It was identified as a product of arachidonic acid metabolism made by microsomes isolated from sheep seminal vesicle glands and by intact human platelets.

12-HHT is a particularly abundant product of these pro-clotting responses, accounting for about one third of the total amount of arachidonic acid metabolites formed by physiologically stimulated human platelets.

[5][6][7] While the latter studies were conducted using recombinant cytochrome enzymes or sub-fractions of disrupted cells, the human monocyte, a form of blood circulating leukocyte, increases its expression of CYP2S1 when forced to differentiate into a macrophage phenotype by interferon gamma or lipopolysaccharide (i.e. endotoxin); associated with these changes, the differentiated macrophage metabolized arachidonic acid to 12-HHT by a CYP2S1-dependent mechanism.

[1][6][2][9] This non-enzymatic pathway may explain findings that cells can make 12-HHT in excess of TXA2 and also in the absence of active cycloxygenase and/or thromboxane synthase enzymes.

[15] Fourteen years after the first publication on its detection in 1973, 12-HHT was reported to stimulate fetal bovine aortic and human umbilical vein endothelial cells to metabolize arachidonic acid to prostaglandin I2 (PGI2 or prostacyclin), a powerful inhibitor of platelet activation and stimulator of vasodilation (see Prostacyclin synthase).

[18] Thus, 12-HHT forms simultaneously with, and by stimulating PGI2 production, inhibits TXA2-mediated platelet activation responses while 12-oxo-HT blocks TXA2 receptor binding to reduce not only TXA2-induced thrombosis and blood clotting but possibly also vasospasm and other actions of TXA2.

Initially thought to be a second and low affinity receptor for the neutrophil tripeptide chemotactic factor, N-formyl-met-leu-phe, subsequent studies showed that it was a high affinity receptor for the arachidonic acid metabolite, lipoxin A4, but also bound and was activated by a wide range of peptides, proteins, and other agents.

On the other hand, the immortalized human skin cell line HaCaT expresses BLT2 receptors and responds to ultraviolet B (UVB) radiation by generating toxic reactive oxygen species which in turn cause the HaCaT cells to die by activating apoptotic pathways in a BLT2 receptor-dependent reaction.

[29] These results suggest that the 12-HHT/BLT2 axis can act to suppress inflammation by promoting the orderly death of damaged cells and blocking IL-6 production.

In a mice model of ovalbumin-induced allergic airway disease, 12-HHT and its companion cyclooxygenase metabolites, prostaglandin E2 and prostaglandin D2, but not 12 other lipoxygenase or cycloxygenase metabolites, showed a statistically significantly increase in bronchoalveolar lavage fluid levels after intratracheal ovalbumin challenge; after this challenge, only 12-HHT, among the monitored BLT2 receptor-activating ligands (LTB4, the 12(S) stereoisomer of 12-HETE, and 15(S)-HETE) attained levels capable of activating BLT2 receptors.

Finally, BLT2 receptor expression was significantly reduced in allergy-regulating CD4+ T cells from patients with asthma compared to healthy control subjects.

Companion studies using an in vitro scratch test assay indicated that 12-HHT stimulated human and mouse keratinocyte migration by a BLT2 receptor-dependent mechanism that involved the production of tumor necrosis factor α and metalloproteinases.

This mechanism may underlie the suppression of wound healing that accompanies the high dose intake of aspirin and, based on mouse studies, other non-steroidal anti-inflammatory agents (NSAIDs) in humans.