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Inhibition of cloned HERG potassium channels by the antiestrogen tamoxifen.
Naunyn Schmiedebergs Arch Pharmacol. 2003 Jul; 368(1):41-8.NS

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.

Authors+Show Affiliations

Department of Cardiology, Medical University Hospital Heidelberg, Bergheimerstrasse 58, 69115 Heidelberg, Germany. dierk_thomas@med.uni-heidelberg.deNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12827215

Citation

Thomas, Dierk, et al. "Inhibition of Cloned HERG Potassium Channels By the Antiestrogen Tamoxifen." Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 368, no. 1, 2003, pp. 41-8.
Thomas D, Gut B, Karsai S, et al. Inhibition of cloned HERG potassium channels by the antiestrogen tamoxifen. Naunyn Schmiedebergs Arch Pharmacol. 2003;368(1):41-8.
Thomas, D., Gut, B., Karsai, S., Wimmer, A. B., Wu, K., Wendt-Nordahl, G., Zhang, W., Kathöfer, S., Schoels, W., Katus, H. A., Kiehn, J., & Karle, C. A. (2003). Inhibition of cloned HERG potassium channels by the antiestrogen tamoxifen. Naunyn-Schmiedeberg's Archives of Pharmacology, 368(1), 41-8.
Thomas D, et al. Inhibition of Cloned HERG Potassium Channels By the Antiestrogen Tamoxifen. Naunyn Schmiedebergs Arch Pharmacol. 2003;368(1):41-8. PubMed PMID: 12827215.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of cloned HERG potassium channels by the antiestrogen tamoxifen. AU - Thomas,Dierk, AU - Gut,Bernd, AU - Karsai,Syrus, AU - Wimmer,Anna-Britt, AU - Wu,Kezhong, AU - Wendt-Nordahl,Gunnar, AU - Zhang,Wei, AU - Kathöfer,Sven, AU - Schoels,Wolfgang, AU - Katus,Hugo A, AU - Kiehn,Johann, AU - Karle,Christoph A, Y1 - 2003/06/25/ PY - 2003/02/12/received PY - 2003/05/05/accepted PY - 2003/6/27/pubmed PY - 2004/5/5/medline PY - 2003/6/27/entrez SP - 41 EP - 8 JF - Naunyn-Schmiedeberg's archives of pharmacology JO - Naunyn Schmiedebergs Arch Pharmacol VL - 368 IS - 1 N2 - 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. SN - 0028-1298 UR - https://www.unboundmedicine.com/medline/citation/12827215/Inhibition_of_cloned_HERG_potassium_channels_by_the_antiestrogen_tamoxifen_ L2 - https://dx.doi.org/10.1007/s00210-003-0766-8 DB - PRIME DP - Unbound Medicine ER -