12-Hydroxyeicosatetraenoic acid

changed 477189498 12-Hydroxyeicosatetraenoic acid.png 200px (5Z,8Z,10E,12S,14Z)-12-Hydroxyicosa-5,8,10,14-tetraenoic acid 12-HETE; 12(S)-HETE 3404 correct chemspider correct EBI 34146 4446279 1/C20H32O3/c1-2-3-4-5-10-13-16-19(21)17-14-11-8-6-7-9-12-15-18-20(22)23/h7-11,13-14,17,19,21H,2-6,12,15-16,18H2,1H3,(H,22,23)/b9-7-,11-8-,13-10-,17-14+/t19-/m0/s1 ZNHVWPKMFKADKW-LQWMCKPYBD O=C(O)CCC\C=C/C/C=C\C=C\[C@@H](O)C\C=C/CCCCC correct chemspider 1S/C20H32O3/c1-2-3-4-5-10-13-16-19(21)17-14-11-8-6-7-9-12-15-18-20(22)23/h7-11,13-14,17,19,21H,2-6,12,15-16,18H2,1H3,(H,22,23)/b9-7-,11-8-,13-10-,17-14+/t19-/m0/s1 correct chemspider ZNHVWPKMFKADKW-LQWMCKPYSA-N correct CAS 71030-37-0 54397-83-0 correct CAS (S) correct CAS 59985-28-3 (non-specific) correct FDA Q6F9H3VPC0 correct FDA WG8M7C9ALT (S) 13786989 CCCCC/C=C\C[C@@H](/C=C/C=C\C/C=C\CCCC(=O)O)O 20 32 3 12-Hydroxyeicosatetraenoic acid (12-HETE) is a derivative of the 20 carbon polyunsaturated fatty acid, arachidonic acid, containing a hydroxyl residue at carbon 12 and a 5Z,8Z,10E,14Z cis–trans configuration (Z=cis, E=trans) in its four double bonds. It was first found as a product of arachidonic acid metabolism made by human and bovine platelets through their 12S-lipoxygenase (i.e. ALOX12) enzyme(s). 4215079 433780 1974 Hamberg M Prostaglandin endoperoxides. Novel transformations of arachidonic acid in human platelets Proceedings of the National Academy of Sciences of the United States of America 71 9 3400–4 Samuelsson B 10.1073/pnas.71.9.3400 1974PNAS...71.3400H free 804329 1975 Nugteren D. H. Arachidonate lipoxygenase in blood platelets Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism 380 2 299–307 10.1016/0005-2760(75)90016-8 However, the term 12-HETE is ambiguous in that it has been used to indicate not only the initially detected "S" stereoisomer, 12S-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (12(S)-HETE or 12S-HETE), made by platelets, but also the later detected "R" stereoisomer, 12(R)-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (also termed 12(R)-HETE or 12R-HETE) made by other tissues through their 12R-lipoxygenase enzyme, ALOX12B. The two isomers, either directly or after being further metabolized, have been suggested to be involved in a variety of human physiological and pathological reactions. Unlike hormones which are secreted by cells, travel in the circulation to alter the behavior of distant cells, and thereby act as endocrine signalling agents, these arachidonic acid metabolites act locally as autocrine signalling and/or paracrine signaling agents to regulate the behavior of their cells of origin or of nearby cells, respectively. In these roles, they may amplify or dampen, expand or contract cellular and tissue responses to disturbances. Production In humans, arachidonate 12-lipoxygenase (12-LO, 12-LOX, ALO12, or platelet type 12-lipoxygenase) is encoded by the ALOX12 gene and expressed primarily in platelets and skin. ALOX12 metabolizes arachidonic acid almost exclusively to 12(S)-hydroperoxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (12(S)-HpETE or 12S-HpETE). 12432922 2002 Yoshimoto T Arachidonate 12-lipoxygenases Prostaglandins & Other Lipid Mediators 68–69 245–62 Takahashi Y 10.1016/s0090-6980(02)00034-5 Arachidonate 15-lipoxygenase-1 (15-LO-1, 15-LOX-1, ALOX15), which is expressed in far more tissues that ALOX12, metabolizes arachidonic acid primarily to 15(S)-HpETE along with other metabolites of the 15-hydroxyicosatetraenoic acid family; during this metabolism, however, ALOX15 also forms 12(S)-HpETE as a minor product. Arachidonate 12-lipoxygenase, 12R type, also termed 12RLOX and encoded by the ALOX12B gene, is expressed primarily in skin and cornea; it metabolizes arachidonic acid to 12(R)-HpETE. 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 2–3 258–63 10.1016/0005-2760(93)90106-j 12664563 2002 Schneider C 507 49–53 Boeglin W. E. Brash A. R. Eicosanoids and Other Bioactive Lipids in Cancer, Inflammation, and Radiation Injury, 5 Analysis of Cyclooxygenase-Substrate Interactions Using Stereospecificallylabeled Arachidonic Acids Advances in Experimental Medicine and Biology 10.1007/978-1-4615-0193-0_8 978-1-4613-4960-0 Cytochrome P450 enzymes convert arachidonic acid to a variety of hydroperoxy, epoxy, and dihydroxy derivatives including racemic mixtures of 12(S)-HpETE and 12(R)-HpETE or 12(S)-HETE and 12(R)-HETE; the R stereoisomer predominates in these mixtures. 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 20941528 2962793 2010 Panigrahy D Cytochrome P450-derived eicosanoids: The neglected pathway in cancer Cancer and Metastasis Reviews 29 4 723–35 Kaipainen A Greene E. R. Huang S 10.1007/s10555-010-9264-x The initial 12(S)-HpETE and 12(R)-HpETE products, regardless of their pathway of formation, are rapidly reduced to 12(S)-HETE and 12(R)-HETE, respectively, by ubiquitous cellular peroxidases, including in particular glutathione peroxidases 25240838 2015 Pace-Asciak C. R. Pathophysiology of the hepoxilins Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1851 4 383–96 10.1016/j.bbalip.2014.09.007 or, alternatively, are further metabolized as described below. Sub-primate mammals, such as the mouse, rat, rabbit, cow, and pig, express platelet type 12-lipoxygenase but also a leukocyte type 12-lipoxygenase (also termed 12/15-lipoxygenase, 12/15-LOX or 12/15-LO) which is an ortholog of, and metabolically equivalent to, human 15-LO-1 in that it forms predominantly 15(S)-HpETE with 12(S)-HpETE as a minor product. 