Soluble Epoxide Hydrolase - Function

Function

sEH has a restricted substrate selectivity, and has not been shown to hydrolyze any toxic or mutagenic xenobiotics. Conversely, the sEH plays a major role in the in vivo metabolism of endogenous lipid epoxides, such as the EETs and squalene oxide, a key intermediate in the synthesis of cholesterol. EETs are lipid signaling molecules that function in an autocrine and paracrine manner. They are produced when arachidonic acid is metabolized by cytochrome p450s (CYPs). These enzymes epoxidize the double bonds in arachidonic acid to form four regioisomers. Arachidonic acid is also the precursor of the prostaglandins and the leukotrienes, which are produced by cyclooxygenases and lipoxygenases, respectively. These lipids play a role in asthma, pain, and inflammation and are the targets of several pharmaceuticals. The EET receptor or receptors have not been identified, but several tools for the study of EET biology have been developed, these include small molecule sEH inhibitors, EET mimics and sEH genetic models. Through the use of these tools, as well as the EETs themselves, the EETs have been found to have anti-inflammatory and vasoactive properties. Several disease models have been used, including Ang-II induced hypertension and surgical models of brain and heart ischemia. In vitro models such as isolated coronary rings and platelet aggregation assays have also been employed.

The proposed role of sEH in the regulation of hypertension can be used as a simple model of sEH function in the kidney. Here the EETs are vasodilatory, and can be thought of as balancing other vasoconstrictive signals. sEH hydrolyzes the EETs to form the dihydroxyeicosatrienoic acids (DHETs). These molecules are more water soluble and are more easily metabolized by other enzymes, so the vasodilatory signal is removed from the site of action through excretion, tipping the balance of vasoconstrictive and vasodilatory signals towards vasoconstriction. This change in the lipid signaling increases vascular resistance to blood flow and blood pressure. By reducing sEH epoxide hydrolase activity, and thereby shutting off the major route of metabolism of the EETs, the levels of these molecules can be stabilized or increased, increasing blood flow and reducing hypertension. This reduction in sEH activity can be achieved in genetic models in which sEH has been knocked out, or through the use of small molecule sEH inhibitors.

This simplified model is complicated by a number of factors in vivo. The EETs display different properties in different vascular beds. The DHETs are more readily excreted, but they have yet to be fully characterized, and may possess biological properties themselves, complicating the balance of signals described in the simplified model. There are epoxides of other lipids besides arachidonic acid such as the omega three docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) epoxides. These lipid epoxides have been shown to have biological effects in vitro in which they inhibit platelet aggregation. In fact, in some assays they are more potent than the EETs. Other epoxidized lipids include the 18-carbon leukotoxin and isoleukotoxin. The diepoxide of linoleic acid can form tetrahydrofuran diols,

The phosphatase activity of sEH has been shown to hydrolyze in vitro lipid phosphates such as terpene pyrophosphates or lysophosphatidic acids. However, its biological role is still unknown.