Nutrition, Metabolism & Cardiovascular Diseases
Volume 17, Issue 9 , Pages 666-675 , November 2007

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

  • Eberhard P. Scholz

      Affiliations

    • Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany
    • Corresponding Author InformationCorresponding author. Tel.: +49 6221 563 8881; fax: +49 6221 4876 8902.
    • These authors contributed equally to this work.
  • ,
  • Edgar Zitron

      Affiliations

    • Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany
    • These authors contributed equally to this work.
  • ,
  • Claudia Kiesecker

      Affiliations

    • Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany
  • ,
  • Dierk Thomas

      Affiliations

    • Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany
  • ,
  • Sven Kathöfer

      Affiliations

    • Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany
  • ,
  • Jörg Kreuzer

      Affiliations

    • St. Vincenz Hospital, Limburg, Germany
  • ,
  • Alexander Bauer

      Affiliations

    • Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany
  • ,
  • Hugo A. Katus

      Affiliations

    • Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany
  • ,
  • Andrew Remppis

      Affiliations

    • Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany
  • ,
  • Christoph A. Karle

      Affiliations

    • Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany
  • ,
  • Johannes Greten

      Affiliations

    • German Society of Traditional Chinese Medicine, Heidelberg, Germany

Received 29 March 2006 ,Revised 13 June 2006 ,Accepted 17 June 2006.

