Inhibition of key cardiac enzyme by heart rhythm controlling drug
18 Apr 2016. NUS scientists have discovered for the first time that dronedarone inhibits human cardiac cytochrome P450 2J2 (CYP2J2).
Patients suffering from heart failure are susceptible to irregular heart rhythm (arrhythmia) and are routinely prescribed heart rhythm controlling drugs such as dronedarone. However, dronedarone is known to worsen heart complications in these patients via unknown mechanism. A team led by Prof Eric CHAN and PhD student Mr Aneesh KARKHANIS from the Department of Pharmacy in NUS has discovered for the first time that dronedarone and its major metabolite inhibit CYP2J2 via irreversible mechanism-based inactivation and multiple-mode reversible inhibition. As CYP2J2 is instrumental in metabolising arachidonic acid in the heart to downstream cardioactive epoxyeicosatrienoic acids, the inhibition of CYP2J2 by dronedarone has important clinical implications.
The chronic management of cardiac arrhythmia is an increasingly important healthcare priority given a rapidly ageing population. While amiodarone is a gold standard therapy of arrhythmia, it gives rise to thyroid and pulmonary toxicity. Hence dronedarone was designed with the aim of eliminating the organ-specific toxicity associated with amiodarone. Unfortunately, the use of dronedarone in patients with heart failure has been severely limited as it worsens the heart failure condition. Therefore, the scientists’ discovery of the inhibition of CYP2J2 by dronedarone is pertinent as it can help interrogate the underlying mechanism of its cardiac adverse effect and yield novel knowledge in designing safer heart rhythm controlling drugs.
As it is important to correlate the observed inhibition of CYP2J2 by dronedarone to the toxicity phenotype, the scientists aim to extend their study by testing the hypothesis using a novel human cardiac model such as the human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). This is a critical step in bridging their research discovery from bench to bedside.
The discovery made by the scientists is published in the Biochemical Pharmacology journal .
Figure shows the multiple-mode of inhibition of CYP2J2 heart rhythm controlling drugs [Image credits: KIOH Yan Qin, Dorinda]
A Karkhanis, HY Lam, G Venkatesan, SK Koh, CLL Chai, L Zhou, Y Hong, P Kojodjojo, ECY Chan. "Multiple modes of inibition of human cytochrome P450 2J2 by dronedarone, amiodarone and their active metabolites." Biochemical Pharmocology (2016) DOI: 10.1016/j.bcp.2016.03.005 In press.