Enzymology
Arachidonic acid cytochrome P450 epoxygenase pathway

https://doi.org/10.1194/jlr.R800038-JLR200Get rights and content
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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.

dihydroxyeicosatrienoic acid
eicosapentaenoic acid
endocannabinoids
epoxyeicosatrienoic acid
2-epoxyeicosatrienoylglycerol
fatty acid binding protein
peroxisome proliferator-activated receptor
phospholipids
soluble epoxide hydrolase

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Work from my laboratory cited in this review was supported by National Institutes of Health grants HL049264 and HL072845.

Abbreviations

BKCa, large-conductance Ca2+-activated K+ channels

CYP, cytochrome P450

cPLA2, cytosolic phospholipase A2

DHET, dihydroxyeicosatrienoic acid

EDHF, endothelium-derived hyperpolarizing factor

EET, epoxyeicosatrienoic acid

17,18-EETr, 17,18-epoxyeicosatetraenoic acid

FABP, fatty acid binding protein

PPAR, peroxisome proliferator-activated receptor

sEH, soluble epoxide hydrolase

Published, JLR Papers in Press, October 23, 2008.