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DOI: 10.1055/s-2008-1074525
© Georg Thieme Verlag KG Stuttgart · New York
Glucuronidated Metabolites of the Flavonoid Quercetin do not Auto-Oxidise, do not Generate Free Radicals and do not Decrease Nitric Oxide Bioavailability
Publication History
Received: October 31, 2007
Revised: March 6, 2008
Accepted: March 19, 2008
Publication Date:
16 May 2008 (online)
Abstract
Quercetin, the most abundant flavonoid in the diet, reduces blood pressure and restores endothelial dysfunction in hypertensive animals. However, quercetin (as the aglycone) is usually not present in plasma, but it is rapidly metabolised during absorption by methylation, glucuronidation and sulfation. Depending on the experimental conditions, quercetin can show anti-oxidant or pro-oxidant effects. We have analysed the pro-oxidant effects of quercetin and its methylated (3-methylquercetin or isorhamnetin), sulfated (quercetin 3′-sulfate), glucuronidated (quercetin 3-glucuronide) and methylated plus glucuronidated (isorhamnetin 3-glucuronide) metabolites. Auto-oxidation, O2 - release and NO scavenging were analysed by means of absorption spectra, lucigenin chemiluminescence or superoxide dismutase inhibitable cytochrome C reduction and an amperometric electrode, respectively. The biological activity of NO was tested in rat aortic rings. Quercetin, isorhamnetin and quercetin 3′-sulfate auto-oxidized in aqueous buffer and generated superoxide radical. Quercetin but not the glucuronide scavenged NO. In contrast, the glucuronides were without effect. Quercetin, but not quercetin 3-glucuronide, inhibited the biological activity of NO. These data indicate that, in contrast to quercetin, its main circulating forms, i. e., the glucuronides, do not exert pro-oxidant effects.
Abbreviations
DMSO: dimethyl sulfoxide
NO: nitric oxide
O2 -: superoxide
ROS: reactive oxygen species
Key words
Quercetin - conjugated metabolites - nitric oxide - pro-oxidant and antioxidant effects
References
- 1 Hertog M GL, Feskens E JM, Hollman P CH, Katan M B, Kromhout D. Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. Lancet. 1993; 342 1007-11
- 2 Huxley R R, Neil H A. The relation between dietary flavonol intake and coronary heart disease mortality: a meta-analysis of prospective cohort studies. Eur J Clin Nutr. 2003; 57 904-8
- 3 Duarte J, Perez Vizcaino F, Utrilla P, Jimenez J, Tamargo J, Zarzuelo A. Vasodilatory effects of flavonoids in rat aortic smooth muscle. Structure-activity relationships. Gen Pharmacol. 1993; 24 857-62
- 4 Perez-Vizcaino F, Ibarra M, Cogolludo A L, Duarte J, Zaragoza-Arnaez F, Moreno L. et al . Endothelium-independent vasodilator effects of the flavonoid quercetin and its methylated metabolites in rat conductance and resistance arteries. J Pharmacol Exp Ther. 2002; 302 66-72
- 5 Ibarra M, Perez-Vizcaino F, Cogolludo A L, Duarte J, Zaragoza-Arnaez F, Lopez-Lopez J G. et al . Cardiovascular effects of isorhamnetin and quercetin in isolated rat and porcine vascular smooth muscle and isolated atria. Planta Med. 2002; 68 307-10
- 6 Duarte J, Perez-Palencia R, Vargas F, Ocete M A, Perez-Vizcaino F, Zarzuelo A et a l.. Antihypertensive effects of the flavonoid quercetin in spontaneously hypertensive rats. Br J Pharmacol. 2001; 133 117-24
- 7 Duarte J, Jimenez R, O′Valle F, Galisteo M, Perez-Palencia R, Vargas F. et al . Protective effects of the flavonoid quercetin in chronic nitric oxide deficient rats. J Hypertens. 2002; 20 1843-54