18258795 2008 Collins J. F. Induction of arachidonate 12-lipoxygenase (Alox15) in intestine of iron-deficient rats correlates with the production of biologically active lipid mediators AJP: Gastrointestinal and Liver Physiology 294 4 G948–62 Hu Z Ranganathan P. N. Feng D Garrick L. M. Garrick M. D. Browne R. W. 10.1152/ajpgi.00274.2007 3923200 Mice also express an epidermal type 15-lipoxygenase (e-12LO) which has 50.8% amino acid sequence identity to human 15-LOX-2 and 49.3% sequence identity to mouse arachidonate 8-lipoxygenase. 9518531 1998 Krieg P CDNA cloning of a 8-lipoxygenase and a novel epidermis-type lipoxygenase from phorbol ester-treated mouse skin 1391 1 7–12 Kinzig A Heidt M Marks F Fürstenberger G Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism 10.1016/s0005-2760(97)00214-2 Mouse e-12LO metabolizes arachidonic acid predominantly to 12(S)-HETE and to a lesser extent 15(S)-HETE. 11204741 2001 McDonnell M Characterization of the murine epidermal 12/15-lipoxygenase Prostaglandins & Other Lipid Mediators 63 3 93–107 Davis Jr W Li H Funk C. D. 10.1016/s0090-6980(00)00100-3 Sub-human primates, although not extensively examined, appear to have 12-lipoxygenase expression patterns that resemble those of sub-primate mammals or humans depending on the closeness of there genetic relatedness to these species. 20106647 2010 Johannesson M Cloning, purification and characterization of non-human primate 12/15-lipoxygenases Prostaglandins, Leukotrienes and Essential Fatty Acids 82 2–3 121–9 Backman L Claesson H. E. Forsell P. K. 10.1016/j.plefa.2009.11.006 Further metabolism In human (and mouse) skin epidermis, 12(R)-HpETE is metabolized by Epidermis-type lipoxygenase, i.e. eLOX3 (encoded by the ALOXE3 gene), to two products: a) a specific hepoxilin, 8R-hydroxy-11R,12R-epoxy-5Z,9E,14Z-eicosatetraenoic acid (i.e. 8R-hydroxy-11R,12R-epoxy-hepoxilin A3 or 8R-OH-11R,12R-epoxy-hepoxilin A3) and b) 12-oxo-5Z,8Z,10E,14Z-eicosatetraenoic acid (12-oxo-HETE, 12-oxoETE, 12-Keto-ETE, or 12-KETE); 8R-hydroxy-11R,12R-epoxy-hepoxilin A3 is further metabolized by soluble epoxide hydrolase 2 (sEH) to 8R,11R,12R-trihydroxy-5Z,9E,14Z-eicosatetraenoic acid. 17652088 2007 Valmsen K A critical role of non-active site residues on cyclooxygenase helices 5 and 6 in the control of prostaglandin stereochemistry at carbon 15 Journal of Biological Chemistry 282 38 28157–63 Boeglin W. E. Järving R Järving I Varvas K Brash A. R. Samel N 10.1074/jbc.M704950200 free 12(R)-HpETE also spontaneously decomposes to a mixture of hepoxilins and trihydroxy-eicosatetraenoic acids that possess R or S hydroxy and epoxy residues at various sites while 8R-hydroxy-11R,12R-epoxy-hepoxilin A3 spontaneously decomposes to 8R,11R,12R-trihydroxy-5Z,9E,14Z-eicosatetraenoic acid. These decompositions may occur during tissue isolation procedures. Recent studies indicate that the metabolism by ALOXE3 of the R stereoisomer of 12-HpETE made by ALOX12B and therefore possibly the S stereoisomer of 12-HpETE made by ALOX12 or ALOX15 is responsible for forming various hepoxilins in the epidermis of human and mouse skin and tongue and possibly other tissues. 24021977 4116325 2014 Muñoz-Garcia A The importance of the lipoxygenase-hepoxilin pathway in the mammalian epidermal barrier Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1841 3 401–8 Thomas C. P. Keeney D. S. Zheng Y Brash A. R. 10.1016/j.bbalip.2013.08.020 23954555 2014 Krieg P The role of lipoxygenases in epidermis Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1841 3 390–400 Fürstenberger G 10.1016/j.bbalip.2013.08.005 Human skin metabolizes 12(S)-HpETE in reactions strictly analogous to those of 12(R)-HpETE; it metabolized 12(S)-HpETE by eLOX3 to 8R-hydroxy-11S,12S-epoxy-5Z,9E,14Z-eicosatetraenoic acid and 12-oxo-ETE, with the former product then being metabolized by sEH to 8R,11S,12S-trihydroxy-5Z,9E,14Z-eicosatetraenoic acid. 12(S)-HpETE also spontaneously decomposes to a mixture of hepoxilins and trihydroxy-eicosatetraenoic acids (trioxilins) that possess R or S hydroxy and R,S or S,R epoxide residues at various sites while 8R-hydroxy-11S,12S-epoxy-hepoxilin A3 spontaneously decomposes to 8R,11S,12S-trihydroxy-5Z,9E,14Z-eicosatetraenoic acid. In other tissues and animal species, numerous hepoxilins form but the hepoxilin synthase activity responsible for their formation is variable. (Hepoxilin A3 [8R/S-hydroxy-11,12-epoxy-5Z,9E,14Z-eicosatrienoic acid] and hepoxilin B3 [10R/S-hydroxy-11,12-epxoy-5Z,8Z,14Z-eicosatrienoic acid] refer to a mixture of diastereomers and⁄or enantiomers derived from arachidonic acid.) Cultured RINm5F rat insulinoma cells convert 12(S)-HpETE to hepoxilin A3 in a reaction that is completely dependent on, and co-localizes with, the cells' leukocyte type 12-LOX; furthermore, recombinant rat and porcine leukocyte type 12-LOX as well as human platelet type 12-LOX metabolize 12(S)-HpETE to hepoxilin A3. 