Planta Med 2005; 71(12): 1118-1122
DOI: 10.1055/s-2005-873174
Original Paper
Pharmacology
© Georg Thieme Verlag KG Stuttgart · New York

The Action of Quercetin on the Mitochondrial NADH to NAD+ Ratio in the Isolated Perfused Rat Liver

Gisele D. Buss1 , Jorgete Constantin1 , Leonardo C. N. de Lima1 , Graziele R. Teodoro1 , Jurandir F. Comar1 , Emy L. Ishii-Iwamoto1 , Adelar Bracht1
  • 1Laboratory of Liver Metabolism, University of Maringá, 87020900 Maringá, Brazil
Further Information

Publication History

Received: February 10, 2005

Accepted: June 10, 2005

Publication Date:
10 November 2005 (online)

Abstract

It has been suggested that active forms of quercetin (o-semiquinones) are able to oxidize NADH in mammalian cells. The purpose of this study was to investigate this proposition by measuring the β-hydroxybutyrate to acetoacetate ratio as an indicator of the mitochondrial NADH/NAD+ redox ratio in the isolated perfused rat liver. The NADH to NAD+ ratio was reduced by quercetin; half-maximal reduction occurred at a concentration of 32.6 μM. Additionally, quercetin (25 to 300 μM) stimulated the Krebs cycle (14CO2 production) and inhibited oxygen uptake (50 to 300 μM). Low quercetin concentrations (25 μM) stimulated oxygen uptake. The results of the present work confirm the hypothesis that quercetin is able to participate in the oxidation of NADH in mammalian cells, shifting the cellular conditions to a more oxidized state (prooxidant activity). Stimulation of the Krebs cycle was probably caused by the increased NAD+ availability whereas the decreased NADH availability and the inhibition of mitochondrial energy transduction could be the main causes for oxygen uptake inhibition.

