Endocannabinoid Virodhamine Is an Endogenous Inhibitor of Human Cardiovascular CYP2J2 Epoxygenase

Abstract

The human body contains endogenous cannabinoids (endocannabinoids) that elicit similar effects as Δ9-tetrahydrocanabinol, the principal bioactive component of cannabis. The endocannabinoid virodhamine (O-AEA) is the constitutional isomer of the well-characterized cardioprotective and anti-inflammatory endocannabinoid anandamide (AEA). The chemical structures of O-AEA and AEA contain arachidonic acid (AA) and ethanolamine, however AA in O-AEA is connected to ethanolamine via an ester linkage whereas AA in AEA is connected through an amide linkage. We show that O-AEA is found at 9.6 fold higher levels than AEA in porcine left ventricle and is involved in regulating blood pressure and cardiovascular function. On a separate note, the cytochrome P450 (CYP) epoxygenase CYP2J2 is the most abundant CYP in the heart where it catalyzes the metabolism of AA and AA-derived eCBs to bioactive epoxides that are involved in diverse cardiovascular functions. Herein, using competitive binding studies, kinetic metabolism measurements, molecular dynamics and wound healing assays we have shown that O-AEA is an endogenous inhibitor of CYP2J2 epoxygenase. Together, the role of O-AEA as an endogenous eCB inhibitor of CYP2J2 may provide a new mode of regulation to control the activity of cardiovascular CYP2J2 in vivo and suggests a potential cross talk between the cardiovascular endocannabinoids and cytochrome P450 system.

Anti-inflammatory dopamine- and serotonin-based endocannabinoid epoxides reciprocally regulate cannabinoid receptors and the TRPV1 channel

“…3 and 4). We have previously observed complex inhibition and regioselectivity changes for endogenous substrates of CYP2J2 34,49,50 ; however, this is the first report of a potentiation of CYP2J2 metabolism. Overall, the finding implies that the co-substrate AEA potentiates the metabolism of NADA and NA5HT by CYP2J2 in vitro.…”

“…A 3D global fit of the data ( Supplementary Fig. 28) yields a K i of 7.50 ± 0.88 μM for the inhibition of AEA by NADA, which is among the strongest endogenous inhibitors of CYP2J2 as compared to virodhamine 49 . NA5HT was a noncompetitive inhibitor (Eq.…”

Identification of Potential Metabolic Markers of Hypertension in Chinese Children

“…Ethanolamine and sn-glycero-3-phosphocholine necessary for the biosynthesis of phosphatidylethanolamine and phosphatidylcholine (KEGG map00564) have been implicated in the regulation of endothelial cell function and in the development of atherosclerotic lesions [ 27 ]. In addition, anandamide, which is formed enzymatically by the condensation of arachidonic acid with ethanolamine, has been demonstrated to be relevant in the regulation of the cardiovascular system given its ability to induce vasorelaxation in the vessel [ 34 , 35 ]. Ethanolamine also affects left ventricle diastolic function and cardiac fibrosis [ 36 ].…”

Soluble Epoxide Hydrolase Regulation of Lipid Mediators Limits Pain

“…Of note, the endocannabinoid AEA can also be metabolized by cytochrome P450 (CYP450) enzymes into the epoxyeicosatrienoic acid ethanolamines, EET-EAs [46,47], and these epoxy-AEA metabolites are further substrate for the sEH enzyme [48]. Interestingly, the ester-linked constitutional isomer AEA (O-AEA, virodhamine) has been identified as an endogenous inhibitor of CYP2J2 [49], and this inhibition stimulated the migration of endothelial cells and inhibited wound healing. Because of the abundance of CYP2J2 in the heart, and based on the above findings, caution must be taken when considering targeting CYP2J2 systemically with repurposed drugs [50].…”