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eoxin A4

Eoxins are proposed to be a family of proinflammatory eicosanoids (signaling compounds that regulate inflammatory and immune responses). They are produced by human eosinophils (a class of white blood cells), mast cells, the L1236 Reed–Sternberg cell line derived from Hodgkin's lymphoma, and certain other tissues. These cells produce the eoxins by initially metabolizing arachidonic acid, an omega-6 (ω-6) fatty acid, via any enzyme possessing 15-lipoxygenase activity. The product of this initial metabolic step, 15(S)-hydroperoxyeicosatetraenoic acid, is then converted to a series of eoxins by the same enzymes that metabolize the 5-lipoxygenase product of arachidonic acid metabolism, i.e. 5-Hydroperoxy-eicosatetraenoic acid to a series of leukotrienes.[1][2] That is, the eoxins are 14,15-disubstituted analogs of the 5,6-disubstituted leukotrienes.[2][3]

A closely related set of 15-lipoxygenase metabolites are derived from anandamide (i.e. arachidonic acid containing ethanolamine esterified to its carboxy residue). These eoxin-like metabolites, termed eoxamides, are also formed by L1235 Reed-Sternberg cells and proposed to play a role in Hodgkins disease.[4]

Eoxins have been suggested to contribute to inflammation in airway allergies and the development and/or progression of certain types of cancer, particularly Hodgkin's lymphoma (a cancer originating from white blood cells), prostate cancer, and colon carcinoma.[3]

History and name

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The eoxins are 14,15-analogs of LTA4, LTC4, LTD4, and LTE4. Because the leukotrienes and 14,15-leukotrienes have very similar names, the 14,15-leukotrienes were renamed "eoxins" to avoid the confusion that might arise from referring to both group as "leukotrienes".[2][5] The eoxins derive their name from eosinophils, the cell type where they were originally discovered in abundance.[2][5]

Types

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As indicated in the following Biochemistry section, there are 4 types of chemically distinct eoxins that are made serially from the 15-lipoxygenase metabolite of arachidonic acid viz., 15(S)-hydroperoxy-5Z,8Z,11Z,13E-eicosatetraenoic acid (i.e. 15(S)-HpETE):

Biochemistry

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A 15-lipoxygenase (i.e. ALOX15 or ALOX15B) metabolizes arachidonic acid to 15(S)-HpETE (see 15-Hydroxyicosatetraenoic acid); 15(S)-HpETE is then converted to its 14,15-trans-epoxide, 14,15-trans-epoxide oxido-5Z,8Z,10E,13E-eicosatetraenoic acid (i.e., Eoxin A4 (also termed EXA4) by one of the 15-lipoxygenases. 15-(S)-HpETE is then metabolized to 14(R)-glutothionyl-15(S)hydroxy-5Z,8Z,10E,13E-eicosatetraenoic acid (i.e. Eoxin C4 or EXC4) by conjugation to glutathione through the action of leukotriene C4 synthase.[2][3][6] 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.[2] These metabolic transformations are similar to and therefore thought to be mediated by the same enzymes that metabolize the 5-hydroperoxyeicosatetraenoci acid of arachidonic acid (i.e. 5(S)-HpETE) to the peptide-leukotriens, LTA4, LTC4, LTD4, and LTE4.[2][3][6]

The eoxin-forming pathway sequence is as follows:[3][7][8]

  1. Arachidonic acid → 15(S)-hydroperoxy-5Z,8Z,11Z,13E-eicosatetraenoic acid (15(S)-HPETE)) via 15-LOX-1 or possibly 15-LOX-2, i.e. ALOX15 and ALOX15B, respectively
  2. 15(S)-HPETE → EXA4 via 15-LOX-1
  3. EXA4 → EXC4 via LTC4 synthase aka "glutathione S-transferase II"
  4. EXC4 → EXD4 via unidentified gamma-glutamyltransferase class enzyme
  5. EXD4 → EXE4 via unidentified dipeptidase class enzyme

The Arachidonic acid + O2 → 15(S)-HpETE → EXA4 → EXC4 → EXD4 → EXE4) metabolic pathway is analogous to the leukotriene-forming pathway (i.e. Arachidonic acid + O2 → 5(S)-HpETE → LTA4 → LTC4 → LTD4 → LTE4). EXA4, similar to LXA4, is viewed as an intracellular intermediate that is rapidly converted to down-stream products while EXC4, EXD4, and EXE4, similar to LTC4, LTD4, and LTE4, are regarded as extracellular agents which stimulate cell function.[2][3][6]