15123652 2004 Nigam S The rat leukocyte-type 12-lipoxygenase exhibits an intrinsic hepoxilin A3 synthase activity Journal of Biological Chemistry 279 28 29023–30 Patabhiraman S Ciccoli R Ishdorj G Schwarz K Petrucev B Kühn H Haeggström J. Z. 10.1074/jbc.M307576200 free However, transfection of HEK293 human embryonic kidney cells with each of the 6 rat lipoxygenases, including rat eLOX3, found that hepoxilin B3 production required eLOX3; furthermore, the development of inflammation-induced tactile pain hypersensitivity (hyperesthesia; tactile allodynia) in rats required eLOX3-dependent production of hepoxilin B3 by spinal tissue. 23382512 3633813 2013 Gregus A. M. Systematic analysis of rat 12/15-lipoxygenase enzymes reveals critical role for spinal eLOX3 hepoxilin synthase activity in inflammatory hyperalgesia The FASEB Journal 27 5 1939–49 Dumlao D. S. Wei S. C. Norris P. C. Catella L. C. Meyerstein F. G. Buczynski M. W. Steinauer J. J. Fitzsimmons B. L. Yaksh T. L. Dennis E. A. 10.1096/fj.12-217414 free Thus, the production of hepoxilins from 12(S)-HpETE may result from the intrinsic activity of platelet or leukocyte type 12-LOX's, require eLOX3, or even result from 12(S)-HpETE spontaneous (and perhaps artefactual) decomposition during isolation. The majority of reports on hepoxilin formation have not defined the pathways evolved. Human and other mammalian cytochrome P450 enzymes convert 12(S)-HpETE to 12-oxo-ETE. 12-HETE (stereoisomer not determined), 12(S)-HETE, 12-oxo-ETE, hepoxilin B3, and trioxilin B3 are found in the sn-2 position of phospholipids isolated from normal human epidermis and human psoriatic scales. 118490 1979 Stenson W. F. 12-L-hydroxy-5,8,10,14-eicosatetraenoic acid, a chemotactic fatty acid, is incorporated into neutrophil phospholipids and triglyceride Prostaglandins 18 2 285–92 Parker C. W. 10.1016/0090-6980(79)90115-1 11851887 2002 Antón R Hepoxilin B3 and its enzymatically formed derivative trioxilin B3 are incorporated into phospholipids in psoriatic lesions Journal of Investigative Dermatology 118 1 139–46 Camacho M Puig L Vila L 10.1046/j.0022-202x.2001.01593.x free This indicates that the metabolites are acylated into the sn-2 position after being formed and/or directly produced by the metabolism of the arachidonic acid at the sn-2 position of these phospholipids. These acylation reactions may sequester and thereby inactivate or store the metabolites for release during cell stimulation. 7790387 1995 Joulain C Esterification of 12(S)-hydroxy-5,8,10,14-eicosatetraenoic acid into the phospholipids of human peripheral blood mononuclear cells: Inhibition of the proliferative response Journal of Cellular Physiology 164 1 154–63 Meskini N Anker G Lagarde M Prigent A. F. 10.1002/jcp.1041640120 34318830 12(S)-HETE and 12(R)-HETE are converted to 12-oxo-ETE by microsomal NAD+-dependent 12-hydroxyeicosanoid dehydrogenase in porcine polymophonuclear leukocytes; a similar pathway may be active in rabbit corneal epithelium, cow corneal epithelium, and mouse keratinocytes although this pathway has not been described in human tissues. 25449650 5710736 2015 Powell W. S. Biosynthesis, biological effects, and receptors of hydroxyeicosatetraenoic acids (HETEs) and oxoeicosatetraenoic acids (oxo-ETEs) derived from arachidonic acid Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1851 4 340–55 Rokach J 10.1016/j.bbalip.2014.10.008 12-oxo-ETE is metabolised by cytosolic NADH-dependent 12-oxoeicosinoid Δ10-reductase to 12-oxo-5Z,8Z,14Z-eicosatrienoic acid (12-oxo-ETrE); 12-ketoreductase may then reduce this 12-oxo-ETrE to 12(R)-hydroxy-5Z,8Z,14Z-eicosatrienoic acid (12(R)-HETrE) and to a lesser extent 12(S)-hydroxy-5Z,8Z,14Z-eicosatrienoic acid (12(S)-HETrE). Receptor targets and mechanisms of action The G protein-coupled receptor, GPR31, cloned from PC3 human prostate cancer cell line is a high affinity (Kd=4.8 nM) receptor for 12(S)-HETE; GPR31 does not bind 12(R)-HETE and has relatively little affinity for 5(S)-HETE or 15(S)-HETE. 21712392 3190773 2011 Guo Y Identification of the orphan G protein-coupled receptor GPR31 as a receptor for 12-(S)-hydroxyeicosatetraenoic acid Journal of Biological Chemistry 286 39 33832–40 Zhang W Giroux C Cai Y Ekambaram P Dilly A. K. Hsu A Zhou S Maddipati K. R. Liu J Joshi S Tucker S. C. Lee M. J. Honn K. V. 10.1074/jbc.M110.216564 free GPR31 mRNA is expressed at low levels in several human cell lines including K562 cells (human myelogenous leukemia cell line), Jurkat cells, (T lymphocyte cell line), Hut78 cells (T cell lymphoma cell line), HEK 293 cells (primary embryonic kidney cell line), MCF7 cells (mammary adenocarcinoma cell line), and EJ cells (bladder carcinoma cell line). This mRNA appears to be more highly expressed in PC3 and DU145 prostate cancer cell lines as well as in human umbilical vein endothelial cells (HUVEC), human umbilical vein endothelial cells (HUVEC), human brain microvascular endothelial cells (HBMEC), and human pulmonary aortic endothelial cells (HPAC). In PC-3 prostate cancer cells, GPR31 receptor mediates the action of 12(S)-HETE in activating the mitogen-activated protein kinase kinase/extracellular signal-regulated kinases-1/2 pathway and NFκB pathway that lead to cell growth and other functions. Studies have not yet determined the role, if any, in GPR31 receptor in the action of 12(S)-HETE in other cell types. A G protein-coupled receptor for the 5(S),12(R)-dihydroxy metabolite of arachidonic acid, leukotriene B4, vis., leukotriene B4 receptor 2 (BLT2), but not its leukotriene B4 receptor 1, mediates responses to 12(S)-HETE, 12(R)-HETE, and 12-oxo-ETE in many cell types. 