5-Hydroxyeicosatetraenoic acid

In vitro studies suggest that 5(S)-HETE and/or other of its family members may also be active in promoting the growth of certain types of cancers, in simulating bone reabsorption, in signaling for the secretion of aldosterone and progesterone, in triggering parturition, and in contributing to other responses in animals and humans.

The Nobel laureate, Bengt I. Samuelsson, and colleagues first described 5(S)-HETE in 1976 as a metabolite of arachidonic acid made by rabbit neutrophils.

[1] Biological activity was linked to it several years later when it was found to stimulate human neutrophil rises in cytosolic calcium, chemotaxis, and increases in their cell surface adhesiveness as indicated by their aggregation to each other.

[2] Since a previously discovered arachidonic acid metabolite made by neutrophils, leukotriene B4 (LTB4), also stimulates human neutrophil calcium rises, chemotaxis, and auto-aggregation and is structurally similar to 5(S)-HETE in being a 5(S)-hydroxy-eicosateraenoate, it was assumed that 5(S)-HETE stimulated cells through the same cell surface receptors as those used by LTB4 viz., the leukotriene B4 receptors.

Human ALOX5 is highly expressed in cells that regulate innate immunity responses, particularly those involved in inflammation and allergy.

However, ALOX5 can become overexpressed at high levels in certain types of human cancer cells such as those of the prostate, lung, colon, colorectal and pancreatic as a consequence of their malignant transformation.

[6][7][8][9] 5(S)-HETE may also be made in combination with 5(R)-HETE along with numerous other (S,R)-hydroxy polyunsaturated fatty acids as a consequence of the non-enzymatic oxidation reactions.

[3][17][18] Progress in proving the role of the 5-HETE family of agonists and their OXER1 receptor in human physiology and disease has been made difficult because mice, rats, and the other rodents so far tested lack OXER1.

[17][23] 5(S)-HETE and other family members were first detected as products of arachidonic acid made by stimulated human polymorphonuclear neutrophils (PMN), a leukocyte blood cell type involved in host immune defense against infection but also implicated in aberrant pro-inflammatory immune responses such as arthritis; soon thereafter they found to be active also in stimulating these cells to migrate (i.e. chemotaxis), degranulate (i.e. release the anti-bacterial and tissue-injuring contents of their granules), produce bacteriocidal and tissue-injuring reactive oxygen species, and mount other pro-defensive as well as pro-inflammatory responses of the innate immune system.

And, in vivo studies, the injection of 5-oxo-ETE into the skin of human volunteers causes the local accumulation of PMN and monocyte-derived macrophages.

[17] Furthermore, the production of one or more 5(S)-HETE family members as well as the expression of orthologs of the human OXER1 receptor occur in various mammalian species including dogs, cats, cows, sheep, elephants, pandas, opossums, and ferrets and in several species of fish; for example, cats undergoing experimentally induced asthma accumulate 5-oxo-ETE in their lung lavage fluid, feline leucocytes make as well as respond to 5-oxo-ETE by an oxer1-dependent mechanism; and an OXER1 ortholog and, apparently, 5-oxo-ETE are necessary for the inflammatory response to tissue damage caused by osmolarity insult in zebrafish.

[12][24][19] These results given above suggest that members of the 5-oxo-ETE family and the OXER1 receptor or its orthologs may contribute to protection against microbes, the repair of damaged tissues, and pathological inflammatory responses in humans and other animal species.

[17][25] Additionally, cultured human airway epithelial cell lines, normal bronchial epithelium, and bronchial smooth muscle cells convert 5(S)-HETE to 5-oxo-ETE in a reaction that is greatly increase by oxidative stress, which is a common component in allergic inflammatory reactions.

[17] It is also exceptionally potent in stimulating eosinophils to activate cytosolic phospholipase A2 (PLA2G4A) and possibly thereby to form platelet-activating factor (PAF) as well as metabolites of the 5-HETE family.

[17][31] The role of 5-HETE family agonists in the bronchoconstriction of airways (a hallmark of allergen-induced asthma) in humans is currently unclear.

Human cancers whose growth has been implicated by these studies as being mediated at least in part by a member(s) of the 5-oxo-ETE family include those of the prostate, breast, lung, ovary, and pancreas.

[39][40] The results suggest that trophic hormones (e.g., leutenizing hormone, adrenocorticotropic hormone) stimulate these steroid producing cells to make 5(S)-HETE and 5(S)-HpEPE which in turn increase the synthesis of steroidogenic acute regulatory protein; the latter protein promotes the rate-limiting step in steroidogenesis, transfer of cholesterol from the outer to the inner membrane of mitochondria and thereby acts in conjunction with trophic hormone-induce activation of protein kinase A to make progesterone and testosterone.

[20] In any event, Human H295R adrenocortical cells do express OXER1 and respond to 5-oxo-ETE by an increasing the transcription of steroidogenic acute regulatory protein messenger RNA as well as the production of aldosterone and progesterone by an apparent OXER1-dependent pathway.

[20] In an in vitro mixed culture system, 5(S)-HETE is released by monocytes to stimulate, at sub-nanomolar concentrations, osteoclast-dependent bone reabsorption.

[48] 5(S)-HETE acylated into phosphatidylethanolamine is reported to increase the stimulated production of superoxide anion and interleukin-8 release by isolated human neutrophils and to inhibit the formation of neutrophil extracellular traps (i.e. NETS); NETS trap blood-circulating bacteria to assist in their neutralization.

[22] 5(S)-HETE esterified to phosphatidylcholine and glycerol esters by human endothelial cells is reported to be associated with the inhibition of prostaglandin production.