DELINEATING THE MECHANISMS OF CARDIAC ADVERSE EFFECTS OF DRONEDARONE: A ROLE OF CYP2J2

Abstract

Unlike amiodarone, dronedarone exacerbates cardiac failure despite the structural and pharmacological similarities. The exact causes for the cardiac adverse effects of dronedarone are unknown. CYP2J2, a predominantly cardiac CYP450 enzyme metabolizes arachidonic acid (AA) to cardioprotective and electrophysiologically active epoxyeicosatrienoic acids (EETs). In this project, I investigated mechanisms of dronedarone-induced cardiotoxicity with a spotlight on CYP2J2 and AA metabolic pathway. Firstly, I found that dronedarone potently inhibited CYP2J2 and associated EET formation. Secondly, dronedarone inhibited mitochondrial electron transport chain (ETC) complexes, uncoupled ETC, dissipated mitochondrial membrane potential and reduced intracellular ATP levels in rat cardiac cells. Moreover, EETs protected the cells from mitotoxic effects of dronedarone emphasizing their cardioprotective role. Finally, dronedarone significantly increased the beat rate variability and thereby in vitro drug-induced proarrhythmia in human cardiac cells. Our studies delineate possible mechanisms such as AA metabolic perturbation, mitochondrial toxicity and drug-induced proarrhythmia accountable for dronedarone-induced cardiac failure.