11278893 2001 Yokomizo T Hydroxyeicosanoids bind to and activate the low affinity leukotriene B4 receptor, BLT2 Journal of Biological Chemistry 276 15 12454–9 Kato K Hagiya H Izumi T Shimizu T 10.1074/jbc.M011361200 free Based on the effects of LTB4 receptor antagonists, for example, leukotriene B4 receptor 2 mediates: the rise in cytosolic Ca2+ concentration (a key signal for cell activation) in human neutrophils 10477044 1999 Sarau H. M. In vitro and in vivo pharmacological characterization of SB 201993, an eicosanoid-like LTB4 receptor antagonist with anti-inflammatory activity Prostaglandins, Leukotrienes, and Essential Fatty Acids 61 1 55–64 Foley J. J. Schmidt D. B. Martin L. D. Webb E. F. Tzimas M. N. Breton J. J. Chabot-Fletcher M Underwood D. C. Hay D. W. Kingsbury W. D. Chambers P. A. Pendrak I Jakas D. R. Sathe G. M. Van Horn S Daines R. A. Griswold D. E. 10.1054/plef.1999.0074 1661162 1991 Naccache P. H. Calcium mobilization and right-angle light scatter responses to 12-oxo-derivatives of arachidonic acid in neutrophils: Evidence for the involvement of the leukotriene B4 receptor 1133 1 102–6 Leblanc Y Rokach J Patrignani P Fruteau De Laclos B Borgeat P Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 10.1016/0167-4889(91)90247-u 7803484 1994 O'Flaherty J. T. Chemical and biological characterization of oxo-eicosatetraenoic acids 1201 3 505–15 Cordes J. F. Lee S. L. Samuel M Thomas M. J. Biochimica et Biophysica Acta (BBA) - General Subjects 10.1016/0304-4165(94)90083-3 and the rise in cytosolic Ca2+ concentration and chemotaxis in Chinese hamstery ovarian cells stimulated by 12(S)-HETE, 12(R)-HETE, and/or 12-oxo-ETE; the itch response to 12(S)-HETE and PMN inflammatory infiltration response to 12(R)-HETE 7601505 1995 Fretland D. J. Antiinflammatory effects of second-generation leukotriene B4 receptor antagonist, SC-53228: Impact upon leukotriene B4- and 12(R)-HETE-mediated events Inflammation 19 2 193–205 Anglin C. P. Bremer M Isakson P Widomski D. L. Paulson S. K. Docter S. H. Djuric S. W. Penning T. D. Yu S 10.1007/bf01534461 25122723 triggered by the injection these metabolites into the skin of mice and guinea pigs, respectively; and an in vitro angiogenic response by human umbilical vein endothelial cells (HUVEC) and in vivo angiogenic response by mice to 12(S)-HETE. 19286633 2009 Kim G. Y. Role of the low-affinity leukotriene B4 receptor BLT2 in VEGF-induced angiogenesis Arteriosclerosis, Thrombosis, and Vascular Biology 29 6 915–20 Lee J. W. Cho S. H. Seo J. M. Kim J. H. 10.1161/ATVBAHA.109.185793 free The BLT2 receptor, in contrast to the GPR31 receptor, appears to be expressed at a high level in a wide range of tissues including neutrophils, eosinophils, monocytes, spleen, liver, and ovary. However, 12-hydroxyheptadecatrienoic acid (i.e. 12-(S)-hydroxy-5Z,8E,10E-heptadecatrienoic acid or 12-HHT), a product made when prostaglandin H2 is metabolized to thromboxane A2 by thromboxane synthase or spontaneously rearranges non-enzymatically is the most potent BLT2 receptor agonist detected to date. 18378794 2292216 2008 Okuno T 12(S)-Hydroxyheptadeca-5Z, 8E, 10E-trienoic acid is a natural ligand for leukotriene B4 receptor 2 The Journal of Experimental Medicine 205 4 759–66 Iizuka Y Okazaki H Yokomizo T Taguchi R Shimizu T 10.1084/jem.20072329 To clarify the role of BLT2 versus GPC31 receptors in responses to 12(S)-HETE, and the role(s) of LTB4, 12(S)-HETE, versus 12-HHT in BLT2-mediated responses, it will be necessary to determine: a) if leukotriene B4 interacts with the GPR31 receptor; b) if BLT2 receptor antagonists interfere with the GPR31 receptor; and c) the relative concentrations and availability of LTB4, 12(S)-HETE, and 12-HHT in tissues exhibiting BLT2-dependent responses. Ultimately, both receptors and all three ligands may prove to be responsible for some tissue responses in vivo. 12(S)-HETE and 12(R)-HETE bind to and act as competitive antagonists of the thromboxane receptor which mediates the actions of thromboxane A2 and prostaglandin H2. 2169775 1990 Mais D. E. Interaction of 5-HETE, 12-HETE, 15-HETE and 5,12-diHETE at the human platelet thromboxane A2/prostaglandin H2 receptor Eicosanoids 3 2 121–4 Saussy Jr D. L. Magee D. E. Bowling N. L. 1837628 1991 Fonlupt P 12-HETE inhibits the binding of PGH2/TXA2 receptor ligands in human platelets Thrombosis Research 63 2 239–48 Croset M Lagarde M 10.1016/0049-3848(91)90287-7 This antagonistic activity was responsible for the ability of 12(S)-HETE and 12(R)-HETE to relax mouse mesenteric arteries pre-constricted with a thromboxane A2 mimetic, U46619. 