title: Blockade of HERG cardiac K+ current by antifungal drug miconazole.
abstract: 1. Miconazole, an imidazole antifungal agent, is associated with acquired long QT syndrome and ventricular arrhythmias. Miconazole increases the plasma concentration of QT-prolonging drugs by inhibiting the hepatic cytochrome P450 metabolic pathway, but whether it has direct effects on cardiac ion channels has not been elucidated. 2. To determine the mechanism underlying these clinical findings, we investigated the effect of miconazole on human ether-a-go-go-related gene (HERG) K+ channels. 3. HERG channels were heterologously expressed in human embryonic kidney 293 (HEK293) cells and whole-cell currents were recorded using a patch-clamp technique (23 degrees C). 4. Miconazole inhibited HERG peak tail current in a concentration-dependent manner (0.4-40 microM) with an IC50 of 2.1 microM (n=3-5 cells at each concentration, Hill coefficient 1.2). HERG block was not frequency-dependent. It required channel activation, occurred rapidly, and had very slow dissociation properties. 5. The activation curve was shifted in a negative direction (V(1/2): -9.5+/-2.3 mV in controls and -15.3+/-2.4 mV after 4 microM miconazole, P<0.05, n=6). Miconazole did not change other channel kinetics (activation, deactivation, onset of inactivation, recovery from inactivation, steady-state inactivation). 6. The S6 domain mutation, F656C, abolished the inhibitory action of miconazole on HERG current indicating that miconazole preferentially binds to an aromatic amino-acid residue within the pore-S6 region. 7. Our findings indicate that miconazole causes HERG channel block by binding to a common drug receptor, and this involves preferential binding to activated channels. Thus, miconazole prolongs the QT interval by direct inhibition of HERG channels.
authors.affiliation: Second Department of Internal Medicine, University of Occupational and Environmental Health Japan, Kitakyushu, Japan.
authors.forename: Kan
authors.initials: K
authors.lastname: Kikuchi
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Nagatomo
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Abe
authors.forename: Kazunobu
authors.initials: K
authors.lastname: Kawakami
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Duff
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Makielski
authors.forename: Craig T
authors.initials: CT
authors.lastname: January
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Nakashima
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000935:Antifungal Agents / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D020128:Inhibitory Concentration 50; D008133:Long QT Syndrome; D008825:Miconazole / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024642:Potassium Channels, Voltage-Gated
chemical_list: D000935:Antifungal Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D008825:Miconazole