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Potent inhibition of human cardiac potassium (HERG) channels by the anti-estrogen agent clomiphene-without QT interval prolongation.
Biochem Biophys Res Commun. 2004 May 28; 318(2):556-61.BB

Abstract

The acquired form of the long-QT syndrome (LQTS) is a major safety consideration for the development and subsequent use of both cardiac and non-cardiac drugs; it is usually associated with pharmacological inhibition of cardiac HERG-encoded potassium channels. Clomiphene is an anti-estrogen agent used extensively in the treatment of infertility and is not associated with a risk of QT interval prolongation, in contrast to a structurally related compound tamoxifen. We describe here a potent inhibitory effect (IC(50) = 0.18 microM) of clomiphene on HERG ionic current (I(HERG)) recorded from a mammalian cell line expressing HERG channels. Inhibition of I(HERG) by clomiphene showed voltage-dependence and developed quickly following membrane depolarisation, indicating contingency of block on HERG channel gating. At 100 nM, clomiphene and the related anti-estrogen tamoxifen produced similar levels of I(HERG) blockade (p > 0.05). Experiments on guinea-pig isolated perfused hearts revealed that, despite its inhibitory action on I(HERG), clomiphene produced no significant effect at 1 microM on uncorrected QT interval (p > 0.1) nor on rate-corrected QT interval (QT(c); p > 0.1 for QT(c) determined using Van de Water's formula). The disparity between clomiphene's potent I(HERG) inhibition and its lack of effect on the QT interval underscores the notion that I(HERG) pharmacology may best be used alongside other screening methods when investigating the QT-prolonging tendency and related cardiotoxicity of non-cardiac drugs.

Authors+Show Affiliations

Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, University Walk, Bristol BS8 1TD, UK.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

15120636

Citation

Yuill, Kathryn H., et al. "Potent Inhibition of Human Cardiac Potassium (HERG) Channels By the Anti-estrogen Agent Clomiphene-without QT Interval Prolongation." Biochemical and Biophysical Research Communications, vol. 318, no. 2, 2004, pp. 556-61.
Yuill KH, Borg JJ, Ridley JM, et al. Potent inhibition of human cardiac potassium (HERG) channels by the anti-estrogen agent clomiphene-without QT interval prolongation. Biochem Biophys Res Commun. 2004;318(2):556-61.
Yuill, K. H., Borg, J. J., Ridley, J. M., Milnes, J. T., Witchel, H. J., Paul, A. A., Kozlowski, R. Z., & Hancox, J. C. (2004). Potent inhibition of human cardiac potassium (HERG) channels by the anti-estrogen agent clomiphene-without QT interval prolongation. Biochemical and Biophysical Research Communications, 318(2), 556-61.
Yuill KH, et al. Potent Inhibition of Human Cardiac Potassium (HERG) Channels By the Anti-estrogen Agent Clomiphene-without QT Interval Prolongation. Biochem Biophys Res Commun. 2004 May 28;318(2):556-61. PubMed PMID: 15120636.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Potent inhibition of human cardiac potassium (HERG) channels by the anti-estrogen agent clomiphene-without QT interval prolongation. AU - Yuill,Kathryn H, AU - Borg,John J, AU - Ridley,John M, AU - Milnes,James T, AU - Witchel,Harry J, AU - Paul,Ashok A, AU - Kozlowski,Roland Z, AU - Hancox,Jules C, PY - 2004/04/07/received PY - 2004/5/4/pubmed PY - 2004/6/26/medline PY - 2004/5/4/entrez SP - 556 EP - 61 JF - Biochemical and biophysical research communications JO - Biochem Biophys Res Commun VL - 318 IS - 2 N2 - The acquired form of the long-QT syndrome (LQTS) is a major safety consideration for the development and subsequent use of both cardiac and non-cardiac drugs; it is usually associated with pharmacological inhibition of cardiac HERG-encoded potassium channels. Clomiphene is an anti-estrogen agent used extensively in the treatment of infertility and is not associated with a risk of QT interval prolongation, in contrast to a structurally related compound tamoxifen. We describe here a potent inhibitory effect (IC(50) = 0.18 microM) of clomiphene on HERG ionic current (I(HERG)) recorded from a mammalian cell line expressing HERG channels. Inhibition of I(HERG) by clomiphene showed voltage-dependence and developed quickly following membrane depolarisation, indicating contingency of block on HERG channel gating. At 100 nM, clomiphene and the related anti-estrogen tamoxifen produced similar levels of I(HERG) blockade (p > 0.05). Experiments on guinea-pig isolated perfused hearts revealed that, despite its inhibitory action on I(HERG), clomiphene produced no significant effect at 1 microM on uncorrected QT interval (p > 0.1) nor on rate-corrected QT interval (QT(c); p > 0.1 for QT(c) determined using Van de Water's formula). The disparity between clomiphene's potent I(HERG) inhibition and its lack of effect on the QT interval underscores the notion that I(HERG) pharmacology may best be used alongside other screening methods when investigating the QT-prolonging tendency and related cardiotoxicity of non-cardiac drugs. SN - 0006-291X UR - https://www.unboundmedicine.com/medline/citation/15120636/Potent_inhibition_of_human_cardiac_potassium__HERG__channels_by_the_anti_estrogen_agent_clomiphene_without_QT_interval_prolongation_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006291X04007909 DB - PRIME DP - Unbound Medicine ER -