Department of Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, China.
Eur J Pharmacol. 2011 Jan 10;650(1):138-44. doi: 10.1016/j.ejphar.2010.10.010. Epub 2010 Oct 15.
Fluconazole, a commonly used azole antifungal drug, can induce QT prolongation, which may lead to Torsades de Pointes and sudden death. To investigate the arrhythmogenic side effects of fluconazole, we studied the effect of fluconazole on human ether-a-go-go-related gene (hERG) K(+) channels (wild type, Y652A and F656C) expressed in human embryonic kidney (HEK293) cells using a whole-cell patch clamp technique, Western blot analysis and confocal microscopy. Fluconazole inhibited wild type hERG currents in a concentration-dependent manner, with a half-maximum block concentration (IC(50)) of 48.2±9.4μM. Fluconazole did not change other channel kinetics (activation and steady-state inactivation) of hERG channel. Mutations in drug- binding sites (Y652A or F656C) of the hERG channel significantly attenuated the hERG current blockade by fluconazole. In addition, fluconazole inhibited the trafficking of hERG protein by Western blot analysis and confocal microscopy, respectively. These findings indicate that fluconazole may cause acquired long QT syndrome (LQTS) via a direct inhibition of hERG current and by disrupting hERG protein trafficking, and the mutations Y652 and F656 may be obligatory determinants in inhibition of hERG current for fluconazole.
氟康唑是一种常用的唑类抗真菌药物，可引起 QT 间期延长，从而导致尖端扭转型室性心动过速和猝死。为了研究氟康唑的致心律失常副作用，我们使用全细胞膜片钳技术、Western blot 分析和共聚焦显微镜研究了氟康唑对人胚肾（HEK293）细胞中表达的人 ether-a-go-go 相关基因（hERG）K(+)通道（野生型、Y652A 和 F656C）的影响。氟康唑以浓度依赖性方式抑制野生型 hERG 电流，半数最大阻断浓度（IC(50)）为 48.2±9.4μM。氟康唑不改变 hERG 通道的其他通道动力学（激活和稳态失活）。hERG 通道药物结合部位（Y652A 或 F656C）的突变显著减弱了氟康唑对 hERG 电流的阻断作用。此外，氟康唑通过 Western blot 分析和共聚焦显微镜分别抑制 hERG 蛋白的转运。这些发现表明，氟康唑可能通过直接抑制 hERG 电流和破坏 hERG 蛋白转运，导致获得性长 QT 综合征（LQTS），而 Y652 和 F656 突变可能是氟康唑抑制 hERG 电流的必需决定因素。
