8443245 1993 Oliw E. H. Bis-Allylic hydroxylation of linoleic acid and arachidonic acid by human hepatic monooxygenases Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism 1166 2–3 258–263 10.1016/0005-2760(93)90106-j 9435160 1998 Bylund J Cytochromes P450 with bisallylic hydroxylation activity on arachidonic and linoleic acids studied with human recombinant enzymes and with human and rat liver microsomes The Journal of Pharmacology and Experimental Therapeutics 284 1 51–60 Kunz T Valmsen K Oliw E. H. 10.1016/S0022-3565(24)37230-1 Autoxidation: The spontaneous and non-enzymatically induced autoxidation of arachidonic acid yields 15(R,S)-hydroperoxy-5Z,8Z,11Z,13E-eicosatetraenoic acids. This non-enzymatic reaction is promoted in cells undergoing oxidative stress. Cells forming this racemic mixture of 15-hydroperoxy products may convert then to 15(R,S)-HETEs and other products. However, the uncontrolled overproduction of the 15-hydroperoxy products may react with other elements to produce cell injury.10.1016/0090-6980(80)90156-2 7384539 Prostaglandins 19 1 87–97 1980 Preparation and characterization of hydroperoxy-eicosatetraenoic acids (HPETEs) J. M. Boeynaems J. A. Oates W. C. Hubbard https://dipot.ulb.ac.be/dspace/bitstream/2013/50155/4/17ac6ca9-dd31-4fd8-b4eb-c7d568536ea3.txt 2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/50155 free 7258296 1903737 104 Neutrophil-aggregating activity of monohydroxyeicosatetraenoic acids 1981 Am. J. Pathol. 55–62 O'Flaherty JT, Thomas MJ, Lees CJ, McCall CE 1 Further metabolism The newly formed products formed by the pathways cited in the previous section are bioactive but may also flow into down-stream pathways to form other metabolites with a different sets of bioactivity. The initially formed 15(S)-HpETE may be further metabolized by its parent cell or pass it to nearby cell by a process termed transcellular metabolism. 15(S)-HpETE may be: Rapidly reduced to 15(S)-HETE by ubiquitous cellular peroxidase reactions including those possessed by prostaglandin-endoperoxide synthase-1 and -2,10.1016/0003-9861(88)90246-9 3140729 1988 162–170 Prostaglandin H synthase: Distinct binding sites for cyclooxygenase and peroxidase substrates Archives of Biochemistry and Biophysics 266 1 Marshall Paul J. Kulmacz Richard J. prostacyclin synthase, thromboxane synthase, 17459323 2041921 2007 Yeh H. C. Reaction mechanisms of 15-hydroperoxyeicosatetraenoic acid catalyzed by human prostacyclin and thromboxane synthases Archives of Biochemistry and Biophysics 461 2 159–168 Tsai A. L. Wang L. H. 10.1016/j.abb.2007.03.012 and various glutathione peroxidases. 1314541 1992 Ochi H Roles of glutathione and glutathione peroxidase in the protection against endothelial cell injury induced by 15-hydroperoxyeicosatetraenoic acid Archives of Biochemistry and Biophysics 294 2 407–411 Morita I Murota S 10.1016/0003-9861(92)90704-z Acylated into membrane phospholipids, particularly phosphatidylinositols 2117277 54510 1990 Brezinski M. E. Selective incorporation of (15S)-hydroxyeicosatetraenoic acid in phosphatidylinositol of human neutrophils: Agonist-induced deacylation and transformation of stored hydroxyeicosanoids Proceedings of the National Academy of Sciences of the United States of America 87 16 6248–6252 Serhan C. N. 10.1073/pnas.87.16.6248 1990PNAS...87.6248B free 1850411 1991 Legrand A. B. Substitution of 15-hydroxyeicosatetraenoic acid in the phosphoinositide signaling pathway The Journal of Biological Chemistry 266 12 7570–7577 Lawson J. A. Meyrick B. O. Blair I. A. Oates J. A. 10.1016/S0021-9258(20)89485-X free and phosphatidylethanolamine. 3662534 1987 Bergholte J. M. Oxidation of 15-hydroxyeicosatetraenoic acid and other hydroxy fatty acids by lung prostaglandin dehydrogenase Archives of Biochemistry and Biophysics 257 2 444–450 Soberman R. J. Hayes R Murphy R. C. Okita R. T. 10.1016/0003-9861(87)90589-3 23060450 3516716 2012 Hammond V. J. Novel keto-phospholipids are generated by monocytes and macrophages, detected in cystic fibrosis, and activate peroxisome proliferator-activated receptor-γ Journal of Biological Chemistry 287 50 41651–41666 Morgan A. H. Lauder S Thomas C. P. Brown S Freeman B. A. Lloyd C. M. Davies J Bush A Levonen A. L. Kansanen E Villacorta L Chen Y. E. Porter N Garcia-Diaz Y. M. Schopfer F. J. O'Donnell V. B. 10.1074/jbc.M112.405407 free The 15(S)-HpETE is bound primarily at the sn-2 position of these phospholipids (see Phospholipase) and may be reduced to 15(S)-HETE thereby forming their 15(S)-HETE-bound phospholipoid analogs. Phosphatidylinositol phospholipids with 15(S)-HETE in the sn-2 position can be attacked by phospholipase C to form corresponding diglycerides with 15(S)-HETE at their sn-2 positions. 