Fluconazole inhibits hERG K(+) channel by direct block and disruption of protein trafficking.
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.
Department of Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, China.
Shengna
S
Han
Yu
Y
Zhang
Qiu
Q
Chen
Yanyan
Y
Duan
Tenghao
T
Zheng
Xiangjie
X
Hu
Zhao
Z
Zhang
Lirong
L
Zhang
D003001:Cloning, Molecular; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D015725:Fluconazole / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D009154:Mutation; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D026902:Potassium Channel Blockers; D015725:Fluconazole