Cytochrome P450-dependent eicosanoid production and crosstalk.

PURPOSE OF REVIEW

This review highlights recent advances in eicosanoid biology, especially linked to the cytochrome P450 (CYP)/soluble epoxide hydrolase (sEH) axis in vascular biology and disease.

RECENT FINDINGS

Since the first reports that CYP-derived metabolites of arachidonic acid can elicit vascular smooth muscle hyperpolarization and relaxation, it has become clear that fatty acid epoxides and diols are important lipid signaling molecules. Targeting CYP epoxygenases in vivo is difficult as these enzymes are involved in the metabolism of many currently used clinical agents. However, targeting the sEH which metabolizes fatty acid epoxides to their corresponding diols is a highly effective way of manipulating levels of these lipid mediators in vivo. Indeed, sEH-/- mice are protected against the development of some forms of hypertension, and have altered adipocyte metabolism and insulin resistance, phenomena reproduced by selective sEH inhibitors.

SUMMARY

Given that elevated epoxide levels have been linked with decreased blood pressure and inflammation in animal models, inhibitors of the sEH are currently being developed for the treatment of human hypertension and inflammation/atherosclerosis. This review focuses on outlining recent insights gained in the beneficial as well as the potentially adverse aspects of interfering with the CYP/sEH axis.