10484452 1999 Alpert S. E. 15-HETE-substituted diglycerides selectively regulate PKC isotypes in human tracheal epithelial cells The American Journal of Physiology 277 3 Pt 1 L457–L464 Walenga R. W. Mandal A Bourbon N Kester M 10.1152/ajplung.1999.277.3.L457 Metabolized by 15-LO-1 to its 14,15-trans-epoxide, 14,15-trans-epoxide-oxido-5Z,8Z,10E,13E-eicosatetraenoic acid (i.e., eoxin A4 or EXA4), and thereafter to 14(R)-glutothionyl-15(S)-hydroxy-5Z,8Z,10E,13E-eicosatetraenoic acid (i.e. eoxin C4 or EXC4) by leukotriene C4 synthase. 18184802 2206596 2008 Feltenmark S Eoxins are proinflammatory arachidonic acid metabolites produced via the 15-lipoxygenase-1 pathway in human eosinophils and mast cells Proceedings of the National Academy of Sciences 105 2 680–685 Gautam N Brunnström A Griffiths W Backman L Edenius C Lindbom L Björkholm M Claesson H. E. 10.1073/pnas.0710127105 2008PNAS..105..680F free 20920774 2010 Sachs-Olsen C Eoxins: A new inflammatory pathway in childhood asthma Journal of Allergy and Clinical Immunology 126 4 859–867.e9 Sanak M Lang A. M. Gielicz A Mowinckel P Lødrup Carlsen K. C. Carlsen K. H. Szczeklik A 10.1016/j.jaci.2010.07.015 1137911 https://ruj.uj.edu.pl/xmlui/handle/item/156900 subscription EXC4 contains glutathione (i.e. γ-L-glutamyl-L-cysteinylglycine) bound in the R configuration to carbon 14. EXC4 is further metabolized by removal of the γ-L-glutamyl residue to form EXD4 which is in turn further metabolized by removal of the glycine residue to form EXE4. These metabolic transformations are similar to those in the pathway that metabolizes arachidonic acid to LTA4, LTC4, LTD4, and LTE4 and presumed to be conducted by the same enzymes 19130894 2009 Claesson H. E. On the biosynthesis and biological role of eoxins and 15-lipoxygenase-1 in airway inflammation and Hodgkin lymphoma Prostaglandins & Other Lipid Mediators 89 3–4 120–125 10.1016/j.prostaglandins.2008.12.003 (Eoxins are also termed 14,15-leukotrienes or 14,15-LTs). Metabolized alternatively by 15-LO-1 to various 8,15-diHETEs including the two 8(R) and 8(S) diastereomers of 8,15(S)-dihydroxy-5,9,11,13-eicosatetraenoic acid (8,15-leukotrienes B4) and to two isomeric erythro-14,15-dihydroxy-5-cis-8,10,12-eicosatetraenoic acids (14,15-leukotrienes B4). 7247953 1981 Jubiz W Novel leukotrienes: Products formed by initial oxygenation of arachidonic acid at C-15 Biochemical and Biophysical Research Communications 99 3 976–986 Rådmark O Lindgren J. A. Malmsten C Samuelsson B 10.1016/0006-291x(81)91258-4 1981BBRC...99..976J 6272308 348778 1981 Maas R. L. A second pathway of leukotriene biosynthesis in porcine leukocytes Proceedings of the National Academy of Sciences of the United States of America 78 9 5523–5527 Brash A. R. Oates J. A. 1981PNAS...78.5523M 10.1073/pnas.78.9.5523 free 8334154 1993 Kühn H Overexpression, purification and characterization of human recombinant 15-lipoxygenase 1169 1 80–89 Barnett J Grunberger D Baecker P Chow J Nguyen B Bursztyn-Pettegrew H Chan H Sigal E Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism 10.1016/0005-2760(93)90085-n Metabolized by 15-LOX-2 to 11(S)-hydroxy-14(S),15(S)-epoxy-5(Z),8(Z),12(E)-eicosatrienoic acid and 13(R)-hydroxy-14(S),15(S)-epoxy-5(Z),8(Z),11(Z)-eicosatrienoic acid; these two products are novel hepoxilins produced by ALOX15 rather than ALOX12, the enzyme responsible for making the various other hepoxilins in humans. 23093885 3471176 2011 Vogler S Pharmaceutical policies in European countries in response to the global financial crisis Southern Med Review 4 2 69–79 Zimmermann N Leopold C De Joncheere K 10.5655/smr.v4i2.1004 The two novel hepoxilins are termed respectively 14,15-HXA3 and 14,15-HXB3. 