References 

  1. Middleton E, Kandaswami C, Theoharides TC. The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacol Rev. 2000;52:673–751
  2. Erlund I, Meririnne E, Alfthan G, Aro A. Plasma kinetics and urinary excretion of the flavanones naringenin and hesperetin in humans after ingestion of orange juice and grapefruit juice. J Nutr. 2001;131(2):235–241
  3. Knekt P, Jarvinen R, Reunanen A, Maatela J. Flavonoid intake and coronary mortality in Finland: a cohort study. BMJ. 1996;312:478–481
  4. Hertog MG, Feskens EJ, Hollman PC, Katan MB, Kromhout D. Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen elderly study. Lancet. 1993;342:1007–1011
  5. Geleijnse JM, Launer LJ, Van der Kuip DAM, Hofmann A, Wittemann JCM. Inverse association of tea and flavonoid intakes with incident myocardial infarction: the Rotterdam study. Am J Clin Nutr. 2002;75:880–886
  6. Yochum L, Kushi LH, Meyer K, Folsom AR. Dietary flavonoid intake and risk of cardiovascular disease in postmenopausal women. Am J Epidemiol. 1999;149:943–949
  7. Rimm EB, Katan MB, Ascheiro A, Stampfer MJ, Willet WC. Relation between intake of flavonoids and risk for coronary heart disease in male health professionals. Ann Intern Med. 1996;125:384–389
  8. Ambra R, Rimbach G, dePascual T, Fuchs D, Wenzel U, Daniel H, et al. Genistein affects the expression of genes involved in blood pressure regulation and angiogenesis in primary human endothelial cells. Nutr Metab Cardiovasc Dis. 2006;16:35–43
  9. Mukamal KJ, Maclure M, Muller JE, Sherwood JB, Mittleman MA. Tea consumption and mortality after acute myocardial infarction. Circulation. 2002;105:2476–2481
  10. Singh BN, Nademanee K. Control of cardiac arrhythmias by selective lengthening of repolarization: theoretic considerations and clinical observations. Am Heart J. 1985;109:421–430
  11. Curran ME, Splawski I, Timothy KW, Vincent GM, Green ED, Keating MT. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT-syndrome. Cell. 1995;80:795–803
  12. Sanguinetti MC, Jurkiewicz NK. Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by class III antiarrhthmic agents. J Gen Physiol. 1990;96(1):195–215
  13. Trudeau MC, Warmke JW, Ganetzky YB, Robertson GA. HERG, a human inward rectifier in the voltage-gated potassium channel family. Science. 1995;269:92–95
  14. Zitron E, Scholz E, Owen RW, Luck S, Kiesecker C, Thomas D, et al. QTc prolongation by grapefruit juice and its potential pharmacological basis: HERG channel blockade by flavonoids. Circulation. 2005;111(7):835–838
  15. Scholz EP, Zitron E, Kiesecker C, Lueck S, Kathöfer S, Thomas D, et al. Drug binding to aromatic residues in the HERG channel pore cavity as possible explanation for acquired long QT syndrome by antiparkinsonian drug budipine. Naunyn Schmiedebergs Arch Pharmacol. 2003;368:404–414
  16. Mitcheson JS, Chen J, Lin M, Culberson C, Sanguinetti MC. A structural basis for drug-induced long QT syndrome. Proc Natl Acad Sci U S A. 2000;97(22):12329–12333
  17. Scholz EP, Zitron E, Kiesecker C, Luck S, Thomas D, Kathofer S, et al. Inhibition of cardiac HERG channels by grapefruit flavonoid naringenin: implications for the influence of dietary compounds on cardiac repolarisation. Naunyn Schmiedebergs Arch Pharmacol. 2005;371(6):516–525
  18. Fernandez D, Ghanta A, Kauffman G, Sanguinetti M. Physicochemical features of the HERG channel drug binding site. J Biol Chem. 2004;279:10120–10127
  19. Pearlstein RA, Vaz RJ, Kang J, Chen XL, Preobrazhenskaya M, Shchekotikhin AE, et al. Characterization of HERG potassium channel inhibition using CoMSiA 3D QSAR and homology modelling approaches. Bioorg Med Chem Lett. 2003;13:1829–1835
  20. Ho PC, Saville DJ, Wanwimolruk S. Inhibition of human CYP3A4 activity by grapefruit flavonoids, furanocoumarins and related compounds. J Pharm Sci. 2001;4(3):217–227
  21. Redfern WS, Carlsson L, Davis AS, Lynch WG, MacKenzie I, Palethorpe S, et al. 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. Cardiovasc Res. 2003;58:32–45
  22. Nielsen ILF, Chee WSS, Poulsen L, Offord-Cavin E, Rasmussen SA, Frederiksen H, et al. Bioavailability is improved by enzymatic modification of the citrus flavonoid hesperidin in humans: a randomized, double-blind, crossover-trial. J Nutr. 2006;136(2):404–408
  23. Doostdar H, Burke MD, Mayer RT. Bioflavonoids: selective substrates and inhibitors for cytochrome p450 cyp1a1 and cyp1b1. Toxicology. 2000;144(1–3):31–38
  24. Breinholt VM, Offord EA, Brouwer C, Nielsen SE, Brosen K, Friedberg T. In vitro investigation of cytochrome p450-mediated metabolism of dietary flavonoids. Food Chem Toxicol. 2002;40(5):609–616
  25. Silbergerg M, Morand C, Mathevon T, Besson C, Manach C, Scalbert A, et al. The bioavailability of polyphenols is highly governed by the capacity of the intestine and the liver to secrete conjugated metabolites. Eur J Nutr. 2006;45(2):88–96
  26. Roden DM. Proarrhythmia as a pharmacogenomic entity: a critical review and formulation of a unifying hypothesis. Cardiovasc Res. 2005;67:419–425
  27. Roden DM, Viswanathan PC. Genetics of acquired long QT syndrome. J Clin Invest. 2005;115:2025–2032
  28. Huikuri HV, Castellanos A, Myerburg RJ. Sudden death due to cardiac arrhythmias. N Engl J Med. 2001;345:1473–1482
  29. Roden DM, Balser JR, George AL, Anderson ME. Cardiac ion channels. Annu Rev Physiol. 2002;64:431–475
  30. Kiehn J, Thomas D, Karle CA, Schöls W, Kübler W. Inhibitory effects of the class III antiarrhythmic drug amiodarone on cloned HERG potassium channels. Naunyn-Schmiedeberg's Arch Pharmacol. 1999;359:212–219

PII: S0939-4753(06)00140-2

doi: 10.1016/j.numecd.2006.06.002

Nutrition, Metabolism & Cardiovascular Diseases
Volume 17, Issue 9 , Pages 666-675 , November 2007