Sources

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Cells and tissues rich in 15-LOX-1 activity such as human eosinophils, umbilical cord-derived mast cells, nasal polyps from allergic subjects, airway epitheleal cells, and L1236 Reed-Sternberg cells derived from Hodgkin's Disease tumors produce eoxins.[2][3][6][9] EC4 is also made by a mixture of polymorphonuclear neutrophis and eosinophils isolated from the blood of allergen-treated mini pigs and ECA4 is made by mouse eosinophils; lacking 15-LOX-1, it is assumed that these cells employ 12/15-lipoxygenase to initiate this synthesis.[10] Indeed, mice made deficient of 12/15-lipooxygenase exhibit an attenuated allergic airway inflammation response compared to wild type control mice.[3]

Function

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The eoxins were first defined in 2008 and have not yet been determined to have any roles in human physiology or pathology. However, their production is stimulated in human eosinophils by physiological agonists such as prostaglandin D2, leukotriene C4, and interleukin 5.[2] Furthermore, Eoxins stimulate vascular permeability in an ex vivo human vascular endothelial model system,[2] and in a small study of 32 volunteers EXC4 production by eosinophils isolated from severe and aspirin-intolerant asthmatics was greater than that from healthy volunteers and mild asthmatic patients.[11] These findings have led to suggestions that eoxins have pro-inflammatory actions and are involved in severe asthma, aspirin-induced asthma attacks, and perhaps other allergic reactions. A subsequent study found that eoxin levels in the exhaled breath of aspirin-sensitive and aspirin-intolerant asthmatic individuals did not rise after aspirin challenge and did not correlate with disease severity.[12]

The production of eoxins by Reed-Sternburg cells has also led to suggestion that they are involve in the lymphoma of Hodgkins disease and, possibly, prostate cancer, colon cancer, and other cancer types.[3]

Eoxamides

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The same pathways that metabolize arachidonic acid to eoxines have been shown to metabolize anandamide, N-arachidonoylethanolamine (i.e. arachidonic acid containing ethanolamine esterified to its carboxy residue) into a set of eoxamides that are identical to their eoxin counterparts except that they possess an ethanolamine ester. These metabolites have been named EXA4 ethanol amide, EXC4 ethanol amide, EXD4 ethanol amide, and EXE4 ethanol amide. These products were formed by the L1236 Reed Sternberg cell line presented with anandamide; human platelets presented with eoxamideA4 produced EXC4 ethanol amide, EXD4 ethanol amide, and EXE4 ethanol amide. The activity and function of these ethanol amide metabolites has not been reported.[4]

