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Journal of Lipid Research, Vol. 50, S52-S56, April 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Enzymology

Arachidonic acid cytochrome P450 epoxygenase pathway

Arthur A. Spector¹

Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA 52242

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

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

¹ To whom correspondence should be addressed. e-mail: arthur-spector{at}uiowa.edu

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 (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.

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

Abbreviations: BK_Ca, 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

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