23203967 3774504 2013 Siangjong L Endothelial 12(S)-HETE vasorelaxation is mediated by thromboxane receptor inhibition in mouse mesenteric arteries AJP: Heart and Circulatory Physiology 304 3 H382–92 Gauthier K. M. Pfister S. L. Smyth E. M. Campbell W. B. 10.1152/ajpheart.00690.2012 12(S)-HETE binds with high affinity to a 50 kilodalton (kDa) subunit of a 650 kDa cytosolic and nuclear protein complex. Herbertsson H, Kühme T, Hammarström S The 650-kDa 12(S)-hydroxyeicosatetraenoic acid binding complex: occurrence in human platelets, identification of hsp90 as a constituent, and binding properties of its 50-kDa subunit Archives of Biochemistry and Biophysics 367 1 33–8 Jul 1999 10375396 10.1006/abbi.1999.1233 Activities and possible clinical significance Inflammation and inflammatory diseases 12(S)-HpETE, 12(R)-HETE, racemic mixtures of these 12-HETEs, and/or 12-oxo-ETE stimulate: a) the directed migration (chemotaxis) of human, rat, and rabbit neutrophils as well as rabbit macrophages; 367961 1977 Sahu S Lipid chemotaxins isolated from culture filtrates of Escherichia coli and from oxidized lipids Inflammation 2 1 47–54 Lynn W. S. 10.1007/bf00920874 8701131 6247746 1980 Goetzl E. J. Unique aspects of the modulation of human neutrophil function by 12-L-hydroperoxy-5,8,10,14-eicosatetraenoic acid Prostaglandins 19 1 71–85 Hill H. R. Gorman R. R. 10.1016/0090-6980(80)90155-0 6251514 1980 Palmer R. M. Chemokinetic activity of arachidonic and lipoxygenase products on leuocyctes of different species Prostaglandins 20 2 411–8 Stepney R. J. Higgs G. A. Eakins K. E. 10.1016/s0090-6980(80)80058-x b) human neutrophils to adhere to each other (i.e. aggregate) and in cooperation with tumor necrosis factor alpha or platelet-activating factor, to release their granule-bound enzymes; 7258296 1903737 1981 O'Flaherty J. T. Neutrophil-aggregating activity of monohydroxyeicosatetraenoic acids The American Journal of Pathology 104 1 55–62 Thomas M. J. Lees C. J. McCall C. E. c) the binding of human vascular epithelial cells to human monocytes; 16461778 2006 Huber J Specific monocyte adhesion to endothelial cells induced by oxidized phospholipids involves activation of cPLA2 and lipoxygenase The Journal of Lipid Research 47 5 1054–62 Fürnkranz A Bochkov V. N. Patricia M. K. Lee H Hedrick C. C. Berliner J. A. Binder B. R. Leitinger N 10.1194/jlr.M500555-JLR200 free 10073973 1999 Honda H. M. Induction of monocyte binding to endothelial cells by MM-LDL: Role of lipoxygenase metabolites Arteriosclerosis, Thrombosis, and Vascular Biology 19 3 680–6 Leitinger N Frankel M Goldhaber J. I. Natarajan R Nadler J. L. Weiss J. N. Berliner J. A. 10.1161/01.atv.19.3.680 free d) DNA synthesis and mitogenesis in the immortalized human keratinocyte cell line HaCaT; 17521953 2007 Yoo H Insulin-like growth factor-II regulates the 12-lipoxygenase gene expression and promotes cell proliferation in human keratinocytes via the extracellular regulatory kinase and phosphatidylinositol 3-kinase pathways The International Journal of Biochemistry & Cell Biology 39 6 1248–59 Kim S. J. Kim Y Lee H Kim T. Y. 10.1016/j.biocel.2007.04.009 and e) when injected in the skin of human volunteers, the extravasation and local accumulation of circulating blood neutrophils and mononuclear cells. 3998504 1985 Dowd P. M. Cutaneous responses to 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE) The Journal of Investigative Dermatology 84 6 537–41 Kobza Black A Woollard P. M. Camp R. D. Greaves M. W. 10.1111/1523-1747.ep12273537 free 2813813 1989 Wollard P. M. A comparison of the proinflammatory effects of 12(R)- and 12(S)-hydroxy-5,8,10,14-eicosatetraenoic acid in human skin Prostaglandins 38 4 465–71 Cunnigham F. M. Murphy G. M. Camp R. D. Derm F. F. Greaves M. W. 10.1016/0090-6980(89)90129-9 These results suggest these metabolites contribute to the inflammation that occurs at sites where they are formed in abnormal amounts such as in human rheumatoid arthritis, inflammatory bowel disease, contact dermatitis, psoriasis, various forms of ichthyosis including congenital ichthyosiform erythroderma, and corneal inflammatory diseases. 6305285 1983 Voorhees J. J. Leukotrienes and other lipoxygenase products in the pathogenesis and therapy of psoriasis and other dermatoses Archives of Dermatology 119 7 541–7 10.1001/archderm.1983.01650310003001 3010612 1985 Kragballe K Arachidonic acid in psoriasis. Pathogenic role and pharmacological regulation Acta Dermato-Venereologica. Supplementum 120 12–7 Voorhees J. J. 23792437 3740074 2013 Fox T Dysregulated heme oxygenase-ferritin system in pterygium pathogenesis Cornea 32 9 1276–82 Gotlinger K. H. Dunn M. W. Lee O. L. Milman T Zaidman G Schwartzman M. L. Bellner L 10.1097/ICO.0b013e3182936915 Since BLT2 appears to mediate the responses of leukocytes to 12(S)-HpETE, 12(S)-HETE, 12(R)-HETE, and 12-oxo-ETE but GPR31 is expressed by various other cells (e.g. vascular endothelium) involved in inflammation, the pro-inflammatory actions of 12-HETE in humans may involve both types of G protein-coupled receptors. Itch perception 12(S)-HpETE and 12(S)-HETE induce itching responses when injected into the skin of mice; this has led to the suggestion that these metabolites contribute to the itching (i.e. clinical pruritus) which accompanies such conditions as atopic dermatitis, contact dermatitis, urticaria, chronic renal failure, and cholestasis. 