See also

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References

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  1. ^ Greene ER, Huang S, Serhan CN, Panigrahy D (November 2011). "Regulation of inflammation in cancer by eicosanoids". Prostaglandins Other Lipid Mediat. 96 (1–4): 27–36. doi:10.1016/j.prostaglandins.2011.08.004. PMC 4051344. PMID 21864702. A well-studied group of autacoid mediators that are the products of arachidonic acid metabolism include: the prostaglandins, leukotrienes, lipoxins and cytochrome P450 (CYP) derived bioactive products. These lipid mediators are collectively referred to as eicosanoids and are generated by distinct enzymatic systems initiated by cyclooxygenase (COX 1 and 2), lipoxygenases (5-LOX, 12-LOX, 15-LOXa, 15-LOXb), and cytochrome P450s, respectively. These pathways are the target of approved drugs for the treatment of inflammation, pain, asthma, allergies, and cardiovascular disorders.
  2. ^ a b c d e f g h i j k Feltenmark S, Gautam N, Brunnström A, Griffiths W, Backman L, Edenius C, Lindbom L, Björkholm M, Claesson HE (January 2008). "Eoxins are proinflammatory arachidonic acid metabolites produced via the 15-lipoxygenase-1 pathway in human eosinophils and mast cells". Proc. Natl. Acad. Sci. U.S.A. 105 (2): 680–685. Bibcode:2008PNAS..105..680F. doi:10.1073/pnas.0710127105. PMC 2206596. PMID 18184802.
  3. ^ a b c d e f g h i Claesson HE (September 2009). "On the biosynthesis and biological role of eoxins and 15-lipoxygenase-1 in airway inflammation and Hodgkin lymphoma". Prostaglandins Other Lipid Mediat. 89 (3–4): 120–5. doi:10.1016/j.prostaglandins.2008.12.003. PMID 19130894.
  4. ^ a b Forsell PK, Brunnström A, Johannesson M, Claesson HE (2012). "Metabolism of anandamide into eoxamides by 15-lipoxygenase-1 and glutathione transferases". Lipids. 47 (8): 781–91. doi:10.1007/s11745-012-3684-z. PMID 22684912. S2CID 3993616.
  5. ^ a b "European patent specification: METHODS FOR IDENTIFYING MODULATORS OF EOXIN FORMATION" (PDF). www.lens.org. 18 August 2010. p. 26. Retrieved 5 January 2015. Since eosinophils are a rich source of these novel metabolites, we suggest the name eoxin instead of 14,15-leukotriene to avoid confusion with compounds produced via the 5-LO pathway. Thus, the names 14,1 5-leukotriene A4, C4, D4 and E4 are replaced with eoxin (Eox) A4, EoxC4, EoxD4 and EoxE4, respectively (fig. 33). Eoxins have never been reported to be produced from arachidonic acid in human cells. Human basophils, however, has earlier been found to convert exogenous 14,15-leukotriene A4 to 14,15-leukotriene C4 (33)14(R),15(s)-DHETE
  6. ^ a b c d Sachs-Olsen C, Sanak M, Lang AM, Gielicz A, Mowinckel P, Lødrup Carlsen KC, Carlsen KH, Szczeklik A (2010). "Eoxins: a new inflammatory pathway in childhood asthma". J. Allergy Clin. Immunol. 126 (4): 859–867.e9. doi:10.1016/j.jaci.2010.07.015. PMID 20920774. S2CID 1137911.
  7. ^ "3. Eoxins". The AOCS Lipid Library. 26 May 2014. Archived from the original on 6 March 2015. Retrieved 5 January 2015. Recently, novel eicosanoids related to the cysteinyl-leukotrienes were characterized as products of the 12/15-lipoxygenase (15-LOX-1) of human eosinophils and mast cells. The primary product of the lipoxygenase, 15-HPETE is believed to react with the enzyme further to produce the 14,15-epoxide, designated eoxin A4, and then by analogy with leukotriene biosynthesis this in turn reacts with glutathione to produce eoxin C4, and thence eoxin D4 (linked to Cys-Gly) and eoxin E4 (linked to Cys only). Like the cysteinyl-leukotrienes, the eoxins are potent pro-inflammatory agents. ... Eoxins have been implicated in inflammation of the airways in asthma patients, and in those with Hodgkin lymphoma, a malignant disorder with many characteristics of an inflammatory illness.
  8. ^ "Synthesis of Leukotrienes (LT) and Eoxins (EX) [Homo sapiens]". Reactome. Archived from the original on 2 March 2016. Retrieved 7 January 2015.
  9. ^ Claesson HE, Griffiths WJ, Brunnström A, Schain F, Andersson E, Feltenmark S, Johnson HA, Porwit A, Sjöberg J, Björkholm M (2008). "Hodgkin Reed-Sternberg cells express 15-lipoxygenase-1 and are putative producers of eoxins in vivo: novel insight into the inflammatory features of classical Hodgkin lymphoma". FEBS J. 275 (16): 4222–34. doi:10.1111/j.1742-4658.2008.06570.x. PMID 18647347. S2CID 25515353.
  10. ^ Brunnström Å, Backman L, Tryselius Y, Claesson HE (2012). "Biosynthesis of eoxin C4 by porcine leukocytes". Prostaglandins Leukot. Essent. Fatty Acids. 87 (4–5): 159–63. doi:10.1016/j.plefa.2012.07.003. hdl:10616/41399. PMID 22921794.
  11. ^ James A, Daham K, Backman L, Brunnström A, Tingvall T, Kumlin M, Edenius C, Dahlén SE, Dahlén B, Claesson HE (2013). "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): 135–42. doi:10.1159/000351422. PMID 23921438. S2CID 29180895.
  12. ^ Mastalerz L, Sanak M, Kumik J, Gawlewicz-Mroczka A, Celejewska-Wójcik N, Cmiel A, Szczeklik A (2012). "Exhaled Eicosanoids following Bronchial Aspirin Challenge in Asthma Patients with and without Aspirin Hypersensitivity: The Pilot Study". Journal of Allergy. 2012: 696792. doi:10.1155/2012/696792. PMC 3265180. PMID 22291720.
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