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Naunyn Schmiedebergs Arch Pharmacol
2005 Jun 01;3716:516-25. doi: 10.1007/s00210-005-1069-z.
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Inhibition of cardiac HERG channels by grapefruit flavonoid naringenin: implications for the influence of dietary compounds on cardiac repolarisation.
Scholz EP
,
Zitron E
,
Kiesecker C
,
Lück S
,
Thomas D
,
Kathöfer S
,
Kreye VA
,
Katus HA
,
Kiehn J
,
Schoels W
,
Karle CA
.
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Flavonoids are naturally occurring food ingredients that have been associated with reduced cardiovascular mortality in epidemiological studies. In a previous study, we demonstrated for the first time that flavonoids are inhibitors of cardiac human ether-à-go-go-related gene (HERG) channels. Furthermore, we observed that grapefruit juice induced mild QTc prolongation in healthy subjects. HERG blockade by grapefruit flavonoid naringenin is most likely to be the mechanism underlying this effect. Therefore, the electrophysiological properties of HERG blockade by naringenin were analysed in detail. HERG potassium currents expressed in Xenopus oocytes were measured with a two-microelectrode voltage clamp. Naringenin blocked HERG potassium channels with an IC50 value of 102.6 microM in Xenopus oocytes. The onset of blockade was fast. The effect was completely reversible upon wash-out. Naringenin binding to HERG required aromatic residue F656 in the putative pore binding site. Channels were blocked in the open and inactivated states but not in the closed states. Naringenin did not affect HERG current activation. However, the half maximal inactivation voltage was shifted by 14.9 mV towards more negative potentials and current inactivation at negative potentials was accelerated. No frequency dependence of blockade was observed. Naringenin inhibits HERG channels with pharmacological characteristics similar to those of well-known HERG antagonists. From a clinical point of view, this effect could have both proarrhythmic and antiarrhythmic consequences. This may have important implications for phytotherapy and for dietary recommendations for cardiologic patients. Therefore, electrophysiological effects of flavonoids deserve further investigation.
Ameer,
Flavanone absorption after naringin, hesperidin, and citrus administration.
1996, Pubmed
Ameer,
Flavanone absorption after naringin, hesperidin, and citrus administration.
1996,
Pubmed
Curran,
A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome.
1995,
Pubmed
de Lorgeril,
Mediterranean diet in the prevention of coronary heart disease.
1998,
Pubmed
Erlund,
Plasma kinetics and urinary excretion of the flavanones naringenin and hesperetin in humans after ingestion of orange juice and grapefruit juice.
2001,
Pubmed
Fernandez,
Physicochemical features of the HERG channel drug binding site.
2004,
Pubmed
,
Xenbase
Geleijnse,
Inverse association of tea and flavonoid intakes with incident myocardial infarction: the Rotterdam Study.
2002,
Pubmed
Hertog,
Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study.
1993,
Pubmed
Ho,
Inhibition of human CYP3A4 activity by grapefruit flavonoids, furanocoumarins and related compounds.
2001,
Pubmed
Huikuri,
Sudden death due to cardiac arrhythmias.
2001,
Pubmed
Jurkiewicz,
Rate-dependent prolongation of cardiac action potentials by a methanesulfonanilide class III antiarrhythmic agent. Specific block of rapidly activating delayed rectifier K+ current by dofetilide.
1993,
Pubmed
Karle,
The antiarrhythmic drug BRL-32872.
2002,
Pubmed
Kiesecker,
Class Ia anti-arrhythmic drug ajmaline blocks HERG potassium channels: mode of action.
2004,
Pubmed
,
Xenbase
Knekt,
Flavonoid intake and coronary mortality in Finland: a cohort study.
1996,
Pubmed
Madeja,
Follicular tissues reduce drug effects on ion channels in oocytes of Xenopus laevis.
1997,
Pubmed
,
Xenbase
Middleton,
The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer.
2000,
Pubmed
Mitcheson,
A structural basis for drug-induced long QT syndrome.
2000,
Pubmed
,
Xenbase
Mukamal,
Tea consumption and mortality after acute myocardial infarction.
2002,
Pubmed
Numaguchi,
Probing the interaction between inactivation gating and Dd-sotalol block of HERG.
2000,
Pubmed
Pearlstein,
Characterization of HERG potassium channel inhibition using CoMSiA 3D QSAR and homology modeling approaches.
2003,
Pubmed
Pratt,
Pure class III agents for prevention of sudden cardiac death.
2003,
Pubmed
Priori,
Genetic defects of cardiac ion channels. The hidden substrate for torsades de pointes.
2002,
Pubmed
Redfern,
Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development.
2003,
Pubmed
Renaud,
Wine, alcohol, platelets, and the French paradox for coronary heart disease.
1992,
Pubmed
Rimm,
Relation between intake of flavonoids and risk for coronary heart disease in male health professionals.
1996,
Pubmed
Scholz,
Drug binding to aromatic residues in the HERG channel pore cavity as possible explanation for acquired Long QT syndrome by antiparkinsonian drug budipine.
2003,
Pubmed
,
Xenbase
Singh,
Control of cardiac arrhythmias by selective lengthening of repolarization: theoretic considerations and clinical observations.
1985,
Pubmed
Spector,
Class III antiarrhythmic drugs block HERG, a human cardiac delayed rectifier K+ channel. Open-channel block by methanesulfonanilides.
1996,
Pubmed
,
Xenbase
Waldo,
Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD Investigators. Survival With Oral d-Sotalol.
1996,
Pubmed
Walker,
Comparative effects of azimilide and ambasilide on the human ether-a-go-go-related gene (HERG) potassium channel.
2000,
Pubmed
Witchel,
Troubleshooting problems with in vitro screening of drugs for QT interval prolongation using HERG K+ channels expressed in mammalian cell lines and Xenopus oocytes.
2002,
Pubmed
,
Xenbase
Yochum,
Dietary flavonoid intake and risk of cardiovascular disease in postmenopausal women.
1999,
Pubmed
Zitron,
QTc prolongation by grapefruit juice and its potential pharmacological basis: HERG channel blockade by flavonoids.
2005,
Pubmed
,
Xenbase
Zitron,
Bertosamil blocks HERG potassium channels in their open and inactivated states.
2002,
Pubmed
,
Xenbase
