Eoxin

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eoxin A4

Eoxins are proposed to be a family of proinflammatory

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

colon carcinoma.[3]

History and name

The eoxins are 14,15-analogs of

eosinophils, the cell type where they were originally discovered in abundance.[2][5]

Types

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

A 15-lipoxygenase (i.e.

LTE4.[2][3][6]

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

  1. 15-LOX-2
    , i.e. ALOX15 and ALOX15B, respectively
  2. 15(S)-HPETE → EXA4 via
    15-LOX-1
  3. LTC4 synthase
    aka "glutathione S-transferase II"
  4. EXC4 → EXD4 via unidentified gamma-glutamyltransferase
    class enzyme
  5. 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

Cells and tissues rich in 15-LOX-1 activity such as human

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

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

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

References

  1. 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. ^
    PMID 18184802
    .
  3. ^
    PMID 19130894
    .
  4. ^
    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. ^
    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. S2CID 25515353
    .
  10. PMID 22921794
    .
  11. S2CID 29180895
    .
  12. PMID 22291720
    .

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