Effects of dronedarone, amiodarone and their active metabolites on sequential metabolism of arachidonic acid to epoxyeicosatrienoic and dihydroxyeicosatrienoic acids

What is it about?

Cardiac enzymes such as cytochrome P450 2J2 (CYP2J2) metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic acids (EETs), which in turn are metabolized by soluble epoxide hydrolase (sEH) to dihydroxyeicosatrienoic acids (DHETs). As EETs and less potent DHETs exhibit cardioprotective and vasoprotective functions, optimum levels of cardiac EETs are paramount in cardiac homeostasis. Previously, we demonstrated that dronedarone, amiodarone and their main metabolites, namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA), potently inhibit human cardiac CYP2J2-mediated astemizole metabolism in vitro. In this study, we investigated the inhibition of recombinant human CYP450 enzymes (rhCYP2J2, rhCYP2C8, rhCYP2C9)-mediated AA metabolism and human recombinant sEH (rhsEH)-mediated EET metabolism by dronedarone, amiodarone, NDBD and NDEA.

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Why is it important?

Metabolites of polyunsaturated fatty acids (PUFAs) such as arachidonic acid (AA), collectively termed as eicosanoids are a structurally and functionally diverse class of endogenous lipid mediators. Apart from cyclooxygenases and lipoxygenases, AA is metabolized by an array of cytochrome P450 enzymes to form either epoxy (CYP1A2/2C8/2C9/2J2) or hydroxy metabolites (CYP4A1/4A2/4F12). Cytochrome P450 metabolites of AA namely epoxyeicosatrienoic acids (EETs) have come into limelight due to their notable vasoprotective, renoprotective and cardioprotective effects. CYP2C8, CYP2C9 and CYP2J2 are the main CYP450 enzymes catalyzing the metabolism of AA to regioisomeric EETs in human heart. Apart from CYP2J2, CYP2C8 and CYP2C9 are predominantly expressed in human cardiomyocytes and coronary arteries respectively. EETs exhibit vasodilatory, anti-inflammatory, angiogenic, anti-apoptotic and cardiac ion channel modulatory properties. Owing to the cardioprotective properties of EETs, cardiac-specific CYP2J2 overexpression mitigates a number of cardiac pathologies and doxorubicin-induced cardiotoxicity.

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