Blockage of hERG current and the disruption of trafficking as induced by roxithromycin

Area of Science:

• Cardiovascular Pharmacology
• Molecular Cardiology
• Drug Safety

Background:

• Roxithromycin, an oral macrolide antibiotic, is associated with Q-T interval prolongation and torsades de pointes.
• The underlying molecular mechanisms for these cardiotoxic effects require further investigation.

Purpose of the Study:

• To elucidate the molecular mechanisms by which roxithromycin induces cardiotoxicity.
• To investigate the effects of roxithromycin on human ether-à-go-go-related gene (hERG) K(+) channels.

Main Methods:

• Studied roxithromycin's effects on wild-type and mutant hERG channels expressed in HEK293 cells.
• Utilized electrophysiology to measure hERG currents.
• Employed Western blot and confocal microscopy to assess hERG protein trafficking.

Main Results:

• Roxithromycin inhibited wild-type hERG currents in a concentration-dependent manner (IC50 = 55.8 ± 9.1 μmol/L).
• Mutations in hERG drug-binding sites (Y652A, F656C) reduced current inhibition by roxithromycin.
• Roxithromycin impaired hERG protein trafficking to the cell membrane.

Conclusions:

• Roxithromycin may cause acquired long-QT syndrome through direct hERG channel inhibition.
• Disruption of hERG protein trafficking is another mechanism contributing to roxithromycin's cardiotoxicity.
• While mutations attenuated direct channel block, they did not significantly affect trafficking disruption.