14,15-eet

(±)14(15)-EET is a metabolite of arachidonic acid that is formed via epoxidation of arachidonic acid by cytochrome P450.[1],[2] It prevents increases in leukotriene B4, ICAM-1, and chemokine (C-C motif) ligand 1 (CCL2) induced by oxidized LDL in primary rat pulmonary artery endothelial cells (RPAECs) when used at a concentration of 1 μM.[3] (±)14(15)-EET induces dilation of preconstricted isolated canine coronary arterioles (EC50 = 0.2 pM).[4] It reduces myocardial infarct size as a percentage of the area at risk in a canine model of ischemia-reperfusion injury induced by left anterior descending coronary artery (LAD) occlusion when administered at a dose of 0.128 mg kg prior to occlusion or reperfusion.[5] Reference：[1]. Chacos, N., Falck, J.R., Wixtrom, C., et al. Novel epoxides formed during the liver cytochrome P-450 oxidation of arachidonic acid. Biochem. Biophys. Res. Commun. 104(3), 916-922 (1982).[2]. Oliw, E.H., Guengerich, F.P., and Oates, J.A. Oxygenation of arachidonic acid by hepatic monooxygenases. Isolation and metabolism of four epoxide intermediates. J. Biol. Chem. 257(7), 3771-3781 (1982).[3]. Jiang, J.-X., Zhang, S.-J., Xiong, Y.-K., et al. EETs attenuate ox-LDL-induced LTB4 production and activity by inhibiting p38 MAPK phosphorylation and 5-LO BLT1 receptor expression in rat pulmonary arterial endothelial cells. PLoS One 10(6), e0128278 (2015).[4]. Oltman, C.L., Weintraub, N.L., VanRollins, M., et al. Epoxyeicosatrienoic acids and dihydroxyeicosatrienoic acids are potent vasodilators in the canine coronary microcirculation. Circ. Res. 83(9), 932-939 (1998).[5]. Nithipatikom, K., Moore, J.M., Isbell, M.A., et al. Epoxyeicosatrienoic acids in cardioprotection: Ischemic versus reperfusion injury. Am. J. Physiol. Heart Circ. Physiol. 291(2), H537-H542 (2006).

14,15-Epoxyeicosatrienoic acid（14,15-EET）是花生四烯酸的代谢物，具有显著的体内抑制血小板聚集的作用。此外，它能促进星形胶质细胞清除Aβ，因而在老年痴呆症的研究中具有潜在应用价值。

Arachidonic acid is metabolized in the vascular endothelium to epoxytrienoic acids (EETs or EpETrEs) by cytochrome P450 enzymes. The EETs are released in response to acetylcholine, bradykinin, arachidonic acid, or cyclic stretch. (±)14(15)-EET-SI is the methyl sulfonamide analog of 14(15)-EET. This substitution results in a metabolically more stable compound because it is not sensitive to β-oxidation or membrane esterification. (±)14(15)-EET-SI is equipotent to 14(15)-EET in vascular agonist activity as measured by relaxation of precontracted bovine coronary arteries. In addition, 14(15)-EET and the methyl sulfonamide analog both stimulate tyrosine phosphorylation and induce mitogenesis in renal epithelial cells.

