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Inhibition of cloned HERG potassium channels by the antiestrogen tamoxifen.
- Source :
-
Naunyn-Schmiedeberg's archives of pharmacology [Naunyn Schmiedebergs Arch Pharmacol] 2003 Jul; Vol. 368 (1), pp. 41-8. Date of Electronic Publication: 2003 Jun 25. - Publication Year :
- 2003
-
Abstract
- Tamoxifen is a nonsteroidal antiestrogen that is commonly used in the treatment of breast cancer. Although antiestrogenic drugs are generally believed not to cause acquired long QT syndrome (LQTS), concerns have been raised by recent reports of QT interval prolongation associated with tamoxifen treatment. Since blockade of human ether-a-go-go-related gene (HERG) potassium channels is critical in the development of acquired LQTS, we investigated the effects of tamoxifen on cloned HERG potassium channels to determine the electrophysiological basis for the arrhythmogenic potential of this drug. HERG channels were heterologously expressed in Xenopus laevis oocytes, and currents were measured using the two-microelectrode voltage clamp technique. Tamoxifen blocked HERG potassium channels with an IC(50) value of 45.3 microM. Inhibition required channel opening and unblocking occurred very slowly. Analysis of the voltage-dependence of block revealed loss of inhibition at positive membrane potentials, indicating that strong channel inactivation prevented block by tamoxifen. No marked changes in electrophysiological parameters such as voltage-dependence of activation or inactivation, or inactivation time constant could be observed, and block was not frequency-dependent. This study demonstrates that HERG potassium channels are blocked by the antiestrogenic drug tamoxifen. We conclude that HERG current inhibition might be an explanation for the QT interval prolongation associated with this drug.
- Subjects :
- Animals
Cation Transport Proteins physiology
Cloning, Molecular
Ether-A-Go-Go Potassium Channels
Patch-Clamp Techniques
Potassium Channels physiology
Time Factors
Xenopus laevis
Cation Transport Proteins drug effects
Estrogen Antagonists pharmacology
Oocytes drug effects
Potassium Channel Blockers pharmacology
Potassium Channels drug effects
Potassium Channels, Voltage-Gated
Tamoxifen pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0028-1298
- Volume :
- 368
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Naunyn-Schmiedeberg's archives of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 12827215
- Full Text :
- https://doi.org/10.1007/s00210-003-0766-8