Inhibition of cloned HERG potassium channels by the antiestrogen tamoxifen.
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.
Thomas
Dierk
D
Department of Cardiology, Medical University Hospital Heidelberg, Bergheimerstrasse 58, 69115 Heidelberg, Germany. dierk_thomas@med.uni-heidelberg.de
Gut
Bernd
B
Karsai
Syrus
S
Wimmer
Anna-Britt
AB
Wu
Kezhong
K
Wendt-Nordahl
Gunnar
G
Zhang
Wei
W
Kathöfer
Sven
S
Schoels
Wolfgang
W
Katus
Hugo A
HA
Kiehn
Johann
J
Karle
Christoph A
CA
D000818:Animals; D027682:Cation Transport Proteins / Q000187:drug effects* / Q000502:physiology; D003001:Cloning, Molecular; D004965:Estrogen Antagonists / Q000494:pharmacology*; D051638:Ether-A-Go-Go Potassium Channels; D009865:Oocytes / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D013629:Tamoxifen / Q000494:pharmacology*; D013997:Time Factors; D014982:Xenopus laevis
D027682:Cation Transport Proteins; D004965:Estrogen Antagonists; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D013629:Tamoxifen