N-Desbutyl dronedarone is an active metabolite of the antiarrhythmic agent dronedarone .1,2,3It is formed from dronedarone by cytochrome P450s (CYPs) and monoamine oxidase (MAO) in human hepatocyte preparations.4N-Desbutyl dronedarone inhibits the binding of 3,3’,5-triiodo-L-thyronine to the thyroid hormone receptors TRα1and TRβ1(IC50s = 59 and 280 μM for the chicken and human receptors, respectively).1It inhibits CYP2J2-mediated formation of 14,15-EET from arachidonic acid and soluble epoxide hydrolase-mediated formation of 14,15-DHET from 14,15-EET (IC50s = 1.59 and 2.73 μM, respectively, in cell-free assays).2N-Desbutyl dronedarone decreases intracellular ATP levels in H9c2 rat cardiomyocytes (IC50= 1.07 μM) and inhibits mitochondrial complex I, also known as NADH dehydrogenase, and mitochondrial complex II, also known as succinate dehydrogenase, activities in isolated rat heart mitochondria (IC50s = 11.94 and 24.54 μM, respectively).3 1.Van Beeren, H.C., Jong, W.M.C., Kaptein, E., et al.Dronerarone acts as a selective inhibitor of 3,5,3’-triiodothyronine binding to thyroid hormone receptor-α1: in vitro and in vivo evidenceEndocrinology144(2)552-558(2003) 2.Karkhanis, A., Tram, N.D.T., and Chan, E.C.Y.Effects of dronedarone, amiodarone and their active metabolites on sequential metabolism of arachidonic acid to epoxyeicosatrienoic and dihydroxyeicosatrienoic acidsBiochem. Pharmacol.146188-198(2017) 3.Karkhanis, A., Leow, J.W.H., Hagen, T., et al.Dronedarone-induced cardiac mitochondrial dysfunction and its mitigation by epoxyeicosatrienoic acidsToxicol. Sci.163(1)79-91(2018) 4.Klieber, S., Arabeyre-Fabre, C., Moliner, P., et al.Identification of metabolic pathways and enzyme systems involved in the in vitro human hepatic metabolism of dronedarone, a potent new oral antiarrhythmic drugPharmacol. Res. Perspec.2(3)e00044(2014)

Epoxyeicosatrienoic acids (EETs), such as 11(12)-EET and 14(15)-EET, are cytochrome P450 metabolites of arachidonic acid that have been identified as endothelium-derived hyperpolarizing factors with vasodilator activity. 14,15-EE-5(Z)-E is a structural analog of 14,15-epoxyeicosatrienoic acids (14,15-EET) that antagonizes EET-induced relaxation of vascular smooth muscle. Relaxation of U46619-constricted bovine arteries by 14,15-EET could be inhibited approximately 80% by 14,15-EE-5(Z)-E at a concentration of 10 μM. 14,15-EE-5(Z)-E does not appear to antagonize nitric oxide- or iloprost-mediated vascular relaxation.

Epoxyeicosatrienoic acids (EETs), such as 11(12)-EET and 14(15)-EET, are cytochrome P450 metabolites of arachidonic acid that have been identified as endothelium-derived hyperpolarizing factors with vasodilator activity. 14,15-EE-8(Z)-E is a structural analog of 14(15)-EET that demonstrates potent vasodilator agonist activity in bovine coronary arteries similar to that of 14(15)-EET.

14S(15R)-EET is an oxylipin and a cytochrome P450 metabolite of arachidonic acid .114S(15R)-EET binds to isolated guinea pig monocytes with a Kivalue of 612.5 nM in a competitive binding assay using [3H]14(15)-EET.2It induces dilation of precontracted isolated canine epicardial arterioles (EC50= 4 pM) and denuded porcine subepicardial arterioles (EC50= 3 pM).3Unlike 14R(15S)-EET, 14S(15R)-EET does not inhibit COX in enzyme assays or isolated platelets.4 1.Daikh, B.E., Lasker, J.M., Raucy, J.L., et al.Regio- and stereoselective epoxidation of arachidonic acid by human cytochromes P450 2C8 and 2C91J. Pharmacol. Exp. Ther.271(3)1427-1433(1994) 2.Wong, P.Y.-K., Lai, P.-S., and Falck, J.R.Mechanism and signal transduction of 14 (R), 15 (S)-epoxyeicosatrienoic acid (14,15-EET) binding in guinea pig monocytesProstaglandins Other Lipid Mediat.62(4)321-333(2000) 3.Zhang, Y., Oltman, C.L., Lu, T., et al.EET homologs potently dilate coronary microvessels and activate BKCa channelsAm. J. Physiol. Heart Circ. Physiol.280(6)H2430-H2440(2001) 4.Fitzpatrick, F.A., Ennis, M.D., Baze, M.E., et al.Inhibition of cyclooxygenase activity and platelet aggregation by epoxyeicosatrienoic acidsJ. Biol. Chem.261(2)15334-15338(1986)