Eoxin

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):

• Eoxin A4
• Eoxin C4
• Eoxin D4
• Eoxin E4

Biochemistry

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. 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. 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.

The eoxin-forming pathway sequence is as follows:

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.

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. Furthermore, Eoxins stimulate vascular permeability in an ex vivo human vascular endothelial model system, 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. 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.

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.

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.