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Review
. 2009 Apr;50 Suppl(Suppl):S52-6.
doi: 10.1194/jlr.R800038-JLR200. Epub 2008 Oct 23.

Arachidonic acid cytochrome P450 epoxygenase pathway

Arthur A Spector  1
Affiliations
Review

Arachidonic acid cytochrome P450 epoxygenase pathway

Arthur A Spector. J Lipid Res. 2009 Apr.

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 Ca2+-activated K+ channels (BKCa). 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.

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Figures

Fig. 1.
Fig. 1.
Epoxyeicosatrienoic acid (EET) synthesis, metabolism, and function. EETs are synthesized by cells that express cytochrome P450 (CYP) epoxygenase. When cytosolic phospholipase A2 (cPLA2) is activated, the arachidonic acid hydrolyzed from intracellular phospholipids is converted to EETs. The EETs are released into the extracellular fluid and produce paracrine effects on other cells in the local environment. This may occur through EET binding to a receptor that is coupled to a signal transduction system, or through uptake and direct interaction of the EET with intracellular effector systems. Cytosolic fatty acid binding protein (FABP) may facilitate the uptake of EETs and modulate their incorporation into cell phospholipids and conversion to dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH). EETs also can produce autacrine effects through similar intracellular or receptor-mediated mechanisms.
Fig. 2.
Fig. 2.
sEH inhibition enhances EET function. Conversion of EET to DHET by sEH is the main pathway of EET metabolism. This attenuates most functional effects of EETs, making sEH a logical target for increasing and prolonging the actions of EETs. sEH inhibition decreases DHET formation and leads to intracellular EET accumulation. This results in more EET incorporation into phospholipids and utilization by other metabolic pathways, including β-oxidation and chain-elongation. Functional responses are increased because of the larger amounts of intracellular unesterified EET and EET-containing phospholipids. Furthermore, more EET is released when intracellular phospholipids are hydrolyzed, maintaining the increased intracellular concentration of unesterified EET.
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