References

  • 1 Chan T, Galati G, O'Brien P J. Oxygen activation during peroxidase catalysed metabolism of flavones or flavanones.  Chem Biol Interact. 1999;  122 15-25
  • 2 Galati G, Sabzevari O, Wilson J X, O’Brien P J. Prooxidant activity and cellular effects of the phenoxyl radicals of dietary flavonoids and other polyphenolics.  Toxicology. 2002;  177 91-104
  • 3 Suolinna E M, Bushsbaum R N, Racker E. The effect of flavonoids on aerobic glycolysis and growth of tumor cells.  Cancer Res. 1975;  35 1865-72
  • 4 Trejo R, Valad Ez-Salazar A, Delhumeau G. Effects of quercetin on rat testis aerobic glycolysis.  Can J Physiol Pharmacol. 1995;  73 1605-15
  • 5 Lamson D W, Brignall M S. Antioxidants and cancer III: Quercetin.  Altern Med Rev. 2000;  5 196-208
  • 6 Ferry D R, Smith A, Malkhandi J, Fyfe D W, de Takats P G, Anderson D. et al . Phase I clinical trial of the flavonoid quercetin: pharmacokinetics and evidence for in vivo tyrosinase kinase inhibition.  Clin Cancer Res. 1996;  2 659-68
  • 7 Hansen R K, Oesterrreich S, Lemieux P, Sarge K D, Fuqua S A. Quercetin inhibits heat shock protein induction but not heat shock factor DNA-binding in human breast carcinoma cells.  Biochem Biophys Res Commun. 1997;  239 851-6
  • 8 Ranelletti F O, Maggiano N, Serra F G, Ricci R, Larocca L M, Lanza P. et al . Quercetin inhibits p21-RAS expression in human colon cancer cell lines and in primary colorectal tumors.  Int J Cancer. 2000;  85 438-45
  • 9 Gasparin F RS, Salgueiro-Pagadigorria C S, Bracht L, Ishii-Iwamoto E L, Bracht A, Constantin J. The action of quercetin on glycogen catabolism in the rat liver.  Xenobiotica. 2003;  33 587-602
  • 10 Gasparin F RS, Spitzner F L, Ishii-Iwamoto E L, Bracht A, Constantin J. Actions of quercetin on gluconeogenesis and glycolysis in rat liver.  Xenobiotica. 2003;  33 903-11
  • 11 Metodiewa D, Jaiswal A K, Cenas N, Dickancaite E, Segura-Aguilar J. Quercetin may act as a cytotoxic prooxidant after its metabolic activation to semiquinone and quinoidal product.  Free Radic Biol Med. 1999;  26 107-16
  • 12 Cenas N K, Kanapieniene J J, Kulys J J. NADH oxidation by quinone electron acceptors.  Biochim Biophys Acta. 1984;  767 108-12
  • 13 Aebi H. Catalase.  In: Methods of Enzymatic Analysis,. Bergmeyer HU, editor New York; Pergamon 1974: pp 673-84
  • 14 Pütter J. Peroxidases.  In: Methods of Enzymatic Analysis,. Bergmeyer HU, editor New York; Academic Press 1974: pp 685-90
  • 15 Mason R P, Fischer V. Free radicals of acetaminophen: their subsequent reactions and toxicological significance.  Fed Proc. 1986;  45 2493-9
  • 16 Komatsu H, Koo A, Ghadishah E, Zeng H, Kuhlenkamp J F, Inoue M. et al . Neutrophill accumulation in ischemic reperfused rat liver: evidence for a role for superoxide free radicals.  Am J Physiol. 1992;  262 G669-76
  • 17 Sies H. Nicotinamide nucleotide compartmentation.  In: Metabolic Compartmentation,. Sies S, editor New York; Academic Press 1982: pp 205-31
  • 18 Kimura R E, Warshaw J B. Control of fatty acid oxidation by intra-mitochondrial [NADH]/[NAD+] in developing rat small intestine.  Pediatr Res. 1988;  23 262-5
  • 19 Morand C, Crespy V, Manach C, Besson C, Demigne C, Remesy C. Plasma metabolites of quercetin and their antioxidant properties.  Am J Physiol. 1998;  275 R212-9
  • 20 Kelmer-Bracht A M, Ishii E L, Andrade P VM, Bracht A. Construction of a liver perfusion apparatus for studies on metabolic regulation and mechanisms of drug action.  Arq Biol Tecnol. 1984;  27 419-38
  • 21 Scholz R, Bücher T. Hemoglobin-free perfusion of rat liver.  In: Control of Energy Metabolism,. Chance B, Estabrook RW, Williamson JR, editors New York; Academic Press 1965: pp 393-414
  • 22 Soboll S, Scholz R, Heldt H W. Subcellular metabolite concentrations. Dependence of mitochondrial and cytosolic ATP systems on the metabolic state of perfused rat liver.  Eur J Biochem. 1978;  87 377-90
  • 23 Soboll S, Heldt H W, Scholz R. Changes in the subcellular distribution of metabolites due to ethanol oxidation in the perfused rat liver.  Hoppe Seylers Z Physiol Chem. 1981;  362 247-60
  • 24 Clark L C. Monitoring and control of blood O2 tension.  Trans Am Soc Artif Intern Organs. 1956;  2 41-9
  • 25 Mellanby J, Williamson D H. Acetoacetate.  In: Methods of Enzymatic Analysis,. Bergmeyer HU, editor New York; Academic Press 1974: pp 1840-3
  • 26 Williamson D H, Mellanby J. D-(-)-3-Hydroxybutyrate.  In: Methods of Enzymatic Analysis,. Bergmeyer HU, editor New York; Academic Press 1974: pp 1836-9
  • 27 Scholz R, Olson M S, Schwab A J, Schwabe U, Noell C H, Braun W. The effect of fatty acids on the regulation of pyruvate dehydrogenase in perfused rat liver.  Eur J Biochem. 1978;  86 519-30
  • 28 Voss D O, Campello A P, Bacila M. The respiratory chain and the oxidative phosphorylation of rat brain mitochondria.  Biochem Biophys Res Commun. 1961;  4 48-51
  • 29 Bracht A, Ishii-Iwamoto E L, Salgueiro-Pagadigorria C L. O estudo do metabolismo energético em mitocôndrias isoladas de tecido animal.  In: Métodos de Laboratório em Biogaímica,. Bracht A, Ishii-Iwamoto EL, editors São Paulo; Manole 2003: pp 227-47
  • 30 Lowry O H, Rosebrough N J, Farr A C, Randall R J. Protein measurement with the Folin phenol reagent.  J Biol Chem. 1951;  193 265-75
  • 31 Chance B, Williams G R. A simple and rapid assay of oxidative phosphorylation.  Nature. 1955;  175 1120-1
  • 32 Gugler R, Leschik M, Dengler H J. Disposition of quercetin in man after single oral and intravenous doses.  Eur J Clin Pharmacol. 1975;  9 229-34
  • 33 Dynnik V V, Temnov A V. A mathematical model of the pyruvate oxidation in liver mitochondria. 1. Regulation of the Krebs cycle by adenine and pyridine nucleotides.  Biokhimiia. 1977;  42 1030-44
  • 34 Pilz H, O'Brien J S, Heipertz R. Human leukocyte peroxidase: activity of a soluble and membrane-bound enzyme form in normal persons and patients with neuronal ceroid-lipofuscinosis.  Metabolism. 1976;  25 561-70
  • 35 Chiovato L, Lapi P, Mariotti S, Del Prete G, De Carli M, Pinchera A. Simultaneous expression of thyroid peroxidase and human leukocyte antigen-DR by human thyroid cells: modulation by thyrotropin, thyroid-stimulating antibody, and interferon-gamma.  J Clin Endocr Metab. 1994;  79 653-6

Adelar Bracht

Laboratory of Liver Metabolism

Department of Biochemistry

University of Maringá

87020900 Maringá

Brazil

Fax: +55-44-3261-4896

Email: adebracht@uol.com.br

    >