Tang Lloyd Wei Tat, Lim Royden Yu Ren, Venkatesan Gopalakrishnan, Chan Eric Chun Yong
Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, 117543, Singapore.
Toxicol Res (Camb). 2022 Mar 28;11(2):311-324. doi: 10.1093/toxres/tfac017. eCollection 2022 Apr.
Deuteration is a chemical modification strategy that has recently gained traction in drug development. The replacement of one or more hydrogen atom(s) in a drug molecule with its heavier stable isotope deuterium can enhance its metabolic stability and pharmacokinetic properties. However, it remains uninterrogated if rational deuteration at bioactivation "hot-spots" could attenuate its associated toxicological consequences. Here, our preliminary screening with benzofuran antiarrhythmic agents first revealed that dronedarone and its major metabolite N-desbutyldronedarone elicited a greater loss of viability and cytotoxicity in human hepatoma G2 (HepG2) cells as compared with amiodarone and its corresponding metabolite N-desethylamiodarone. A comparison of dronedarone and its in-house synthesized deuterated analogue (termed poyendarone) demonstrated that deuteration could attenuate its in vitro toxicity in HepG2 cells by modulating the extent of mitochondrial dysfunction, reducing the dissipation of mitochondrial membrane potential, and evoking a distinct apoptotic kinetic signature. Furthermore, although pretreatment with the CYP3A inducer rifampicin or the substitution of glucose with galactose in the growth media significantly augmented the loss of cell viability elicited by dronedarone and poyendarone, a lower loss of cell viability was consistently observed in poyendarone across all concentrations. Taken together, our preliminary investigations suggested that the rational deuteration of dronedarone at its benzofuran ring reduces aberrant cytochrome P450 3A4/5-mediated bioactivation, which attenuated its mitochondrial toxicity in human hepatic HepG2 cells.
氘代是一种化学修饰策略，最近在药物开发中受到关注。用其较重的稳定同位素氘取代药物分子中的一个或多个氢原子可以增强其代谢稳定性和药代动力学性质。然而，生物活化“热点”处的合理氘代是否能减轻其相关的毒理学后果仍未得到研究。在此，我们用苯并呋喃抗心律失常药物进行的初步筛选首先显示，与胺碘酮及其相应代谢物N-去乙基胺碘酮相比，决奈达隆及其主要代谢物N-去丁基决奈达隆在人肝癌G2（HepG2）细胞中引起更大的活力丧失和细胞毒性。决奈达隆与其内部合成的氘代类似物（称为泊因达隆）的比较表明，氘代可通过调节线粒体功能障碍的程度、减少线粒体膜电位的耗散以及引发独特的凋亡动力学特征来减轻其在HepG2细胞中的体外毒性。此外，尽管用CYP3A诱导剂利福平预处理或在生长培养基中用半乳糖替代葡萄糖显著增加了决奈达隆和泊因达隆引起的细胞活力丧失，但在所有浓度下，泊因达隆的细胞活力丧失始终较低。综上所述，我们的初步研究表明，决奈达隆在其苯并呋喃环处的合理氘代减少了异常的细胞色素P450 3A4/5介导的生物活化，从而减轻了其在人肝HepG2细胞中的线粒体毒性。
