ABSTRACT
We described previously the isolation of hydroxy epoxidecontaining derivatives of arachidonic acid, which we termed hepoxilins. For a review on the formation and actions of the hepoxilins, the reader is referred to (1). The hepoxilins are C20 lipids formed through the enzymatic rearrangement of 12S-hydroperoxyeicosatetraenoic acid (HPETE), the initial product in the 12S-lipoxygenase pathway. Initially, we demonstrated that the native hepoxilins caused the release of insulin from isolated pancreatic islets of Langerhans, and hence the term hepoxilin was coined to reflect both structure and function (hydroxyepoxide and insulin). Two types of hepoxilins are formed from 12S-HPETE, i.e., hepoxilin A3 and hepoxilin B3, both having an 11,12-epoxide and a C8-hydroxyl or a C10-hydroxyl group, respectively. Further, the hydroxyl group can exist in the R or S configuration. Hence four possible hepoxilins can exist (see Fig. 1). We later demonstrated that the native hepoxilins caused rapid release of intracellular calcium from human neutrophils; in so doing, they resulted in a desensitization of the neutrophil to the effects of anti-inflammatory mediators as
Cecil R. Pace-Asciak
Fig. 1. The mechanism of formation of the native hepoxilin (Hx)A and HxB isomers through the 12S-lipoxygenase hepoxilin synthase pathways. Note that experiments are shown in which oxygen-18 was used to demonstrate that the formation of the hepoxilins is carried out through an intramolecular isomerization of the intermediate hydroperoxide, 12S-hydroperoxyeicosatetraenoic acid (HPETE). Each Hx exists as two enantiomers around the 8-or 10-carbon. Also shown is the structure of one of the PBT analogs chemically engineered by replacing through total chemical synthesis the epoxide group by a cyclopropyl group rendering the PBT more chemically and biologically stable. Hence, there are 4 PBTs: PBT-1 and PBT-2 are based on the HxA structure, and PBT-3 and PBT-4 on the HxB structure.
