Published Online
on February 14, 2005

A more recent version of this article appeared on February 22, 2005

This Article Full Text (PDF) All Versions of this Article: 111/7/835    most recent 01.CIR.0000155617.54749.09v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zitron, E. Articles by Karle, C. A. Search for Related Content PubMed PubMed Citation Articles by Zitron, E. Articles by Karle, C. A. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Related Collections Cardiovascular Pharmacology Primary prevention Arrythmias-basic studies Arrhythmias, clinical electrophysiology, drugs

Submitted on May 22, 2004
Revised on November 10, 2004
Accepted on November 17, 2004

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, and 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.

^* To whom correspondence should be addressed. E-mail: Christoph1_karle{at}med.uni-heidelberg.de.

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

This article has been cited by other articles:

				W. Zhang, E. Zitron, M. Homme, L. Kihm, C. Morath, D. Scherer, S. Hegge, D. Thomas, C. P. Schmitt, M. Zeier, et al. Aquaporin-1 Channel Function Is Positively Regulated by Protein Kinase C J. Biol. Chem., July 20, 2007; 282(29): 20933 - 20940. [Abstract] [Full Text] [PDF]

				A. Cogolludo, G. Frazziano, A. M. Briones, L. Cobeno, L. Moreno, F. Lodi, M. Salaices, J. Tamargo, and F. Perez-Vizcaino The dietary flavonoid quercetin activates BKCa currents in coronary arteries via production of H2O2. Role in vasodilatation Cardiovasc Res, January 15, 2007; 73(2): 424 - 431. [Abstract] [Full Text] [PDF]