14,15-HXA3 can be further metabolized by glutathione transferases to 11(S),15(S)-dihydroxy-14(R)-glutathionyl-(5Z),8(Z),12(E)-eicosatrienoic acid (14,15-HXA3C) which is then further metabolized to 11(S),15(S)-dihydroxy-14(R)-cysteinyl-glycyl-(5Z),8(Z),12(E)-eicosatrienoic acid (14,15-HXA3D). Isomerized to 15(S)-hydroxy-11,12-cis-epoxy-5Z,8Z,13E-eicosatrienoic acid (i.e., 15-H-11,12-EETA) by a hydroperoxide isomerase activity and then to 11,12,15-trihydroxy-5Z,8Z,12E-eicosatrienoic acid (i.e. 11,12,15-THETA) and 11,14,15-trihydroxy-5Z,8Z,12E-eicosatrienoic acid (i.e., 11,14,15-THETA) by a soluble epoxide hydrolase activity or, by acid in a non-enzymatic reaction (the R, S configuration of the hydroxy residues in the latter two metabolites has not been defined). 19525377 2724209 2009 Chawengsub Y Role of arachidonic acid lipoxygenase metabolites in the regulation of vascular tone AJP: Heart and Circulatory Physiology 297 2 H495–H507 Gauthier K. M. Campbell W. B. 10.1152/ajpheart.00349.2009 Isomerized to threo and erythro diastereoisomers of 13-hydroxy-14,15-cis-epoxy-5Z,8Z,11Z-eicosatrienoic acid (i.e., 15-H-11,12-EETA) by a hydroperoxide isomerase activity, possibly a cytochrome P450, i.e. CYP2J2. 19737933 2781526 2009 Chawengsub Y Identification of 13-hydroxy-14,15-epoxyeicosatrienoic acid as an acid-stable endothelium-derived hyperpolarizing factor in rabbit arteries Journal of Biological Chemistry 284 45 31280–31290 Gauthier K. M. Nithipatikom K Hammock B. D. John R. Falck Falck J. R. Narsimhaswamy D Campbell W. B. 10.1074/jbc.M109.025627 free Metabolized by cytochrome P450 (CYP) enzymes such as CYP1A1, CYP1A2, CYP1B1, and CYP2S1 to 15-oxo-ETE. 21068195 3033693 2011 Bui P Human CYP2S1 metabolizes cyclooxygenase- and lipoxygenase-derived eicosanoids Drug Metabolism and Disposition 39 2 180–190 Imaizumi S Beedanagari S. R. Reddy S. T. Hankinson O 10.1124/dmd.110.035121 Metabolized in skin epidermis by epidermis-type lipoxygenase 3 (eLOX3, encoded by the ALOXE3 gene) to make two products, hepoxilin A3 (HxA3, i.e., 13R-hydroxy-14(S),15(S)-epoxy-5Z,8Z,11Z-eicosatetraenoic acid) and 15-oxo-ETE). 17608720 2007 Brash A. R. The hepoxilin connection in the epidermis FEBS Journal 274 14 3494–3502 Yu Z Boeglin W. E. Schneider C 10.1111/j.1742-4658.2007.05909.x 9799021 free Converted to its 14,15-epoxide derivative, eoxin A4, and further metabolized to eoxin C4, eoxin D4, and eoxin E4 (there is no eoxin B4). James A, Daham K, Backman L, Brunnström A, Tingvall T, Kumlin M, Edenius C, Dahlén SE, Dahlén B, Claesson HE The influence of aspirin on release of eoxin C4, leukotriene C4 and 15-HETE, in eosinophilic granulocytes isolated from patients with asthma Int. Arch. Allergy Immunol. 162 2 135–142 2013 23921438 10.1159/000351422 29180895 Degraded non-enzymatically to various cell-injuring electrophiles such as 4-hydroxy-2(E)-nonenal and 4-oxo-2(E)-nonenal. 15964853 2005 Lee S. H. Cyclooxygenase-2-mediated DNA damage Journal of Biological Chemistry 280 31 28337–28346 Williams M. V. Dubois R. N. Blair I. A. 10.1074/jbc.M504178200 free 15(S)-HETE may be: Oxidized to its keto analog, 15-oxo-ETE, by the same enzyme that converts prostaglandins of the A, E, and F series to their 15-keto analogs viz., NAD+-dependent 15-hydroxyprostaglandin dehydrogenase; 15-oxo-ETE, similar to 15(S)-HETE, may be acylated into membrane phosphatidylethanolamine or, similar to 15(S)-HpETE, conjugated with glutathione to form a 13-cysteinyl-glycyl-glutamine adduct viz., 13-glutatione,15-oxo-5(S),8(Z),11(E)-eicosatrienoic acid; the latter metabolite is attacked by γ-glutamyl-transferase to form 13-cysteinyl-glycine,15-oxo-5(S),8(Z),11(E)-eicosatrienoic acid. 17910482 2007 Lee S. H. Cyclooxygenase-2-mediated metabolism of arachidonic acid to 15-oxo-eicosatetraenoic acid by rat intestinal epithelial cells Chemical Research in Toxicology 20 11 1665–1675 Rangiah K Williams M. V. Wehr A. Y. Dubois R. N. Blair I. A. 10.1021/tx700130p Acylated into membrane phospholipids, particularly phosphatidylinositol and phosphatidylethanolamine. Phospholipid products contain this 15(S)-HETE most likely at the sn-2 position. 15(S)-HETE-containing-phospholipids may also be made directly by the action of 15-LO-1 on membrane phosphatidylinositols or phosphatidylethanolamines containing arachidonic acid at the sn-2 positions. 