Eoxin

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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

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  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 Lua error in package.lua at line 80: module 'strict' not found.
  4. ↑ 4.0 4.1 Lua error in package.lua at line 80: module 'strict' not found.
  5. ↑ 5.0 5.1 5.2 Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  7. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  8. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  10. ↑ Lua error in package.lua at line 80: module 'strict' not found.

External links

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