A common antitussive drug, clobutinol, precipitates the long QT syndrome 2.
QT prolongation, a classic risk factor for arrhythmias, can result from a mutation in one of the genes governing cardiac repolarization and also can result from the intake of a medication acting as blocker of the cardiac K(+) channel human ether-a-go-go-related gene (HERG). Here, we identified the arrhythmogenic potential of a nonopioid antitussive drug, clobutinol. The deleterious effects of clobutinol were suspected when a young boy, with a diagnosis of congenital long QT syndrome, experienced arrhythmias while being treated with this drug. Using the patch-clamp technique, we showed that clobutinol dose-dependently inhibited the HERG K(+) current with a half-maximum block concentration of 2.9 microM. In the proband, we identified a novel A561P HERG mutation. Two others long QT mutations (A561V and A561T) had been reported previously at the same position. None of the three mutants led to a sizeable current in heterologous expression system. When coexpressed with wild-type (WT) HERG channels, the three Ala561 mutants reduced the trafficking of WT and mutant heteromeric channels, resulting in decreased K(+) current amplitude (dominant-negative effects). In addition, A561P but not A561V and A561T mutants induced a approximately -11 mV shift of the current activation curve and accelerated deactivation, thereby partially counteracting the dominant-negative effects. A561P mutation and clobutinol effects on the human ventricular action potential characteristics were simulated using the Priebe-Beuckelmann model. Our work shows that clobutinol has limited effects on WT action potential but should be classified as a "drug to be avoided by congenital long QT patients" rather than as a "drug with risk of torsades de pointes".
l'Institut du thorax, Institut National de la Sante et de la Recherche Medicale U533, Nantes, France.
Chloé
C
Bellocq
Ronald
R
Wilders
Jean-Jacques
JJ
Schott
Bénédicte
B
Louérat-Oriou
Pierre
P
Boisseau
Hervé
H
Le Marec
Denis
D
Escande
Isabelle
I
Baró
D000409:Alanine / Q000235:genetics; D000605:Amino Alcohols / Q000009:adverse effects*; D000818:Animals; D000996:Antitussive Agents / Q000009:adverse effects*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D019556:COS Cells; D027682:Cation Transport Proteins / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D002522:Chlorocebus aethiops; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced*; D008297:Male; D009154:Mutation; D010375:Pedigree; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D011392:Proline / Q000235:genetics; D013912:Threonine / Q000235:genetics; D014633:Valine / Q000235:genetics
D000605:Amino Alcohols; D000996:Antitussive Agents; D027682:Cation Transport Proteins; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D024642:Potassium Channels, Voltage-Gated; C017135:clobutinol; D013912:Threonine; D011392:Proline; D014633:Valine; D000409:Alanine