9414270 1998 Brinckmann R Membrane translocation of 15-lipoxygenase in hematopoietic cells is calcium-dependent and activates the oxygenase activity of the enzyme Blood 91 1 64–74 Schnurr K Heydeck D Rosenbach T Kolde G Kühn H 10.1182/blood.V91.1.64 free 17519227 2007 Maskrey B. H. Activated platelets and monocytes generate four hydroxyphosphatidylethanolamines via lipoxygenase Journal of Biological Chemistry 282 28 20151–20163 Bermúdez-Fajardo A Morgan A. H. Stewart-Jones E Dioszeghy V Taylor G. W. Baker P. R. Coles B Coffey M. J. Kühn H O'Donnell V. B. 10.1074/jbc.M611776200 free 20061396 2844139 2010 Thomas C. P. Phospholipid-esterified eicosanoids are generated in agonist-activated human platelets and enhance tissue factor-dependent thrombin generation Journal of Biological Chemistry 285 10 6891–6903 Morgan L. T. Maskrey B. H. Murphy R. C. Kühn H Hazen S. L. Goodall A. H. Hamali H. A. Collins P. W. O'Donnell V. B. 10.1074/jbc.M109.078428 free The phosphatidylethanolamine-bound 15-HETE may be converted to phosphatidylethanolamine-bound 15-oxo-ETE. Oxygenated by 5-lipoxygenase (ALOX5) to form its 5,6-trans epoxide derivative which may then rearrange to the lipoxins (LX), LXA4 (i.e. 5(S),6(R),15(S)-trihydroxy-7E,9E,11Z,13E-eicosatetraenoic acid) and LXB4 (i.e., 5(S),14(R),15(S)-trihydroxy-6E,8Z,10E,12E-eicosatetraenoic acid) or to 5(S),15(S)-dihydroperoxy-6E,8Z,11Z,13E-eicosatetraenoate (i.e., 5(S),15(S)-diHETE). 16005201 2005 Serhan C. N. Lipoxins and aspirin-triggered 15-epi-lipoxins are the first lipid mediators of endogenous anti-inflammation and resolution Prostaglandins, Leukotrienes and Essential Fatty Acids 73 3–4 141–162 10.1016/j.plefa.2005.05.002 6806263 1982 Maas R. L. Formation of a novel dihydroxy acid from arachidonic acid by lipoxygenase-catalyzed double oxygenation in rat mononuclear cells and human leukocytes The Journal of Biological Chemistry 257 12 7056–67 Turk J Oates J. A. Brash A. R. 10.1016/S0021-9258(18)34537-X free 5(S),15(S)-diHETE may then be oxidized to 5-oxo-15(S)-hydroxy-6E,8Z,11Z,13E-eicosatetraenoate (i.e., 5-oxo-15(S)-hydroxy-ETE). The latter two metabolites may also be made by 15-LO's metabolism of 5-hydroxyeicosatetraenoic acid (i.e. 5-HETE) and 5-oxo-eicosatetraenoic acid (i.e. 5-oxo-ETE), respectively. 2546590 1989 Serhan C. N. On the relationship between leukotriene and lipoxin production by human neutrophils: Evidence for differential metabolism of 15-HETE and 5-HETE Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism 1004 2 158–168 10.1016/0005-2760(89)90264-6 24056189 2013 Powell W. S. The eosinophil chemoattractant 5-oxo-ETE and the OXE receptor Progress in Lipid Research 52 4 651–665 Rokach J 10.1016/j.plipres.2013.09.001 5710732 15(R)-HpETE may be: Reduced to 15(R)-HETE by the same pathway that reduces 5(S)-HpETE to 15(S)-HETE. Similar to 15(S)-HpETE, subject to decomposition to form various bifuctional potentially toxic electrophiles such as 4-hydroxy-2(E)-nonenal and 4-oxo-2(E)-nonenal. 15(R)-HETE may be: Similar to 15(S)-HETE, oxidized by NAD-dependent 5-hydroxyprostaglandin dehydrogenase to form 15-oxo-ETE which product can be converted its 13-cysteinyl-glycyl-glutamyl and then 13-cysteinyl-glycine products as described above for 5(S)-HETE. Similar to 15(S)-HETE, oxygenated by ALOX5 to form its 5,6-oxido derivative which then rearranges to the 15(R) diastereomers of LXA4 and (LXB4 viz., 15-epi-LXA4 5(S),6(R),15(R)-trihydroxy-7E,9E,11Z,13E-eicosatetraenoic acid) and 15-epi-LXB4 (i.e., 5(S),14(R),15(S)-trihydroxy-6E,8Z,10E,12E-eicosatetraenoic acid, respectively. Activities 15(S)-HpETE and 15(S)-HETE Most studies have analyzed the action of 15(S)-HETE but not that of its less stable precursor 15(S)-HpETE. Since this precursor is rapidly converted to 15(S)-HETE in cells, it is likely that the two metabolites share similar activities. In many studies, however, is not clear that these activities reflect their intrinsic action or reflect their conversion to the metabolites sited above. 15(S)-HpETE and 15(S)-HETE bind to and activate the G protein-coupled receptor, leukotriene B4 receptor 2, i.e. BLT2. 