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(Circulation. 2005;111:835-838.)
© 2005 American Heart Association, Inc.

Arrhythmia/Electrophysiology

QTc Prolongation by Grapefruit Juice and Its Potential Pharmacological Basis

HERG Channel Blockade by Flavonoids

Edgar Zitron, MD^*; Eberhard Scholz, BSc^*; Robert W. Owen, PhD; Sonja Lück, BSc; Claudia Kiesecker, MSc; Dierk Thomas, MD; Sven Kathöfer, MD; Feraydoon Niroomand, MD; Johann Kiehn, MD; Volker A.W. Kreye, MD; Hugo A. Katus, MD; Wolfgang Schoels, MD; Christoph A. Karle, MD

From the Departments of Cardiology (E.Z., E.S., S.L., C.K., D.T., S.K., F.N., J.K., H.A.K., W.S., C.A.K.) and Physiology and Pathophysiology (V.A.W.K.), University of Heidelberg Medical School, and Division of Toxicology and Cancer Risk Factors (R.W.O.), German Cancer Research Center, Heidelberg, Germany.

Correspondence to Dr. Christoph A. Karle, Medical University Hospital Heidelberg, Department of Cardiology, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. E-mail Christoph1_karle{at}med.uni-heidelberg.de

Received May 22, 2004; revision received November 10, 2004; accepted November 17, 2004.

Background— A high intake of dietary flavonoids, which are abundant in fruits, vegetables, tea, and wine, is known to reduce cardiovascular mortality. The effects of flavonoids on cardiac electrophysiology, which theoretically may have both antiarrhythmic and proarrhythmic consequences, have not been studied systematically to date.

Methods and Results— We screened a broad spectrum of flavonoids for their inhibitory activity on HERG channels by using heterologous expression in Xenopus oocytes. At a concentration of 1 mmol/L, 10 compounds caused a significant inhibition of HERG currents, whereas 11 other flavonoids had no effect. The IC₅₀ value for HERG block by naringenin, the most potent inhibitor, was 102.3 µmol/L in Xenopus oocytes and 36.5 µmol/L in HEK cells. To demonstrate the physiological relevance of these findings, we studied the effects of pink grapefruit juice, which contains large amounts of naringenin glycosides (>1000 µmol/L), in human volunteers. In 10 persons, we observed a peak QTc prolongation of 12.5±4.2 ms 5 hours after oral ingestion of 1 L of grapefruit juice. This effect was significant (P=0.02).

Conclusions— We found a significant QTc prolongation by grapefruit juice in healthy volunteers, probably caused by block of HERG channels by flavonoids. These findings reveal new perspectives on the potential for dietary modification of cardiac electrophysiology.

Key Words: antiarrhythmia agents • arrhythmia • ion channels • nutrition • pharmacology

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