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首页> 外文期刊>Canadian Journal of Physiology and Pharmacology >Blockage of hERG current and the disruption of trafficking as induced by roxithromycin
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Blockage of hERG current and the disruption of trafficking as induced by roxithromycin

机译：罗红霉素诱导的hERG电流阻断和运输中断

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摘要

Roxithromycin is an oral macrolide antibiotic agent that has been repeatedly reported to provoke excessive prolongation of the Q-T interval and torsades de pointes in clinical settings. To investigate the mechanisms underlying the arrhyth-mogenic side effects of roxithromycin, we studied the molecular mechanisms of roxithromycin on human ether-a-go-go-related gene (hERG) K~+ channels expressed in human embryonic kidney (HEK293) cells. Roxithromycin was found to inhibit wild-type (WT) hERG currents in a concentration-dependent manner with a half-maximum block concentration (IC_(50)) of 55.8 ± 9.1 mumol/L. S6 residue hERG mutants (Y652A and F656C) showed reduced levels of hERG current blockage attributable to roxithromycin. Roxithromycin also inhibited the trafficking of hERG protein to the cell membrane, as confirmed by Western blot analysis and confocal microscopy. These findings indicate that roxithromycin may cause acquired long-QT syndrome via direct inhibition of hERG current and by disruption of hERG protein trafficking. Mutations in drug-binding sites (Y652A or F656C) of the hERG channel were found to attenuate hERG current blockage by roxithromycin, but did not significantly alter the disruption of trafficking.
机译：罗红霉素是一种口服大环内酯类抗生素，据反复报道会引起Q-T间隔的过度延长和临床环境中的扭转性疾病。为了研究罗红霉素导致心律失常的副作用的机制，我们研究了罗红霉素对人胚胎肾脏（HEK293）细胞中表达的人以太相关基因（hERG）K〜+通道的分子机制。发现罗红霉素以浓度依赖的方式抑制野生型（WT）hERG电流，最大阻断浓度（IC_（50））的一半为55.8±9.1μmol/ L。 S6残基hERG突变体（Y652A和F656C）显示出可归因于罗霉素的hERG电流阻滞水平降低。 Western blot分析和共聚焦显微镜证实，罗红霉素还抑制了hERG蛋白向细胞膜的运输。这些发现表明罗红霉素可能通过直接抑制hERG电流和破坏hERG蛋白的运输而导致获得性长QT综合征。发现hERG通道的药物结合位点（Y652A或F656C）发生了突变，从而减弱了罗红霉素对hERG的电流阻断作用，但并未显着改变贩运的中断。

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