Hepoxilins Activate Phospholipase D in the Human Neutrophil

Abstract

Hepoxilins are hydroxy-epoxide derivatives of arachidonic acid formed from 12-HPETE through an intramolecular rearrangement catalyzed by heme proteins1–3. We introduced the hepoxilin terminology in 1984 in an attempt to combine their structural features (Hydroxy and epoxlde) with their first reported biological activity (Insulin secretion)4. Hepoxilins have been isolated from a variety of tissues in the rat1, 5–9,11–13 and from the Aplysia brain10, and recently were shown to be formed in the red sea algae14. Two hepoxilins are formed, i.e. 8-hydroxy-11,12-epoxyeicosa-5Z, 10E, 14Z-trienoic acid (hepoxilin A3) and 10-hydroxy-11,12-epoxyeicosa-5Z, 8Z, 14Z-trienoicacid (hepoxilin B3)(see Figure 1). Hepoxilin A3 is metabolized through two distinct pathways (see Figure 1), an epoxide hydrolase pathway15 to produce a trihydroxy metabolite which is termed ‘trioxilin’ i.e. trioxilin A3, and a glutathione S-transferase-catalyzed conjugation of the epoxide moiety with glutathione which forms a metabolite termed hepoxilin A3-C8,16.