Epoxyeicosatrienoic acids metabolism

VanRollins M, Kaduce TL, Knapp HR, Spector AA (1993) 14,15-Epoxyeicosatrienoic acid metabolism in endothelial cells. J Lipid Res 34 1931-1942... 

D. C. Zeldin, S. Wei, J. R. Falck, B. D. Hammock, J. P. Snapper, J. H. Capdevilla, Metabolism of Epoxyeicosatrienoic Acids by Cytosolic Epoxide Hydrolase Substrate Structural Determinants of Asymmetric Catalysis , Arch. Biochem. Biophys. 1995, 316, 443 - 451. 

Snider, N. T., Kornilov, A. M., Kent, U. M., and Hollenberg, R F. (2007). Anandamide metabolism by human liver and kidney microsomal cytochrome P450 enzymes to form hydroxyeicosatetraenoic and epoxyeicosatrienoic acid ethanolamides. J. Pharmacol. Exp. Ther. 321, 590—597. 

Arachidonic acid can also be metabolized to a variety of mediators, depending on the cell type. For example, lipoxygenase catalyzes the production of leu-kotrienes, and mixed-function oxygenases catalyze the production of epoxyeicosatrienoic acids. Collectively, these oxygenated metabolites may play a critical role in NSAIEt-induced nephrotic syndrome by shunting arachidonic acid metabolism from prostaglandins to... 

In order to study the metabolism of arachidonic acid by the cytochrome P450 complex, Nithipatikom et al. [38] developed a negative-ion LC-ESI-MS method for the quantitative determination of 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (EET), their corresponding diHET, and 20-HETE. The analytes and their deuterium-labelled internal standards were measured as [M-H] in selected-ion monitoring (SIM) mode. The detection limit was 1 pg (2-mm-ID column). 

CYP2J subfamily. CYP2J2 is the only gene of this subfamily. It is known to be expressed in many extrahepatic tissues and may play a role in the oxidative bioactivation of arachidonic acid to form epoxyeicosatrienoic acids, which modulate bronchial smooth muscle tone and airway transepithelial ion transport [53], CYP2J2 is also active toward other compounds such as linoleic acid and testosterone. Recently, it has been reported that CYP2J2 is involved in the intestinal first-pass metabolism of an antihistamine drug, astemizole [54],... 

Fig. 12. Metabolism of arachidonic acid by cytochrome P-450 enzymes and the formation of three structurally distinct metabolite families.

Another fate of arachidonic acid with potential relevance to atherosclerosis is cytochrome P450 monooxygenase-derived metabolism to epoxyeicosatrienoic acids (EETs) (Chapter 12), which may also be formed non-enzymatically by the interaction of arachidonic acid with free radicals (D.D. Gutterman, 2006). EET synthesis in cultured endothelial cells can be induced by LDL, and EETs are found both in LDL and in human atherosclerotic lesions. Biological effects of EETs include potentially anti-atherogenic effects, such as vasodilatation and prevention of platelet aggregation, and atherogenic responses, such as increased monocyte adhesion. 

Regiospecific and enantioselective metabolism of 8,9-epoxyeicosatrienoic acids by cyclooxygenase. Biochem. Biophys. Res. Commun. 183, 138-143. 

Capdevila, J., P. Mosset, P. Yadagiri, Sun Lumin, and J.R. Falck (1988). NADPH-Dependent microsomal metabolism of 14,15-epoxyeicosatrienoic acid to diepoxides and epoxyalcohols. Arch. Biochem. Biophys. 261, 122-132. 

Keeney, D.S., C. Skinner, S. Wei, T. Friedberg, and M R. Waterman (1998). A keratinocyte-specific epoxygenase, CYP2B12, metabolizes arachidonic acid with unusual selectivity, producing a single major epoxyeicosatrienoic acid. J. Biol. Chem. 273, 9279-9284. 

Multiple CYPs metabolize arachidonic acid. For instance, epoxyeicosatrienoic acids (EETs) can be formed by CYP epoxygenases, primarily CYP2C and CYP2J. Their biosynthesis can be altered by pharmacological, nutritional, and genetic factors that affect CYP expression (see Chapter 3). 

Microsomal cytochrome P450 (CYP) monooxygenases are better known for their role in xenobiotic metabolism, a process which is crucial in the therapeutic and toxic effects associated with pharmaceuticals. However, they are also involved in the biosynthetic transformation of PUFA to epoxy-, mono-hydroxylated- and di-hydroxylated-metabolites. When AA is the substrate, CYP-reactions produce a range of epoxyeicosatrienoic acids (EET), hydroxyeicosatrienoic acids (HETE), and dihydroxyeicosatrienoic acids (DHET) (Eigure 3.5). 

Besides FAME and SAME, other fatty acids have also been shown to have vasoactive properties. For example, AA is a 20-carbon polyunsaturated (d-6 fatty acid (20 4 n-6), which is an essential fatty acid found in peanut oil and eggs/meats. AA has been shown to cause endothelium- and iC-independent vasodilation [13] metabolized by cytochrome P450 enzymes in the liver to form epoxyeicosatrienoic acid (EET) (Figure 2). EETs are produced in the vascular endothelium and causes potent vasodilation in renal, mesenteric, coronary, and cerebral arterioles in a variety of mammalian species [14-17]. EETs hyperpolarize VSMCs by activating calcium-activated potassium chaimels (Kca) chaimels. Several investigators have proposed that EET may serve as a possible candidate for endothelium-derived hyperpolarizing factor (The exact structure and identity of EDHF is currently unknown) due to the fact that EETs are produced in the endothelium [18]. EETs can lower systemic blood pressure in SHR-hypertensive rats suggesting possible therapeutic validity [19, 20]. 

Fig. 13.1 Arachidonic acid is released from lipid bilayers by phospholipase Aj (PLA ) and then metabolized by cyclooxygenase COX), cytochrome P450 (CYP), and lipoxygenase LOX) enzymes to form prostaglandins PGs), epoxyeicosatrienoic acids EETs), hydroxyeicosa-tetraenoic acids HETEs), leukotrienes (LTs), and lipox-ins (LXs)...

Fig. 13.2 Arachidonic acid (AA) is metabolized by cy- form epoxyeicosatrienoic acids (EETs), mid-chain hy-tochrome P450 (CYP) monooxygenases in epoxygenase, droxyeieosatetraenoic acids (HETEs), and co/co-l HETEs, lipoxygenase-like, and co/co-l hydroxylase reactions to respectively...

Zosmer A, Rendell NB, Taylor GW, Elder MG, Sullivan MH (1995) Formation and metabolism of 14,15-epoxyeicosatrienoic acid by human reproductive tissues. Biochim Biophys Acta 1258 234-240... 

Fig. 4.1. Overview of the major pathways ofarachidonate metabolism in vertebrate tissues. Abbre-via tions dihydroxyeicosa trienoic acid, DHT epoxyeicosatrienoic acid, EET hydro(per)oxyeicosa-tetraenoic acid, H(P)ETE ieuko-triene, LT prostaglandin, PC. 

Cytochrome P450 metabolism of arachidonate requires molecular oxygen and NADPH, and consists of two main monooxygenase reactions, illustrated in Figure 4.26 (see ref. 149 for review). First, the epoxidation of the arachidonate double bonds results in the formation of four isomeric epoxyeicosatrienoic acids 5,6-, 8,9-, 11,12-, and 14,15-EET. These metabolites are subsequently hydrolyzed by an epoxide hydrolase activity to yield... 

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