18536755 2451041 2008 Kim H. J. Involvement of the BLT2 receptor in the itch-associated scratching induced by 12-(S)-lipoxygenase products in ICR mice British Journal of Pharmacology 154 5 1073–8 Kim D. K. Kim H Koh J. Y. Kim K. M. Noh M. S. Lee S Kim S Park S. H. Kim J. J. Kim S. Y. Lee C. H. 10.1038/bjp.2008.220 17112507 2007 Kim D. K. 12(S)-HPETE induces itch-associated scratchings in mice European Journal of Pharmacology 554 1 30–3 Kim H. J. Sung K. S. Kim H Cho S. A. Kim K. M. Lee C. H. Kim J. J. 10.1016/j.ejphar.2006.09.057 Since it mediates 12(S)-HETE-induced itching in the mouse model, BLT2 rather than GPR31 may mediate human itch in these reactions. Cancer Prostate cancer 12-HETE (stereoisomer not defined) is the dominant arachidonic acid metabolite in cultured PC3 human prostate cancer cells and its levels in human prostate cancer tissue exceed by >9-fold its levels in normal human prostate tissue. 22895552 3982713 2012 Yang P Arachidonic acid metabolism in human prostate cancer International Journal of Oncology 41 4 1495–503 Cartwright C. A. Li J Wen S Prokhorova I. N. Shureiqi I Troncoso P Navone N. M. Newman R. A. Kim J 10.3892/ijo.2012.1588 Furthermore, 12(S)-HETE a) increases the expression of alpha-v beta-5 cell surface adhesion molecule and associated with this the survival of cultured PC3 cells; 12874035 2003 Pidgeon G. P. Overexpression of platelet-type 12-lipoxygenase promotes tumor cell survival by enhancing alpha(v)beta(3) and alpha(v)beta(5) integrin expression Cancer Research 63 14 4258–67 Tang K Cai Y. L. Piasentin E Honn K. V. b) promotes the phosphorylation of retinoblastoma protein to inhibit its tumor suppressor function while promoting the proliferation of cultured PC3 cells; 17218785 2007 Yang P Zyflamend-mediated inhibition of human prostate cancer PC3 cell proliferation: Effects on 12-LOX and Rb protein phosphorylation Cancer Biology & Therapy 6 2 228–36 Cartwright C Chan D Vijjeswarapu M Ding J Newman R. A. 10.4161/cbt.6.2.3624 free c) stimulates PC3 cells to activate the mitogen-activated protein kinase kinase/extracellular signal-regulated kinases-1/2 pathway and the NFκB pathways that lead to cell proliferation; d) reverses the apoptosis-inducing (i.e. cell-killing) effect of pharmacologically inhibiting 12-LO in cultured DU145 human prostate cancer cells; 11980674 2002 Pidgeon G. P. Mechanisms controlling cell cycle arrest and induction of apoptosis after 12-lipoxygenase inhibition in prostate cancer cells Cancer Research 62 9 2721–7 Kandouz M Meram A Honn K. V. e) promotes the induction of cyclooxygenase-1 and thereby the synthesis of this enzyme's growth-promoting arachidonic acid metabolite, PGE2, in cultured PC3 and LNCaP human prostate cancer cells;PC3 and LNCaP and f) induces cultured PC3 cells to express vascular endothelial growth factor (VEGF), a protein that stimulates the formation of the microvasculature which assists in the metastasis of cancer. 16638750 2006 Nie D Mechanisms regulating tumor angiogenesis by 12-lipoxygenase in prostate cancer cells Journal of Biological Chemistry 281 27 18601–9 Krishnamoorthy S Jin R Tang K Chen Y Qiao Y Zacharek A Guo Y Milanini J Pages G Honn K. V. 10.1074/jbc.M601887200 free These results suggest that the 12(S)-HETE made by prostate cancer tissues serves to promote the growth and spread of this cancer. Since it mediates the action of 12(S)-HETE in stimulating cultured PC3 cells to activate the mitogen-activated protein kinase kinase/extracellular signal-regulated kinases-1/2 pathway and NFκB pathways, the GPR31 receptor may contribute to the pro-malignant activity of 12(S)-HETE. However, LNCaP and PC3 cells also express BLT2 receptors; in LNCaP cells, BLT2 receptors are positively linked (i.e. stimulate the expression of) to the growth- and metastasis-promoting androgen receptor; 22426480 2012 Lee J. W. Androgen receptor is up-regulated by a BLT2-linked pathway to contribute to prostate cancer progression Biochemical and Biophysical Research Communications 420 2 428–33 Kim G. Y. Kim J. H. 10.1016/j.bbrc.2012.03.012 2012BBRC..420..428L in PC3 cells, BLT2 receptors stimulate the NF-κB pathway to inhibit the apoptosis caused by cell detachment from surfaces i.e. anoikis; 23986446 3798474 2013 Lee J. W. Activation of the leukotriene B4 receptor 2-reactive oxygen species (BLT2-ROS) cascade following detachment confers anoikis resistance in prostate cancer cells Journal of Biological Chemistry 288 42 30054–63 Kim J. H. 10.1074/jbc.M113.481283 free and, in BLT2-overexpressing PWR-1E non-malignant prostate cells, 12(S)-HETE diminish anoikis-induced apoptosis. Thus, the role of 12(S)-HETE in human prostate cancer, if any, may involve its activation of one or both of the GPR31 and BLT2 receptors. Other cancers Preclinical