Karkhanis Aneesh V, Venkatesan Gopalakrishnan, Kambayashi Ryuichi, Leow Jacqueline Wen Hui, Han Marcus Qingrui, Izumi-Nakaseko Hiroko, Goto Ai, Pang Jeremy Kah Sheng, Soh Boon Seng, Kojodjojo Pipin, Sugiyama Atsushi, Chan Eric Chun Yong
Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore 117543, Singapore.
Department of Pharmacology, Faculty of Medicine, Toho University, Tokyo 143-8540, Japan.
Acta Pharm Sin B. 2022 Oct;12(10):3905-3923. doi: 10.1016/j.apsb.2022.03.008. Epub 2022 Mar 16.
Cytochrome P4502J2 (CYP2J2) metabolizes arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic acids (EETs). Dronedarone, an antiarrhythmic drug prescribed for treatment of atrial fibrillation (AF) induces cardiac adverse effects (AEs) with poorly understood mechanisms. We previously demonstrated that dronedarone inactivates CYP2J2 potently and irreversibly, disrupts AA-EET pathway leading to cardiac mitochondrial toxicity rescuable EET enrichment. In this study, we investigated if mitigation of CYP2J2 inhibition prevents dronedarone-induced cardiac AEs. We first synthesized a deuterated analogue of dronedarone (termed poyendarone) and demonstrated that it neither inactivates CYP2J2, disrupts AA-EETs metabolism nor causes cardiac mitochondrial toxicity . Our patch-clamp experiments demonstrated that pharmacoelectrophysiology of dronedarone is unaffected by deuteration. Next, we show that dronedarone treatment or CYP2J2 knockdown in spontaneously beating cardiomyocytes indicative of depleted CYP2J2 activity exacerbates beat-to-beat (BTB) variability reflective of proarrhythmic phenotype. In contrast, poyendarone treatment yields significantly lower BTB variability compared to dronedarone in cardiomyocytes indicative of preserved CYP2J2 activity. Importantly, poyendarone and dronedarone display similar antiarrhythmic properties in the canine model of persistent AF, while poyendarone substantially reduces beat-to-beat variability of repolarization duration suggestive of diminished proarrhythmic risk. Our findings prove that deuteration of dronedarone prevents CYP2J2 inactivation and mitigates dronedarone-induced cardiac AEs.
细胞色素P4502J2（CYP2J2）将花生四烯酸（AA）代谢为具有心脏保护作用的环氧二十碳三烯酸（EETs）。决奈达隆是一种用于治疗心房颤动（AF）的抗心律失常药物，可引发心脏不良反应（AEs），但其机制尚不清楚。我们之前证明，决奈达隆能有效且不可逆地使CYP2J2失活，破坏AA-EET途径，导致可通过EET富集挽救的心脏线粒体毒性。在本研究中，我们调查了减轻CYP2J2抑制是否能预防决奈达隆诱导的心脏AEs。我们首先合成了决奈达隆的氘代类似物（称为泊因达隆），并证明它既不会使CYP2J2失活，也不会破坏AA-EETs代谢，也不会引起心脏线粒体毒性。我们的膜片钳实验表明，决奈达隆的药物电生理学不受氘代的影响。接下来，我们发现，在自发搏动的心肌细胞中，决奈达隆治疗或CYP2J2基因敲低（表明CYP2J2活性降低）会加剧逐搏（BTB）变异性，这反映了致心律失常表型。相比之下，在表明CYP2J2活性得以保留的心肌细胞中，泊因达隆治疗产生的BTB变异性明显低于决奈达隆。重要的是，在持续性AF犬模型中，泊因达隆和决奈达隆具有相似的抗心律失常特性，而泊因达隆可显著降低复极持续时间的逐搏变异性，提示致心律失常风险降低。我们的研究结果证明，决奈达隆的氘代可防止CYP2J2失活，并减轻决奈达隆诱导的心脏AEs。
