QTc Prolongation by Grapefruit Juice and Its Potential Pharmacological Basis

Zitron, Edgar; Scholz, Eberhard P.; Owen, Robert W.; Lück, Sonja; Kiesecker, Claudia; Thomas, Dierk; Kathöfer, Sven; Niroomand, Feraydoon; Kiehn, Johann; Kreye, V. A. W.; Katus, Hugo A.; Schoels, Wolfgang; Karle, Christoph A.

doi:10.1161/01.cir.0000155617.54749.09

Cited by 89 publications

(67 citation statements)

References 19 publications

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“…However, inhibition of the same current has also been linked to antiarrhythmic properties and several well-known antiarrhythmics, like amiodarone, dronedarone, and ajmaline inhibit I Kr [78][79][80]. Only recently, we screened a broad spectrum of flavonoids and showed that among others, the citrus flavonoids hesperetin and naringenin potently block hERG potassium channels, which form the molecular basis of I Kr in humans [81][82][83]. Similar results could be found for EGCG, the active component of green tea [84].…”

Section: Inhibition Of Cardiac Potassium Currentssupporting

confidence: 71%

Cardiovascular Ion Channels as a Molecular Target of Flavonoids

Scholz

Zitron

Katus

et al. 2010

Cardiovascular Therapeutics

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SUMMARYFlavonoids are a class of naturally occurring polyphenols abundant in edibles and beverages of plant origin. Epidemiological studies consistently associate high flavonoid intake with a reduced risk for the development of cardiovascular diseases. So far these beneficial effects have been mainly attributed to nonspecific antioxidant and antiinflammatory properties. However, there is an increasing body of evidence that flavonoids specifically target molecular structures including cardiovascular ion channels. Playing a pivotal role in the regulation of vascular tone and cardiac electric activity, ion channels represent a major target for the induction of antihypertensive and cardioprotective effects. Thus, pharmacological properties of flavonoids on cardiovascular ion channels, ion currents and tissue preparations are being increasingly addressed in experimental studies. Whereas it has become clear that cardiovascular ion channels represent an important molecular target of flavonoids, the published data have not yet been systematically reviewed.

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Section: Inhibition Of Cardiac Potassium Currentssupporting

confidence: 71%

Cardiovascular Ion Channels as a Molecular Target of Flavonoids

Scholz

Zitron

Katus

et al. 2010

Cardiovascular Therapeutics

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“…Using this model, the IC 50 of naringenin on HERG inhibition was 173 µ M , which is similar to other reports [8, 9]. Since the follicular membrane surrounding the oocyte may impede the access of the drug to the HERG channel, inhibitory effects of blocking agents may be affected.…”

Section: Discussionsupporting

confidence: 86%

“…Recently, significant QTc prolongation by grapefruit juice in healthy volunteers has been reported. This has been attributed to human ether-a-go-go-related gene (HERG) blockade by grapefruit flavonoids [8]. Naringenin, the principal flavonoid in grapefruit juice, has been identified as the most potent HERG channel blocker among several dietary flavonoids [9].…”

Section: Introductionmentioning

confidence: 99%

The Additive Effects of the Active Component of Grapefruit Juice (Naringenin) and Antiarrhythmic Drugs on HERG Inhibition