11278893 2001 Yokomizo T Hydroxyeicosanoids bind to and activate the low affinity leukotriene B4 receptor, BLT2 Journal of Biological Chemistry 276 15 12454–12459 Kato K Hagiya H Izumi T Shimizu T 10.1074/jbc.M011361200 free This receptor activation may mediate, at least in part, certain cell-stimulating activities of the two metabolites. BLT2 may be responsible in part or whole for mediating the growth-promoting and anti-apoptosis (i.e. anti-cell death) activities of 15(S)-HETE in cultured human breast cancer cells; 23658799 3642080 2013 O'Flaherty J. T. Fatty acid metabolites in rapidly proliferating breast cancer PLOS ONE 8 5 e63076 Wooten R. E. Samuel M. P. Thomas M. J. Levine E. A. Case L. D. Akman S. A. Edwards I. J. 10.1371/journal.pone.0063076 2013PLoSO...863076O free human cancer colon cells, human hepatocellular HepG2 and SMMC7721 cancer cells; 23474367 2013 Ma J 15-lipoxygenase-1/15-hydroxyeicosatetraenoic acid promotes hepatocellular cancer cells growth through protein kinase B and heat shock protein 90 complex activation The International Journal of Biochemistry & Cell Biology 45 6 1031–1041 Zhang L Zhang J Liu M Wei L Shen T Ma C Wang Y Chen Y Zhu D 10.1016/j.biocel.2013.02.018 mouse 3T3 cells (a fibroblast cell line); 16980726 2006 Nieves D Hydroxyeicosatetraenoic acids released through the cytochrome P-450 pathway regulate 3T6 fibroblast growth The Journal of Lipid Research 47 12 2681–9 Moreno J. J. 10.1194/jlr.M600212-JLR200 free rat PA adventitia fibroblasts; 23982954 2014 Zhang L 15-LO/15-HETE mediated vascular adventitia fibrosis via p38 MAPK-dependent TGF-β Journal of Cellular Physiology 229 2 245–257 Li Y Chen M Su X Yi D Lu P Zhu D 10.1002/jcp.24443 311866 free baby hamster kidney cells; 8384883 1993 Kiran Kumar Y. V. Differential effects of 15-HPETE and 15-HETE on BHK-21 cell proliferation and macromolecular composition 1167 1 102–108 Raghunathan A Sailesh S Prasad M Vemuri M. C. Reddanna P Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism 10.1016/0005-2760(93)90223-v and diverse types of vascular endothelial cells. 16103079 2005 Zhang B 15(S)-hydroxyeicosatetraenoic acid induces angiogenesis via activation of PI3K-Akt-mTOR-S6K1 signaling Cancer Research 65 16 7283–7291 Cao H Rao G. N. 10.1158/0008-5472.CAN-05-0633 free 22450700 2012 Soumya S. J. Effect of 15-lipoxygenase metabolites on angiogenesis: 15(S)-HPETE is angiostatic and 15(S)-HETE is angiogenic Inflammation Research 61 7 707–718 Binu S Helen A Anil Kumar K Reddanna P Sudhakaran P. R. 10.1007/s00011-012-0463-5 2297892 24219292 2013 Soumya S. J. 15(S)-HETE-induced angiogenesis in adipose tissue is mediated through activation of PI3K/Akt/mTOR signaling pathway Biochemistry and Cell Biology 91 6 498–505 Binu S Helen A Reddanna P Sudhakaran P. R. 10.1139/bcb-2013-0037 2013BCB....91.0037S 25447678 2015 Li J PGC-1α plays a major role in the anti-apoptotic effect of 15-HETE in pulmonary artery endothelial cells Respiratory Physiology & Neurobiology 205 84–91 Zhang Y Liu Y Shen T Zhang H Xing Y Zhu D 10.1016/j.resp.2014.10.015 27118439 These growth-stimulating effects could contribute to the progression of the cited cancer types in animal models or even humans 23685077 2013 Cabral M Role of arachidonic acid metabolites on the control of non-differentiated intestinal epithelial cell growth The International Journal of Biochemistry & Cell Biology 45 8 1620–1628 Martín-Venegas R Moreno J. J. 10.1016/j.biocel.2013.05.009 and the excess fibrosis that causes the narrowing of pulmonary arteries in hypoxia-induced pulmonary hypertension or narrowing of portal arteries in the portal hypertension accompanying liver cirrhosis. 25347188 4210132 2014 Pandey V Comparative analysis and modeling of the severity of steatohepatitis in DDC-treated mouse strains PLOS ONE 9 10 e111006 Sultan M Kashofer K Ralser M Amstislavskiy V Starmann J Osprian I Grimm C Hache H Yaspo M. L. Sültmann H Trauner M Denk H Zatloukal K Lehrach H Wierling C 10.1371/journal.pone.0111006 2014PLoSO...9k1006P free 15(S)-HETE may also act through BLT2 to stimulate an immediate contractile response in rat pulmonary arteries 20139061 2010 Wang Y Role of the G-protein and tyrosine kinase--Rho/ROK pathways in 15-hydroxyeicosatetraenoic acid induced pulmonary vasoconstriction in hypoxic rats Journal of Biochemistry 147 5 751–764 Liang D Wang S Qiu Z Chu X Chen S Li L Nie X Zhang R Wang Z Zhu D 10.1093/jb/mvq010 and its angiogenic effect on human umbilical and dermal vascular endothelial cells. 15(S)-HpETE and 15(S)-HETE also directly bind with and activate peroxisome proliferator-activated receptor gamma. 