title: Blockage of hERG current and the disruption of trafficking as induced by roxithromycin.
abstract: 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 arrhythmogenic side effects of roxithromycin, we studied the molecular mechanisms of roxithromycin on human ether-à-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 (IC50) of 55.8 ± 9.1 μmol/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.
authors.affiliation: a Department of Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, China.
authors.forename: Sheng-Na
authors.initials: SN
authors.lastname: Han
authors.forename: Song-Hua
authors.initials: SH
authors.lastname: Yang
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yan-Yan
authors.initials: YY
authors.lastname: Duan
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Sun
authors.forename: Qiu
authors.initials: Q
authors.lastname: Chen
authors.forename: Tian-Li
authors.initials: TL
authors.lastname: Fan
authors.forename: Zhen-Kun
authors.initials: ZK
authors.lastname: Ye
authors.forename: Chen-Zheng
authors.initials: CZ
authors.lastname: Huang
authors.forename: Xiang-Jie
authors.initials: XJ
authors.lastname: Hu
authors.forename: Zhao
authors.initials: Z
authors.lastname: Zhang
authors.forename: Li-Rong
authors.initials: LR
authors.lastname: Zhang
mesh_terms: D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008133:Long QT Syndrome / Q000188:drug therapy* / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects* / Q000235:genetics; D009154:Mutation / Q000235:genetics; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D015575:Roxithromycin / Q000494:pharmacology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D000071230:Transcriptional Regulator ERG
chemical_list: C072312:ERG protein, human; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D015575:Roxithromycin