EETs

Epoxyeicosatrienoic acids (EETs) are a family of signaling lipids derived from arachidonic acid by cytochrome P450 epoxygenases. They are produced in many tissues, including the vascular endothelium and brain, and exist as several regioisomers, such as 5,6-, 8,9-, 11,12-, and 14,15-EET. EETs act as local mediators that influence vascular function, inflammation, and tissue responses to injury.

Biosynthesis and metabolism occur when cytochrome P450 enzymes, notably CYP2C and CYP2J isoforms, convert arachidonic acid to epoxides. The signaling activity of EETs is short-lived because they are rapidly hydrolyzed by soluble epoxide hydrolase (sEH) to the corresponding dihydroxy derivatives (DHETs), which are typically less active. Inhibitors of sEH can raise endogenous EET levels and alter physiological responses.

Physiological and pathophysiological roles of EETs are diverse. They promote vasodilation in the microcirculation, in part by activating potassium channels in vascular smooth muscle and enhancing endothelial nitric oxide signaling. EETs also have anti-inflammatory and cytoprotective effects in several tissues and can influence renal function and neural signaling. The mechanisms are multifaceted and do not rely on a single, well-defined receptor; instead, EETs modulate multiple signaling pathways, including ion channels, kinases, and gene regulation.

Therapeutically, strategies that elevate EET levels or mimic their activity—such as sEH inhibitors or synthetic EET analogs—are being explored in preclinical models of hypertension, inflammation, ischemia-reperfusion injury, and pain. Measurement of EETs in biological samples typically uses LC-MS/MS, with interpretation influenced by rapid metabolism and variable tissue distribution.