19903832 2010 Naruhn S 15-hydroxyeicosatetraenoic acid is a preferential peroxisome proliferator-activated receptor beta/delta agonist Molecular Pharmacology 77 2 171–184 Meissner W Adhikary T Kaddatz K Klein T Watzer B Müller-Brüsselbach S Müller R 10.1124/mol.109.060541 30996954 This activation may contribute to the ability of 15(S)-HETE to inhibit the growth of cultured human prostate cancer PC-3, LNCaP, and DU145 cell lines and non-malignant human prostate cells; 11212240 2001 Shappell S. B. 15S-Hydroxyeicosatetraenoic acid activates peroxisome proliferator-activated receptor gamma and inhibits proliferation in PC3 prostate carcinoma cells Cancer Research 61 2 497–503 Gupta R. A. Manning S Whitehead R Boeglin W. E. Schneider C Case T Price J Jack G. S. Wheeler T. M. Matusik R. J. Brash A. R. Dubois R. N. 11839751 2002 Tang S Evidence that arachidonate 15-lipoxygenase 2 is a negative cell cycle regulator in normal prostate epithelial cells Journal of Biological Chemistry 277 18 16189–16201 Bhatia B Maldonado C. J. Yang P Newman R. A. Liu J Chandra D Traag J Klein R. D. Fischer S. M. Chopra D Shen J Zhau H. E. Chung L. W. Tang D. G. 10.1074/jbc.M111936200 free lung adenocarcinoma A549 cells; 12387716 2002 Kudryavtsev I. A. Arachidonic acid metabolism in growth control of A549 human lung adenocarcinoma cells Biochemistry. Biokhimiia 67 9 1021–1026 Golenko O. D. Gudkova M. V. Myasishcheva N. V. 10.1023/A:1020526119866 27912248 human colorectal cancer cells; 14566836 2003 Chen G. G. 15-hydroxy-eicosatetraenoic acid arrests growth of colorectal cancer cells via a peroxisome proliferator-activated receptor gamma-dependent pathway International Journal of Cancer 107 5 837–843 Xu H Lee J. F. Subramaniam M Leung K. L. Wang S. H. Chan U. P. Spelsberg T. C. 10.1002/ijc.11447 36953974 corneal epithelial cells; 15728540 2005 Chang M. S. Detection and subcellular localization of two 15S-lipoxygenases in human cornea Investigative Ophthalmology & Visual Science 46 3 849–856 Schneider C Roberts R. L. Shappell S. B. Haselton F. R. Boeglin W. E. Brash A. R. 10.1167/iovs.04-1166 free and Jurkat T-cell leukemia cells. 18494609 2009 Kumar K. A. Effects of (15S)-hydroperoxyeicosatetraenoic acid and (15S)-hydroxyeicosatetraenoic acid on the acute- lymphoblastic-leukaemia cell line Jurkat: Activation of the Fas-mediated death pathway Biotechnology and Applied Biochemistry 52 Pt 2 121–133 Arunasree K. M. Roy K. R. Reddy N. P. Aparna A Reddy G. V. Reddanna P 10.1042/BA20070264 19055952 The decline in the level of 15(S)-HpETE-forming enzymes and consequential fall in cellular 15-HETE production that occurs in human prostate cancer cells may be one mechanism by which this and perhaps other human cancer cells (e.g. those of the colon, rectum, and lung) avoid the apoptosis-inducing actions of 15(S)-HpETE and/or 15(S)-HETE and thereby proliferate and spread. 10393855 1866677 1999 Shappell S. B. 15-lipoxygenase-2 (15-LOX-2) is expressed in benign prostatic epithelium and reduced in prostate adenocarcinoma The American Journal of Pathology 155 1 235–245 Boeglin W. E. Olson S. J. Kasper S Brash A. R. 10.1016/S0002-9440(10)65117-6 17164141 2007 Tang D. G. 15-lipoxygenase 2 (15-LOX2) is a functional tumor suppressor that regulates human prostate epithelial cell differentiation, senescence, and growth (size) Prostaglandins & Other Lipid Mediators 82 1–4 135–146 Bhatia B Tang S Schneider-Broussard R 10.1016/j.prostaglandins.2006.05.022 In this scenario, 15(S)-HETE and one of its forming enzymes, particularly 15-LOX-2, appear to act as tumor suppressors. Some of the inhibitory effects of 15(S)-HpETE and 15(S)-HETE, particularly when induced by high concentrations (e.g. >1-10 micromolar), may be due to a less specific mechanism: 15(S)-HpETE and to a lesser extent 15(S)-HETE induce the generation of reactive oxygen species. These species trigger cells to activate their death programs, i.e. apoptosis, and/or are openly toxic to the cells. 