Lin

Ke²,

Ranade³

et al. 2007

Cardiology

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Background: Grapefruit juice causes significant QT prolongation in healthy volunteers and naringenin has been identified as the most potent human ether-a-go-go-related gene (HERG) channel blocker among several dietary flavonoids. The interaction between naringenin and I_Kr-blocking antiarrhythmic drugs has not been studied. We evaluated the effect of combining naringenin with I_Kr-inhibiting antiarrhythmic drugs on cardiac I_Kr. Methods and Results:I_Kr current was studied by using HERG expressed in Xenopus oocytes, and the two-electrode voltage clamp technique was employed. Antiarrhythmic drugs (azimilide, amiodarone, dofetilide and quinidine) were tested. Experiments were performed at room temperature. Naringenin blocked HERG current dose dependently with an IC₅₀ of 173.3 ± 3.1 µM. Naringenin 100 µM alone inhibited HERG current by 31 ± 6%, and this inhibitory effect was increased with coadministration of 1 or 10 µM antiarrhythmic drugs. When 100 µM naringenin was added to antiarrhythmic drugs, greater HERG inhibition was demonstrated, compared to the current inhibition caused by antiarrhythmic drugs alone. Addition of naringenin significantly increased current inhibition (p < 0.05). Conclusions: There is an additive inhibitory effect on HERG current when naringenin is combined with I_Kr-blocking antiarrhythmic drugs. This additive HERG inhibition could pose an increased risk of arrhythmias by increasing repolarization delay and possible repolarization heterogeneity.

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“…During the intervention, blood was sampled every 3 mo to determine liver markers, including alanine aminotransferase, aspartate aminotransferase, g-glutamyl transferase, and alkaline phosphatase. A control electrocardiogram was performed 10 d after the beginning of each intervention period and at each visit to avoid any risk of a prolonged corrected Q-T interval in response to grapefruit consumption (18).…”

Section: Methodsmentioning

confidence: 99%

Flavanones protect from arterial stiffness in postmenopausal women consuming grapefruit juice for 6 mo: a randomized, controlled, crossover trial

Habauzit

Verny

Milenković

et al. 2015

The American Journal of Clinical Nutrition

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Background: The consumption of citrus fruits is associated with health benefits. However, clinical data regarding the effects of grapefruit flavanone consumption on vascular function are lacking. Objective: The objective of the present study was to address the role of flavanones in the long-term effects induced by grapefruit juice (GFJ) consumption on vascular function in healthy postmenopausal women. Design: Forty-eight healthy postmenopausal women aged 50-65 y within 3-10 y since menopause, a body mass index (in kg/m 2 ) of 19-30, and a waist size .88 cm completed this double-blind, randomized, controlled, crossover trial. These volunteers were randomly assigned to consume 340 mL GFJ/d, providing 210 mg naringenin glycosides, or a matched control drink without flavanones for 6 mo each, with a 2-mo washout between beverages. The primary endpoint was the assessment of endothelial function in the brachial artery by using flow-mediated dilation. Blood pressure, arterial stiffness, and endothelial function in the peripheral arterial bed were also evaluated as indicators of vascular function. These measurements and blood collection for clinical biochemical markers were performed in overnight-fasted subjects before and after the 6-mo treatment periods. Results: The mean 6 SD carotid-femoral pulse wave velocity, which reflects central aortic stiffness, was statistically significantly lower after consumption of GFJ (7.36 6 1.15 m/s) than after consumption of the matched control drink without flavanones (7.70 6 1.36 m/s), with a P value of 0.019 for the treatment effect. Endothelial function in macro-and microcirculation, blood pressure, anthropometric measures, glucose metabolism, and biomarkers of inflammation and oxidative stress were not affected by the intervention. Conclusions: Regular GFJ consumption by middle-aged, healthy postmenopausal women is beneficial for arterial stiffness. This effect may be related to flavanones present in grapefruit. This trial was registered at clinicaltrials.gov as NCT01272167.Am J Clin Nutr 2015;102:66-74.

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QTc Prolongation by Grapefruit Juice and Its Potential Pharmacological Basis

Abstract: 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.

Cited by 89 publications

References 19 publications

Cardiovascular Ion Channels as a Molecular Target of Flavonoids

Cardiovascular Ion Channels as a Molecular Target of Flavonoids

The Additive Effects of the Active Component of Grapefruit Juice (Naringenin) and Antiarrhythmic Drugs on HERG Inhibition

Flavanones protect from arterial stiffness in postmenopausal women consuming grapefruit juice for 6 mo: a randomized, controlled, crossover trial

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