Eoxin

Eoxins are a family of proinflammatory eicosanoids (signaling compounds that regulate inflammatory and immune responses) that are produced in human eosinophils (a class of white blood cells) and mast cells through the metabolism of arachidonic acid, an omega-6 (ω-6) fatty acid, by the arachidonate 15-lipoxygenase-1 enzyme.[1][2] The eoxins represent 14,15-leukotriene analogs and are synthesized in a similar manner to the standard leukotrienes.[2][3] Eoxins contribute to inflammation in airway allergies and certain types of cancers, particularly Hodgkin's lymphoma (a cancer originating from white blood cells), prostate cancer, and colon carcinoma.[3]

History and name

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][4] The eoxins derive their name from eosinophils, the cell type where they were originally discovered in abundance.[2][4]

Types

As indicated in the following Biochemstry section, there are 4 types of chemically distinct eoxins that are made serially from 15(S)-hydroperoxy-5Z,8Z,11Z,13E-eicosatetraenoic acid:

Biochemistry

A 15-lipoxygenase (i.e. ALOX15 or ALOX15B) metabolizes arachidonic acid to 15(S)-hydroperoxy-5Z,8Z,11Z,13E-eicosatetraenoic acid (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 or EXA4) by ALOX15 and thereafter 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][5] 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 presumed to be mediated by the same enzymes that metabolizes arachidonic acid to LTA4, LTC4, LTD4, and LTE4.[2][3][5]

Human biosynthesis

Pathway sequence:[3][6][7]

  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

Sources

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][5][8] 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.[9]

Function

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.[10] 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. The production of eoxins by Reed-Sternburg cells has also led to suggestion that they are involve in the lymphoma of Hodgkins disease.[3]

See also

References

  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. 1 2 3 4 5 6 7 8 9 10 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. doi:10.1073/pnas.0710127105. PMC 2206596. PMID 18184802.
  3. 1 2 3 4 5 6 7 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. 1 2 "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
  5. 1 2 3 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.
  6. ↑ "3. Eoxins". The AOCS Lipid Library. 26 May 2014. 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.
  7. ↑ "Synthesis of Leukotrienes (LT) and Eoxins (EX) [Homo sapiens]". Reactome. Retrieved 7 January 2015.
  8. ↑ 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.
  9. ↑ 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. PMID 22921794.
  10. ↑ 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.

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