title: Potent inhibition of human cardiac potassium (HERG) channels by the anti-estrogen agent clomiphene-without QT interval prolongation.
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.affiliation: Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, University Walk, Bristol BS8 1TD, UK.
authors.forename: Kathryn H
authors.initials: KH
authors.lastname: Yuill
authors.forename: John J
authors.initials: JJ
authors.lastname: Borg
authors.forename: John M
authors.initials: JM
authors.lastname: Ridley
authors.forename: James T
authors.initials: JT
authors.lastname: Milnes
authors.forename: Harry J
authors.initials: HJ
authors.lastname: Witchel
authors.forename: Ashok A
authors.initials: AA
authors.lastname: Paul
authors.forename: Roland Z
authors.initials: RZ
authors.lastname: Kozlowski
authors.forename: Jules C
authors.initials: JC
authors.lastname: Hancox
mesh_terms: D000818:Animals; D002460:Cell Line; D002996:Clomiphene / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D004594:Electrophysiology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008133:Long QT Syndrome; D008297:Male; D009206:Myocardium / Q000378:metabolism; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D004965:Estrogen Antagonists; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D013629:Tamoxifen; D002996:Clomiphene