Interactions at human ether-a-go-go-related gene channels.

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Friemel A, Zunkler BJ

Interactions at human ether-a-go-go-related gene channels.

Toxicol Sci. 2010 Apr;114(2):346-55. doi: 10.1093/toxsci/kfq011. Epub 2010 Jan 13.

PubMed ID

20071423 [ View in PubMed

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Abstract

Several noncardiovascular drugs have the potential to induce Torsades de Pointes cardiac arrhythmias via blockade of the rapid component of the cardiac delayed rectifier K(+) current (I(Kr)), which is encoded by human ether-a-go-go-related gene (hERG). The aim of the present study was to characterize possible interactions between terfenadine, binding to a site located inside the central cavity, and the following substances with various binding sites: dofetilide, fluvoxamine, chlorobutanol, and a hERG-specific toxin isolated from scorpion venom (CnErg1). The whole-cell configuration of the patch-clamp technique was employed on hERG channels stably expressed in human embryonic kidney 293 cells. Terfenadine does not interact with dofetilide or fluvoxamine at hERG channels. Slight subadditive inhibitory effects on hERG peak tail currents were observed when terfenadine and CnErg1 were administered in combination. Terfenadine and chlorobutanol synergistically inhibit hERG peak tail currents and enhance each other's inhibitory effect in a concentration-dependent way. In conclusion, terfenadine interacts with CnErg1 and chlorobutanol, but not with dofetilide or fluvoxamine, at hERG channels. It is shown that interactions between chlorobutanol and a hERG channel blocker binding inside the central cavity (terfenadine) produce synergistic effects on hERG currents.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Chlorobutanol	Potassium voltage-gated channel subfamily H member 2	Protein	Humans	Unknown	Not Available	Details
Fluvoxamine	Potassium voltage-gated channel subfamily H member 2	Protein	Humans	Unknown	Not Available	Details