It was first found as a product of arachidonic acid metabolism made by human and bovine platelets through their 12S-lipoxygenase (i.e. ALOX12) enzyme(s).

The two isomers, either directly or after being further metabolized, have been suggested to be involved in a variety of human physiological and pathological reactions.

In these roles, they may amplify or dampen, expand or contract cellular and tissue responses to disturbances.

Sub-primate mammals, such as the mouse, rat, rabbit, cow, and pig, express platelet type 12-lipoxygenase but also a leukocyte type 12-lipoxygenase (also termed 12/15-lipoxygenase, 12/15-LOX or 12/15-LO) which is an ortholog of, and metabolically equivalent to, human 15-LO-1 in that it forms predominantly 15(S)-HpETE with 12(S)-HpETE as a minor product.

[12] Sub-human primates, although not extensively examined, appear to have 12-lipoxygenase expression patterns that resemble those of sub-primate mammals or humans depending on the closeness of there genetic relatedness to these species.

These acylation reactions may sequester and thereby inactivate or store the metabolites for release during cell stimulation.

[21] 12(S)-HETE and 12(R)-HETE are converted to 12-oxo-ETE by microsomal NAD+-dependent 12-hydroxyeicosanoid dehydrogenase in porcine polymophonuclear leukocytes; a similar pathway may be active in rabbit corneal epithelium, cow corneal epithelium, and mouse keratinocytes although this pathway has not been described in human tissues.

[24] Based on the effects of LTB4 receptor antagonists, for example, leukotriene B4 receptor 2 mediates: the rise in cytosolic Ca2+ concentration (a key signal for cell activation) in human neutrophils[25][26][27] and the rise in cytosolic Ca2+ concentration and chemotaxis in Chinese hamstery ovarian cells[24] stimulated by 12(S)-HETE, 12(R)-HETE, and/or 12-oxo-ETE; the itch response to 12(S)-HETE[28] and PMN inflammatory infiltration response to 12(R)-HETE[29] triggered by the injection these metabolites into the skin of mice and guinea pigs, respectively; and an in vitro angiogenic response by human umbilical vein endothelial cells (HUVEC) and in vivo angiogenic response by mice to 12(S)-HETE.

[32][33] This antagonistic activity was responsible for the ability of 12(S)-HETE and 12(R)-HETE to relax mouse mesenteric arteries pre-constricted with a thromboxane A2 mimetic, U46619.

[43][44] These results suggest these metabolites contribute to the inflammation that occurs as sites where they are formed in abnormal amounts such as in human rheumatoid arthritis, inflammatory bowel disease, contact dermatitis, psoriasis, various forms of ichthyosis including congenital ichthyosiform erythroderma, and corneal inflammatory diseases.

12(S)-HpETE and 12(S)-HETE induce itching responses when injected into the skin of mice; this has led to the suggestion that these metabolites contribute to the itching (i.e. clinical pruritus) which accompanies such conditions as atopic dermatitis, contact dermatitis, urticaria, chronic renal failure, and cholestasis.

Preclinical laboratory studies analogous to those conducted on the pro-malignant effects of 12(S)-HETE and growth-inhibiting effects of blocking 12-HETE production in cultured prostate cancer cell lines, have implicated 12-HETE (stereoisomer sometimes undefined) in cancer cell lines from various other human tissues including those from the liver,[57][58] intestinal epithelium,[59][60] lung,[61] breast,[62][63] skin (melanoma),[64] ovary,[65] pancrease,[66][67] and possibly bladder.

[71][72] TNFα, IL-1β, and IFNγ also reduced insulin secretion in cultured human pancreatic INS-1 beta cells, apparently by inducing the expression of NOX1 (NADPH oxidase 1) and thereby to the production of cell-toxic reactive oxygen species; these cytokine effects were completely dependent on 12-lipoxygenase and mimicked by 12(S)-HETE but not 12(R)-HETE.

[81] These results indicate that the cited metabolites have dilating or constricting effects that depend on the arterial vascular site and or species of animal examined; their role in human blood pressure regulation is unclear.