laboratory studies analogous to those conducted on the pro-malignant effects of 12(S)-HETE and growth-inhibiting effects of blocking 12-HETE production in cultured prostate cancer cell lines, have implicated 12-HETE (stereoisomer sometimes undefined) in cancer cell lines from various other human tissues including those from the liver, 22484589 2012 Xu X. M. Inhibition of 12-lipoxygenase reduces proliferation and induces apoptosis of hepatocellular carcinoma cells in vitro and in vivo Hepatobiliary & Pancreatic Diseases International 11 2 193–202 Yuan G. J. Deng J. J. Guo H. T. Xiang M Yang F Ge W Chen S. Y. 10.1016/s1499-3872(12)60147-7 24661807 4169337 2014 Fitian A. I. Integrated metabolomic profiling of hepatocellular carcinoma in hepatitis C cirrhosis through GC/MS and UPLC/MS-MS Liver International 34 9 1428–44 Nelson D. R. Liu C Xu Y Ararat M Cabrera R 10.1111/liv.12541 intestinal epithelium, 8679690 1996 Bortuzzo C The effect of leukotrienes B and selected HETEs on the proliferation of colon cancer cells 1300 3 240–6 Hanif R Kashfi K Staiano-Coico L Shiff S. J. Rigas B Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism 10.1016/0005-2760(96)00003-3 free 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 1620–8 Martín-Venegas R Moreno J. J. 10.1016/j.biocel.2013.05.009 lung, 16417464 2005 Kudryavtsev I. A. Lipoxygenase pathway of arachidonic acid metabolism in growth control of tumor cells of different type Biochemistry. Biokhimiia 70 12 1396–403 Gudkova M. V. Pavlova O. M. Oreshkin A. E. Myasishcheva N. V. 10.1007/s10541-005-0275-0 55873 breast, 12200139 2002 Tong W. G. The mechanisms of lipoxygenase inhibitor-induced apoptosis in human breast cancer cells Biochemical and Biophysical Research Communications 296 4 942–8 Ding X. Z. Adrian T. E. 10.1016/s0006-291x(02)02014-4 2002BBRC..296..942T 21629247 3142797 2011 Vonach C NF-κB mediates the 12(S)-HETE-induced endothelial to mesenchymal transition of lymphendothelial cells during the intravasation of breast carcinoma cells British Journal of Cancer 105 2 263–71 Viola K Giessrigl B Huttary N Raab I Kalt R Krieger S Vo T. P. Madlener S Bauer S Marian B Hämmerle M Kretschy N Teichmann M Hantusch B Stary S Unger C Seelinger M Eger A Mader R Jäger W Schmidt W Grusch M Dolznig H Mikulits W Krupitza G 10.1038/bjc.2011.194 skin (melanoma), 12394183 2002 Winer I Expression of 12-lipoxygenase as a biomarker for melanoma carcinogenesis Melanoma Research 12 5 429–34 Normolle D. P. Shureiqi I Sondak V. K. Johnson T Su L Brenner D. E. 10.1097/00008390-200209000-00003 27336312 ovary, 21442472 2011 Guo A. M. Role of 12-lipoxygenase in regulation of ovarian cancer cell proliferation and survival Cancer Chemotherapy and Pharmacology 68 5 1273–83 Liu X Al-Wahab Z Maddippati K. R. Ali-Fehmi R Scicli A. G. Munkarah A. R. 10.1007/s00280-011-1595-y 30242522 pancrease, 10405349 1999 Ding X. Z. Lipoxygenase inhibitors abolish proliferation of human pancreatic cancer cells Biochemical and Biophysical Research Communications 261 1 218–23 Iversen P Cluck M. W. Knezetic J. A. Adrian T. E. 10.1006/bbrc.1999.1012 1999BBRC..261..218D 11745456 2001 Ding X. Z. 12-lipoxygenase metabolite 12(S)-HETE stimulates human pancreatic cancer cell proliferation via protein tyrosine phosphorylation and ERK activation International Journal of Cancer 94 5 630–6 Tong W. G. Adrian T. E. 10.1002/ijc.1527 31317515 free and possibly bladder. 21252614 3068295 2011 Seo J. M. Up-regulation of BLT2 is critical for the survival of bladder cancer cells Experimental & Molecular Medicine 43 3 129–37 Cho K. J. Kim E. Y. Choi M. H. Chung B. C. Kim J. H. 10.3858/emm.2011.43.3.014 These studies implicate the interaction of 12-HETE with BLT2 receptors in intestinal epithelium cancer cells, and BLT2 receptors in breast, ovary, pancreas, and bladder cancer cells. 23977445 3744015 2013 Cho N. K. BLT2 is a pro-tumorigenic mediator during cancer progression and a therapeutic target for anti-cancer drug development American Journal of Cancer Research 3 4 347–55 Joo Y. C. Wei J. D. Park J. I. Kim J. H. 18781173 2567081 2008 Hennig R BLT2 is expressed in PanINs, IPMNs, pancreatic cancer and stimulates tumour cell proliferation British Journal of Cancer 99 7 1064–73 Osman T Esposito I Giese N Rao S. M. Ding X. Z. Tong W. G. Büchler M. W. Yokomizo T Friess H Adrian T. E. 10.1038/sj.bjc.6604655 While the studies on these tissues have not been as frequent or diverse as those on prostate cancer cell lines, they are suggested to indicate that 12-HETE contributes to the growth or spread of the corresponding cancer in humans. Diabetes 12(S)-HETE, 12(S)-HpETE, and with far less potency 12(R)-HETE reduced insulin secretion and caused apoptosis in cultured human pancreatic insulin-secreting beta cell lines and prepared pancreatic islets. 