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


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.


CONCLUSIONS
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.
Scholz
Eberhard P
EP
Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany. ebi_scholz@yahoo.de
Zitron
Edgar
E
Kiesecker
Claudia
C
Thomas
Dierk
D
Kathöfer
Sven
S
Kreuzer
Jörg
J
Bauer
Alexander
A
Katus
Hugo A
HA
Remppis
Andrew
A
Karle
Christoph A
CA
Greten
Johannes
J
D024322:Amino Acids, Aromatic / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002318:Cardiovascular Diseases / Q000517:prevention & control*; D032084:Citrus sinensis / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects*; D006569:Hesperidin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D009154:Mutation / Q000502:physiology; D009865:Oocytes / Q000187:drug effects; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000378:metabolism / Q000494:pharmacology*; D014981:Xenopus
D024322:Amino Acids, Aromatic; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D026902:Potassium Channel Blockers; D006569:Hesperidin; C013015:hesperetin