Soluble epoxide hydrolase inhibition reveals novel biological functions of epoxyeicosatrienoic acids (EETs).

Early on, intriguing biological activities were found associated with the EETs using in vitro systems. Although the EETs other than the 5,6-isomer, are quite stable chemically, they are quickly degraded enzymatically with the sEH accounting in many cases for much of the metabolism. This rapid degradation often made it difficult to associate biological effects with the administration of EETs and other lipid epoxides particularly in vivo. Thus, it is the power to inhibit the sEH that has facilitated the demonstration of many physiological processes associated with EETs and possibly other epoxy fatty acids. In the last few years it has become clear that major roles of the EETs include modulation of blood pressure and modulation of inflammatory cascades. There are a number of other physiological functions now associated with the EETs including angiogenesis, neurohormone release, cell proliferation, G protein signaling, modulation of ion channel activity, and a variety of effects associated with modulation of NFkappaB. More recently we observed a role of the EETs as modulated by sEHI in reducing non-neuropathic pain. The array of biological effects observed with sEHI illustrates the power of modulating the degradation of chemical mediators in addition to the modulation of their biosynthesis, receptor binding and signal transduction. Many of these biological effects can be modulated by sEHIs but also by the natural eicosanoids and their mimics all of which offer therapeutic potential.