15729574 2005 Chen M Activation of 12-lipoxygenase in proinflammatory cytokine-mediated beta cell toxicity Diabetologia 48 3 486–95 Yang Z. D. Smith K. M. Carter J. D. Nadler J. L. 10.1007/s00125-005-1673-y free 20089617 2840856 2010 Ma K 12-Lipoxygenase Products Reduce Insulin Secretion and β-Cell Viability in Human Islets The Journal of Clinical Endocrinology & Metabolism 95 2 887–93 Nunemaker C. S. Wu R Chakrabarti S. K. Taylor-Fishwick D. A. Nadler J. L. 10.1210/jc.2009-1102 TNFα, IL-1β, and IFNγ also reduced insulin secretion in cultured human pancreatic INS-1 beta cells, apparently by inducing the expression of NOX1 (NADPH oxidase 1) and thereby to the production of cell-toxic reactive oxygen species; these cytokine effects were completely dependent on 12-lipoxygenase and mimicked by 12(S)-HETE but not 12(R)-HETE. 22502743 2012 Weaver J. R. Integration of pro-inflammatory cytokines, 12-lipoxygenase and NOX-1 in pancreatic islet beta cell dysfunction Molecular and Cellular Endocrinology 358 1 88–95 Holman T. R. Imai Y Jadhav A Kenyon V Maloney D. J. Nadler J. L. Rai G Simeonov A Taylor-Fishwick D. A. 10.1016/j.mce.2012.03.004 29097709 https://escholarship.org/uc/item/4b43h7xz free 12-lipoxygenase-knockout mice (i.e., mice genetically manipulated to remove the Alox12, i.e. 12-lipoxygenase gene, see Lipoxygenase Mouse lipoxygenases) are resistant to a) streptozotocin-induced, b) high fat diet-induced, and c) autoimmune-induced diabetes. 20970452 3012140 2011 Dobrian A. D. Functional and pathological roles of the 12- and 15-lipoxygenases Progress in Lipid Research 50 1 115–31 Lieb D. C. Cole B. K. Taylor-Fishwick D. A. Chakrabarti S. K. Nadler J. L. 10.1016/j.plipres.2010.10.005 10330425 408453 1999 Bleich D Resistance to type 1 diabetes induction in 12-lipoxygenase knockout mice Journal of Clinical Investigation 103 10 1431–6 Chen S Zipser B Sun D Funk C. D. Nadler J. L. 10.1172/JCI5241 Further studies in animal models suggest that the 12S-HETE made by pancreatic beta cells (or possibly alpha cells or other cell types indigenous to or invading the pancreatic islands) orchestrate a local immune response that results in the injury and, when extreme, death of beta cells. These results suggest that the 12-lipoxygenase-12S-HETE pathway is one factor contributing to immunity-based type I diabetes as well as low insulin output type II diabetes. Blood pressure 12(S)-HETE and 12(S)-HpETE stimulate the dilation of rat mesenteric arteries; 15626691 2005 Zhou W Impaired arachidonic acid-mediated dilation of small mesenteric arteries in Zucker diabetic fatty rats AJP: Heart and Circulatory Physiology 288 5 H2210–8 Wang X. L. Kaduce T. L. Spector A. A. Lee H. C. 10.1152/ajpheart.00704.2004 12490584 2003 Miller A. W. Arachidonic acid-induced vasodilation of rat small mesenteric arteries is lipoxygenase-dependent Journal of Pharmacology and Experimental Therapeutics 304 1 139–44 Katakam P. V. Lee H. C. Tulbert C. D. Busija D. W. Weintraub N. L. 10.1124/jpet.102.041780 8284990 12(S)-HETE stimulates the dilation of coronary microvessels in pigs and the mesenteric arteries of mice, 11158968 2001 Zink M. H. 12-lipoxygenase in porcine coronary microcirculation: Implications for coronary vasoregulation American Journal of Physiology. Heart and Circulatory Physiology 280 2 H693–704 Oltman C. L. Lu T Katakam P. V. Kaduce T. L. Lee H Dellsperger K. C. Spector A. A. Myers P. R. Weintraub N. L. 10.1152/ajpheart.2001.280.2.h693 9445489 one or more of these three metabolites are implicated in the vasodilation of rat basilar artery, 11404300 2001 Faraci F. M. Arachidonate dilates basilar artery by lipoxygenase-dependent mechanism and activation of K+ channels American Journal of Physiology. Regulatory, Integrative and Comparative Physiology 281 1 R246–53 Sobey C. G. Chrissobolis S Lund D. D. Heistad D. D. Weintraub N. L. 10.1152/ajpregu.2001.281.1.R246 free 12(R)-HETE and to a slightly lesser extent 12(S)-HETE constrict the renal artery of dogs 1908641 1991 Ma Y. H. Effects of 12-HETE on isolated dog renal arcuate arteries The American Journal of Physiology 261 2 Pt 2 H451–6 Harder D. R. Clark J. E. Roman R. J. 10.1152/ajpheart.1991.261.2.H451 and 12-HETE (stereoisomer undetermined) is implicated in the angiotensin II-induced arterial hypertension response of human placenta. 9052898 1997 Kisch E. S. Role of the lipoxygenase pathway in angiotensin II-induced vasoconstriction in the human placenta Hypertension 29 3 796–801 Jaffe A Knoll E Stern N 10.1161/01.hyp.29.3.796 The vasodilating effect on mouse mesenteric arteries appears due to 12S-HETE's ability to act as a thromboxane receptor antagonist and thereby block the vasoconstricting actions of thromboxane A2. 24685839 2014 Porro B Analysis, physiological and clinical significance of 12-HETE: A neglected platelet-derived 12-lipoxygenase product Journal of Chromatography B 964 26–40 Songia P Squellerio I Tremoli E Cavalca V 10.1016/j.jchromb.2014.03.015 These results indicate that the cited metabolites have dilating or constricting effects that depend on the arterial vascular site and or species of animal examined; their role in human blood pressure regulation is unclear. Toxic effects Excessive 12-HETE production is implicated in psoriasis. See also 5-Hydroxyeicosatetraenoic acid 15-Hydroxyeicosatetraenoic acid References 30em Category:Fatty acids Category:Eicosanoids Category:Cell biology Category:Immunology Category:Inflammations Category:Human physiology Category:Animal physiology