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Endocannabinoid Virodhamine Is an Endogenous Inhibitor of Human Cardiovascular CYP2J2 Epoxygenase

Carnevale, Lauren N., Arango, Andres S., Arnold, William R., Tajkhorshid, Emad, Das, Aditi
Biochemistry 2018 v.57 no.46 pp. 6489-6499
arachidonic acid, bioactive compounds, blood pressure, cannabinoids, catalytic activity, constitutional isomers, cytochrome P-450, enzymes, epoxides, ethanolamine, heart, humans, metabolism, molecular dynamics, swine
The human body contains endogenous cannabinoids (endocannabinoids) that elicit effects similar to those of 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. O-AEA is involved in regulating blood pressure and cardiovascular function. We show that O-AEA is found at levels 9.6-fold higher than that of AEA in porcine left ventricle. 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. As a result, 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 the cytochrome P450 system.