Arachidonic acid cytochrome P450 epoxygenase pathway

Abstract

Cytochrome P450 (CYP) epoxygenases convert arachidonic acid to four epoxyeicosatrienoic acid (EET) regioisomers, 5,6-, 8,9-, 11,12-, and 14,15-EET, that function as autacrine and paracrine mediators. EETs produce vascular relaxation by activating smooth muscle large-conductance Ca 21 -activated K 1 channels (BK Ca ). In addition, they have anti-inflammatory effects on blood vessels and in the kidney, promote angiogenesis, and protect ischemic myocardium and brain. CYP epoxygenases also convert eicosapentaenoic acid to vasoactive epoxy-derivatives, and endocannabinoids containing 11,12-and 14,15-EET are formed. Many EET actions appear to be initiated by EET binding to a membrane receptor that activates ion channels and intracellular signal transduction pathways. However, EETs also are taken up by cells, are incorporated into phospholipids, and bind to cytosolic proteins and nuclear receptors, suggesting that some functions may occur through direct interaction of the EET with intracellular effector systems. Soluble epoxide hydrolase (sEH) converts EETs to dihydroxyeicosatrienoic acids (DHETs). Because this attenuates many of the functional effects of EETs, sEH inhibition is being evaluated as a mechanism for increasing and prolonging the beneficial actions of EETs. Epoxyeicosatrienoic acids (EET) are epoxide derivatives of arachidonic acid. They are formed by cytochrome P450 (CYP) epoxygenases and function as lipid mediators. Epoxidation can occur at any of the four double bonds of arachidonic acid, giving rise to four regioisomers, 5,6-, 8,9-, 11,12-, and 14,15-EET. EETs are synthesized in the endothelium and activate large-conductance Ca 21 -activated K 1 channels (BK Ca ), causing hyperpolarization of the vascular smooth muscle and vasorelaxation. Thus, EETs function as an endothelium-derived hyperpolarizing factor (EDHF) in a number of vascular beds, including the coronary and renal circulations, producing a decrease in blood pressure. Soluble epoxide hydrolase (sEH), which converts EETs to dihydroxyeicosatrienoic acids (DHETs), attenuates many of the functional effects of EETs. These seminal findings have been described in a number of detailed reviews (1-4). Recent results with cultured cells and animal models indicate that EETs have additional potentially beneficial effects on the vascular system, heart, kidneys, and nervous system, and many current studies are directed at these actions (5-9). The other current emphasis is on sEH inhibition as a therapeutic strategy for increasing the beneficial effects of EETs (10, 11). EET SYNTHESIS, METABOLISM, AND FUNCTIONEETs are synthesized by cells that express CYP epoxygenase activity. As illustrated in Fig. 1, these enzymes act on arachidonic acid released from phospholipids when cytosolic phospholipase A 2 (cPLA 2 ) is activated (12). The epoxygenase inserts an oxygen atom on a carbon attached to one of the double bonds of arachidonic acid, and the double bond is reduced as the epoxide forms. Each CYP epoxygenase produces several regioisomers, with one for...

A non‐canonical caleosin from Arabidopsis efficiently epoxidizes physiological unsaturated fatty acids with complete stereoselectivity

“…Increasing the desaturation of C18 fatty acids seemed to greatly facilitate their epoxidation (Table 1). We have confirmed this result by incubating [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]linoleic and [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]linolenic acids in the presence of cumene hydroperoxide and PXG4. Epoxidation occurred readily, i.e.…”

“…The biosynthesis of these metabolites involves various cytochrome P450 isoforms that oxidize unsaturated fatty acids into a multitude of bioactive epoxygenated fatty acid (EFA) regioisomers [4][5][6][7].…”

11,12-Epoxyeicosatrienoic acid induces vasodilator response in the rat perfused mesenteric vasculature

“…The hyperpolarizing effect that results due to the activation of BK Ca channels will lead to relaxation of the smooth muscle in the vasculature, causing hyperpolarization of the vascular smooth muscle and consequently vasorelaxation. Therefore, EETs are recognized to act as ‘endothelium‐derived hyperpolarizing factor’ (EDHF) in several components of the vasculature such as the renal and coronary blood vessels, resulting in reduction of the blood pressure 1, 2. Several effects of EET have been shown to occur due to its binding to a membrane receptor which leads to the activation of ion channels and signalling transduction pathways 2.…”

“…Several effects of EET have been shown to occur due to its binding to a membrane receptor which leads to the activation of ion channels and signalling transduction pathways 2. It is also reported that cells can take up EETs and integrate them into phospholipids, binding to cytosolic proteins and nuclear receptors 1. It is possible that they contribute to the pathogenesis of several disorders 3.…”

“…It is possible that they contribute to the pathogenesis of several disorders 3. The conversion of EETs to dihydroxyeicosatrienoic acids (DHET) is attained by soluble epoxide hydrolase (sEH) 1. The main EET catabolic pathway is conversion to the corresponding DHET by sEH.…”