Erythromycin block of the HERG K+ channel: Accessibility to F656 and Y652

Duncan, Rona S.; Ridley, John; Dempsey, Christopher E.; Leishman, Derek J.; Leaney, Joanne L.; Hancox, Jules C.; Witchel, Harry J.

doi:10.1016/j.bbrc.2006.01.008

Cited by 39 publications

(45 citation statements)

References 21 publications

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“…For example, the macrolide antibiotic erythromycin has been linked to QT interval prolongation [Mishra et al 1999] and inhibits hERG current (I hERG ) with an IC 50 of $3972 mM [Volberg et al 2002;Stanat et al 2003;Duncan et al 2006]. Other macrolides including clarithromycin and roxithromycin also inhibit hERG channel current [Stanat et al 2003].…”

Section: Introductionmentioning

confidence: 99%

Azithromycin, cardiovascular risks, QTc interval prolongation, torsade de pointes, and regulatory issues: A narrative review based on the study of case reports

Hancox

Hasnain

Vieweg

et al. 2013

Therapeutic Advances in Infection

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Over the past year, three articles have appeared in the New England Journal of Medicine describing conflicting findings about azithromycin and cardiac safety, particular azithromycin-induced QTc interval prolongation and torsade de pointes. The FDA wants healthcare providers to consider azithromycin-induced fatal cardiac arrhythmias for patients already at risk for cardiac death and other potentially arrhythmogenic cardiovascular conditions. In a systematic review of case reports we sought to determine factors that link to azithromycininduced/associated QTc interval prolongation and torsade de pointes. We found 12 cases: seven female and five male. Of the nine adults with reported azithromycin doses, concurrent QTc interval measurement, and without congenital long QT syndrome, we found no significant relationship between dose and QTc interval duration. Additional risk factors were female sex, older age, heart disease, QTc interval prolonging drugs and metabolic inhibitors, hypokalemia, and bradycardia. All 12 subjects had at least two additional risk factors. Elderly women with heart disease appear to be at particularly risk for drug-related QTc interval prolongation and torsade de pointes.

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Section: Introductionmentioning

confidence: 99%

Azithromycin, cardiovascular risks, QTc interval prolongation, torsade de pointes, and regulatory issues: A narrative review based on the study of case reports

Hancox

Hasnain

Vieweg

et al. 2013

Therapeutic Advances in Infection

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“…The results from our 'envelope of tails' experiment can only be accounted for by drug association with its target residues proceeding when the channel gates. We have performed docking simulations of ivabradine to a KcsA-based homology model of the closed hERG channel [10,11] (Figure 1). Whilst the channel's inner cavity can certainly accommodate ivabradine in the closed state, occupation of the closed-state cavity by the drug necessitates close approaches between drug and key aromatic residues, in particular, Y652 (Figure 1).…”

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hERG potassium channel inhibition by ivabradine requires channel gating

Melgari

Brack

Zhang

et al. 2015

Journal of Molecular and Cellular Cardiology

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“…However, these studies neither evaluated the manner in which the drugs bound to the channel nor any other possible mechanism that might lead to the reduction in current. It has been reported that F656 mutant channels attenuate hERG current inhibition through erythromycin (Duncan et al 2006). We hypothesize that roxithromycin may inhibit the hERG channel by binding predominantly to pore-S6 regions (such as Y652 and F656).…”

Section: Introductionmentioning

confidence: 87%

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

Han

Yang

Duan

et al. 2013

Can. J. Physiol. Pharmacol.

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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.

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Erythromycin block of the HERG K+ channel: Accessibility to F656 and Y652

Cited by 39 publications

References 21 publications

Azithromycin, cardiovascular risks, QTc interval prolongation, torsade de pointes, and regulatory issues: A narrative review based on the study of case reports

Azithromycin, cardiovascular risks, QTc interval prolongation, torsade de pointes, and regulatory issues: A narrative review based on the study of case reports

hERG potassium channel inhibition by ivabradine requires channel gating

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

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