1520701 1992 Ochi H Mechanism for endothelial cell injury induced by 15-hydroperoxyeicosatetraenoic acid, an arachidonate lipoxygenase product 1136 3 247–252 Morita I Murota S Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 10.1016/0167-4889(92)90113-p 10833416 2000 MacCarrone M Activation of different lipoxygenase isozymes induces apoptosis in human erythroleukemia and neuroblastoma cells Biochemical and Biophysical Research Communications 272 2 345–350 Ranalli M Bellincampi L Salucci M. L. Sabatini S Melino G Finazzi-Agrò A 10.1006/bbrc.2000.2597 2000BBRC..272..345M 19949744 2009 Dymkowska D Arachidonic acid-induced apoptosis in rat hepatoma AS-30D cells is mediated by reactive oxygen species Acta Biochimica Polonica 56 4 711–715 Wojtczak L 10.18388/abp.2009_2506 free Cells. 32:1021-1027, 2011 15(S)-HpETE and 15(S)-HETE inhibit angiogenesis and the growth of cultured human chronic myelogenous leukemia K-562 cells by a mechanism that is associated with the production of reactive oxygen species. 25346880 4207198 2014 Soumya S. J. 15-LOX metabolites and angiogenesis: Angiostatic effect of 15(S)-HPETE involves induction of apoptosis in adipose endothelial cells PeerJ 2 e635 Binu S Helen A Reddanna P Sudhakaran P. R. 10.7717/peerj.635 free 17517376 2007 Mahipal S. V. Effect of 15-lipoxygenase metabolites, 15-(S)-HPETE and 15-(S)-HETE on chronic myelogenous leukemia cell line K-562: Reactive oxygen species (ROS) mediate caspase-dependent apoptosis Biochemical Pharmacology 74 2 202–214 Subhashini J Reddy M. C. Reddy M. M. Anilkumar K Roy K. R. Reddy G. V. Reddanna P 10.1016/j.bcp.2007.04.005 Several bifunctional electrophilic breakdown products of 15(S)-HpETE, e.g. 4-hydroxy-2(E)-nonenal, 4-hydroperoxy-2(E)-nonenal, 4-oxo-2(E)-nonenal, and cis-4,5-epoxy-2(E)-decanal, are mutagens in mammalian cells and thereby may contripute to the development and/or progression of human cancers. 15(R)-HETE Similar to 15(S)-HpETE and 15(S)-HETE and with similar potency, 15(R)-HETE binds with and activates peroxisome proliferator-activated receptor gamma. The precursor of 15(R)-HETE, 15(R)-HpETE may, similar to 15(S)-HpETE, break down to the mutagenic products 4-hydroxy-2(E)-nonenal, 4-hydroperoxy-2(E)-nonenal, 4-oxo-2(E)-nonenal, and cis-4,5-epoxy-2(E)-decanal and therefore be involved in cancer development and/or progression. 15-Oxo-ETE In cultured human monocytes of the THP1 cell line, 15-oxo-ETE inactivates IKKβ (also known as IKK2) thereby blocking this cell's NF-κB-mediated pro-inflammatory responses (e.g. lipopolysaccharide-induced production of TNFα, interleukin 6, and IL1B) while concurrently activating anti-oxidant responses upregulated through the anti-oxidant response element (ARE) by forcing cytosolic KEAP1 to release NFE2L2 which then moves to the nucleus, binds ARE, and induces production of, e.g. hemoxygenase-1, NADPH-quinone oxidoreductase, and possibly glutamate-cysteine ligase modifier. 25450232 4414684 2015 Snyder N. W. 15-Oxoeicosatetraenoic acid is a 15-hydroxyprostaglandin dehydrogenase-derived electrophilic mediator of inflammatory signaling pathways Chemico-Biological Interactions 234 144–153 Golin-Bisello F Gao Y Blair I. A. Freeman B. A. Wendell S. G. 10.1016/j.cbi.2014.10.029 2015CBI...234..144S By these actions, 15-oxo-ETE may dampen inflammatory and/or oxidative stress responses. In a cell-free system, 15-oxo-ETE is a moderately potent (IC50=1 μM) inhibitor of 12-lipoxygenase but not other human lipoxygenases. 24924423 4112157 2014 Armstrong M. M. Inhibitory and mechanistic investigations of oxo-lipids with human lipoxygenase isozymes Bioorganic & Medicinal Chemistry 22 15 4293–4297 Diaz G Kenyon V Holman T. R. 10.1016/j.bmc.2014.05.025 This effect could also have anti-inflammatory and anti-oxidative effects by blocking the formation of 12-HETE and hepoxilins. 15-Oxo-ETE is an example of an α,β unsaturated ketone electrophile. These ketones are highly reactive with nucleophiles, adducting to, for example, the cysteines in transcription and transcription-related regulatory factors and enzymes to form their alkylated and thereby often inactivated products. 24161076 4030715 2014 Delmastro-Greenwood M Redox-dependent anti-inflammatory signaling actions of unsaturated fatty acids Annual Review of Physiology 76 79–105 Freeman B. A. Wendell S. G. 10.1146/annurev-physiol-021113-170341 It is presumed that the preceding activities of 15-oxo-ETE reflect its adduction to the indicated elements. 