Orange flavonoid hesperetin modulates cardiac hERG potassium channel via binding to amino acid F656

Scholz, Eberhard P.; Zitron, Edgar; Kiesecker, Claudia; Thomas, Dierk; Kathöfer, Sven; Kreuzer, Jörg; Bauer, Alexander; Katus, Hugo A.; Remppis, Andrew; Karle, Christoph A.; Greten, Johannes

doi:10.1016/j.numecd.2006.06.002

« Previous Next »Nutrition, Metabolism & Cardiovascular Diseases
Volume 17, Issue 9 , Pages 666-675, November 2007

Orange flavonoid hesperetin modulates cardiac hERG potassium channel via binding to amino acid F656

Eberhard P. Scholz
- Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany
- Corresponding author. Tel.: +49 6221 563 8881; fax: +49 6221 4876 8902.
- These authors contributed equally to this work.
Edgar Zitron
- Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany
- These authors contributed equally to this work.
Claudia Kiesecker
- Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany
Dierk Thomas
- Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany
Sven Kathöfer
- Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany
Jörg Kreuzer
- St. Vincenz Hospital, Limburg, Germany
Alexander Bauer
- Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany
Hugo A. Katus
- Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany
Andrew Remppis
- Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany
Christoph A. Karle
- Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany
Johannes Greten
- German Society of Traditional Chinese Medicine, Heidelberg, Germany

Received 29 March 2006; received in revised form 13 June 2006; accepted 17 June 2006. published online 22 August 2006.

Abstract

Background and aims

Hesperetin belongs to the flavonoid subgroup classified as citrus flavonoids and is the main flavonoid in oranges. A high dietary intake of flavonoids has been associated with a significant reduction in cardiovascular mortality. HERG potassium channels play a major role in cardiac repolarisation and represent the most important pharmacologic target of both antiarrhythmic and proarrhythmic drugs.

Methods and results

We used the two-microelectrode voltage-clamp technique to analyse inhibitory effects of hesperetin on hERG potassium channels heterologously expressed in Xenopus oocytes. Hesperetin blocked hERG potassium channels in a concentration dependent manner. Onset of block was fast and completely reversible upon wash-out. There was no significant effect of hesperetin on channel kinetics. Affinity of hesperetin to mutant F656A hERG channel was significantly decreased compared to WT hERG, indicating a binding site in the channel pore cavity. In contrast, affinity of hesperetin to Y652A hERG was not different from the affinity to WT hERG.

Conclusion

We found an antagonist of cardiac hERG channels that modulates hERG currents by accessing the aromatic pore binding site, particularly amino acid phe-656. Regarding high hesperetin concentrations found in oranges and the increasing consumption of oranges and orange juice in Europe, potential effects of hesperetin on cardiac electrophysiology in vivo deserve further investigation.

Keywords: Flavonoids, Hesperetin, hERG, Potassium channel, Arrhythmia, Repolarisation