Roxithromycin inhibited wild-type hERG currents in a concentration-dependent manner (IC50 55.8 ± 9.1 μmol/L) and disrupted hERG protein trafficking to the cell membrane.
Does roxithromycin inhibit hERG currents and disrupt hERG protein trafficking in HEK293 cells?
Roxithromycin may cause acquired long-QT syndrome via direct inhibition of hERG current and disruption of hERG protein trafficking.
Effect estimate: IC50 55.8 ± 9.1 μmol/L
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.
Han et al. (Tue,) conducted a other in Acquired long-QT syndrome. Roxithromycin was evaluated on hERG current blockage and protein trafficking (IC50 55.8 ± 9.1 μmol/L). Roxithromycin inhibited wild-type hERG currents in a concentration-dependent manner (IC50 55.8 ± 9.1 μmol/L) and disrupted hERG protein trafficking to the cell membrane.