15-Oxo-ETE, at 2-10 μM, also inhibits the proliferation of cultured human umbilical vein endothelial cells and LoVo human colorectal cancer cells 19535459 2730384 2009 Wei C 15-oxo-Eicosatetraenoic acid, a metabolite of macrophage 15-hydroxyprostaglandin dehydrogenase that inhibits endothelial cell proliferation Molecular Pharmacology 76 3 516–525 Zhu P Shah S. J. Blair I. A. 10.1124/mol.109.057489 23945567 3793611 2013 Snyder N. W. Cellular uptake and antiproliferative effects of 11-oxo-eicosatetraenoic acid The Journal of Lipid Research 54 11 3070–3077 Revello S. D. Liu X Zhang S Blair I. A. 10.1194/jlr.M040741 free and at the extremely high concentration of 100 μM inhibits the proliferation of cultured MBA-MD-231 and MCF7 breast cancer cells as well as SKOV3 ovarian cancer cells. 16154383 2005 O'Flaherty J. T. 5-Oxo-ETE analogs and the proliferation of cancer cells Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1736 3 228–236 Rogers L. C. Paumi C. M. Hantgan R. R. Thomas L. R. Clay C. E. High K Chen Y. Q. Willingham M. C. Smitherman P. K. Kute T. E. Rao A Cramer S. D. Morrow C. S. 10.1016/j.bbalip.2005.08.009 They may use a similar "protein-adduction" mechanism; if so the target protein(s) for these effects have not been defined or even suggested. This 15-oxo-ETE action may prove to inhibit the remodeling of blood vessels and reduce the growth of the cited cell types and cancers. At sub-micromolar concentrations, 15-oxo-ETE has weak chemotaxis activity for human monocytes and could serve to recruit this white blood cell into inflammatory responses. 8906847 1996 Sozzani S Stimulating properties of 5-oxo-eicosanoids for human monocytes: Synergism with monocyte chemotactic protein-1 and -3 Journal of Immunology 157 10 4664–4671 Zhou D Locati M Bernasconi S Luini W Mantovani A O'Flaherty J. T. 10.4049/jimmunol.157.10.4664 23499393 free 5-Oxo-15(S)-hydroxy-ETE 5-Oxo-15(S)-hydroxy-ETE is properly a member of the 5-HETE family of agonists which binds to the oxoeicosanoid receptor 1, a G protein-coupled receptor, to activate its various target cells. As such, it is a potent stimulator of leukocytes, particularly eosinophils, as well as other OXE1-bearing cells including MDA-MB-231, MCF7, and SKOV3 cancer cells (see 5-Hydroxyicosatetraenoic acid and 5-Oxo-eicosatetraenoic acid). 8683135 1996 O'Flaherty J. T. 5-Oxo-eicosatetraenoate is a broadly active, eosinophil-selective stimulus for human granulocytes Journal of Immunology 157 1 336–342 Kuroki M Nixon A. B. Wijkander J Yee E Lee S. L. Smitherman P. K. Wykle R. L. Daniel L. W. 10.4049/jimmunol.157.1.336 35264541 free It also binds with and activates PPARγ and thereby can stimulate or inhibit cells independently of OXE1. Lipoxins LXA4, LXB4, AT-LXA4, and AT-LXB4 are specialized proresolving mediators, i.e. they potently inhibit the progression and contribute to the resolution of diverse inflammatory and allergic reactions. Eoxins Eoxin A4, eoxin C4, eoxin D4, and eoxin E4 are analogs of leukotriene A4, C4, leukotriene D4, and E4. Formation of the leukotrienes is initiated by 5-lipoxygenase metabolism of arachidonic acid to form a 5,6-epoxide viz, leukotriene A4; the latter metabolite is then converted to C4, D4, and E4 in succession. Formation of the eoxins is initiated by a 15-lipoxyenase-mediated metabolism of arachiconic acid to a 14,15-epoxide, eoxin A4 followed by its serial conversion to epoxins C4, D4, and E4 using the same pathways and enzymes that metabolize leukotriene A4 to its down-stream products. Preliminary studies have found that the eoxins have pro-inflammatory actions, suggest that they are involved in severe asthma, aspirin-induced asthma attacks, and perhaps other allergic reactions. The production of eoxins by Reed-Sternburg cells has also led to suggestion that they are involve in the lymphoma of Hodgkins disease.Claesson Drugs blocking the 15-lipoxygenases may be useful for inhibiting inflammation by reducing the production of the eoxins. Sadeghian H, Jabbari A 15-Lipoxygenase inhibitors: a patent review Expert Opinion on Therapeutic Patents 26 1 65–88 2016 26560362 10.1517/13543776.2016.1113259 20192361 See also Epi-lipoxin Eoxin Specialized pro-resolving mediators References 30em External links 15-LOX Gene Atlas entry 15-LOX BRENDA homo sapiens entry Category:Fatty acids Category:Eicosanoids Category:Cell biology Category:Immunology