title: QTc prolongation by grapefruit juice and its potential pharmacological basis: HERG channel blockade by flavonoids.
abstract: 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.
authors.affiliation: Department of Cardiology, University of Heidelberg Medical School, Heidelberg, Germany.
authors.forename: Edgar
authors.initials: E
authors.lastname: Zitron
authors.forename: Eberhard
authors.initials: E
authors.lastname: Scholz
authors.forename: Robert W
authors.initials: RW
authors.lastname: Owen
authors.forename: Sonja
authors.initials: S
authors.lastname: Lück
authors.forename: Claudia
authors.initials: C
authors.lastname: Kiesecker
authors.forename: Dierk
authors.initials: D
authors.lastname: Thomas
authors.forename: Sven
authors.initials: S
authors.lastname: Kathöfer
authors.forename: Feraydoon
authors.initials: F
authors.lastname: Niroomand
authors.forename: Johann
authors.initials: J
authors.lastname: Kiehn
authors.forename: Volker A W
authors.initials: VA
authors.lastname: Kreye
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schoels
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Karle
mesh_terms: 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
chemical_list: 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