QTc prolongation by grapefruit juice and its potential pharmacological basis: HERG channel blockade by flavonoids.
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.


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 micromol/L in Xenopus oocytes and 36.5 micromol/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 micromol/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.
Zitron
Edgar
E
Department of Cardiology, University of Heidelberg Medical School, Heidelberg, Germany.
Scholz
Eberhard
E
Owen
Robert W
RW
Lück
Sonja
S
Kiesecker
Claudia
C
Thomas
Dierk
D
Kathöfer
Sven
S
Niroomand
Feraydoon
F
Kiehn
Johann
J
Kreye
Volker A W
VA
Katus
Hugo A
HA
Schoels
Wolfgang
W
Karle
Christoph A
CA
D000328:Adult; D000818:Animals; D000889:Anti-Arrhythmia Agents; D001628:Beverages; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors*; D032083:Citrus paradisi / Q000737:chemistry*; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D044950:Flavanones / Q000494:pharmacology; D005419:Flavonoids / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D009865:Oocytes; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors*; D014161:Transduction, Genetic; D014981:Xenopus
D000889:Anti-Arrhythmia Agents; D027682:Cation Transport Proteins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D044950:Flavanones; D005419:Flavonoids; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D024642:Potassium Channels, Voltage-Gated; C005273:naringenin