- 8 Robak J, Gryglewski R J. Flavonoids are scavengers of superoxide anions. Biochem Pharmacol. 1988; 37 837-41
- 9 de Whalley C V, Rankin S M, Hoult J RS, Jessup W, Wilkins G M, Collard J. et al . Modification of low-density lipoproteins by flavonoids. Biochem Soc Trans. 1990; 18 1172-3
- 10 Duarte J, Galisteo M, Ocete M A, Perez-Vizcaino F, Zarzuelo A, Tamargo J. Effects of chronic quercetin treatment on hepatic oxidative status of spontaneously hypertensive rats. Mol Cell Biochem. 2001; 221 155-60
- 11 Sanchez M, Galisteo M, Vera R, Villar I C, Zarzuelo A, Tamargo J. et al . Quercetin downregulates NADPH oxidase, increases eNOS activity and prevents endothelial dysfunction in spontaneously hypertensive rats. J Hypertens. 2006; 24 75-84
- 12 Ibarra M, Moreno L, Vera R, Cogolludo A, Duarte J, Tamargo J. et al . Effects of the flavonoid quercetin and its methylated metabolite isorhamnetin in isolated arteries from spontaneously hypertensive rats. Planta Med. 2003; 69 995-1000
- 13 Perez Vizcaino F, Duarte J, Andriantsitohaina R. Endothelial function and cardiovascular disease: effects of quercetin and wine polyphenols. Free Radic Res. 2006; 40 1054-65
- 14 Canada A T, Gianella E, Nguyen T D, Mason R P. The production of reactive oxygen species by dietary flavonoids. Free Radic Biol Med. 1990; 9 441-9
- 15 Lopez-Lopez G, Moreno L, Cogolludo A, Galisteo M, Ibarra M, Duarte J. et al . Nitric oxide scavenging and NO protecting effects of quercetin and their biological significance in vascular smooth muscle. Mol Pharmacol. 2004; 65 851-9
- 16 Hajji H E, Nkhili E, Tomao V, Dangles O. Interactions of quercetin with iron and copper ions: complexation and autoxidation. Free Radic Res. 2006; 40 303-20
- 17 Van Acker S A, Tromp M N, Haenen G R, van der Vijgh W J, Bast A. Flavonoids as scavengers of nitric oxide radical. Biochem Biophys Res Commun. 1995; 214 755-9
- 18 Haenen G RMM, Bast A. Nitric oxide radical scavenging of flavonoids. Methods Enzymol. 1999; 301 490-503
- 19 Kroon P A, Clifford M N, Crozier A, Day A J, Donovan J L, Manach C. et al . How should we assess the effects of exposure to dietary polyphenols in vitro?. Am J Clin Nutr. 2004; 80 15-21
- 20 Manach C, Morand C, Crespy V, Demigne C, Texier O, Regerat F. et al . Quercetin is recovered in human plasma as conjugated derivatives which retain antioxidant properties. FEBS Lett. 1998; 24 331-6
- 21 Day A J, Mellon F, Barron D, Sarrazin G, Morgan M RA, Williamson G. Human metabolism of dietary flavonoids: Identification of plasma metabolites of quercetin. Free Radic Res. 2001; 35 941-52
- 22 Needs P W, Kroon P A. Convenient syntheses of metabolically important quercetin glucuronides and sulfates. Tetrahedron. 2006; 62 6862-8
- 23 Cos P, Ying L, Calomme M, Hu J P, Cimanga K, Van Poel B. et al . Structure-activity relationship and classification of flavonoids as inhibitors of xanthine oxidase and superoxide scavengers. J Nat Prod. 1998; 61 71-6
- 24 Shirai M, Moon J H, Tsushida T, Terao J. Inhibitory effect of a quercetin metabolite, quercetin 3-O-beta-d-glucuronide, on lipid peroxidation in liposomal membranes. J Agric Food Chem. 2001; 49 5602-8
- 25 Cogolludo A, Frazziano G, Briones A M, Cobeno L, Moreno L, Lodi F. et al . The dietary flavonoid quercetin activates BKCa currents in coronary arteries via production of H2O2. Role in vasodilatation. Cardiovasc Res. 2007; 73 424-31
- 26 Dangles O, Fargeix G, Dufour C. One-electron oxidation of quercetin and quercetin derivatives in protic and non protic media. J Chem Soc [Perkin I] 1999: 1387-95
- 27 Jimenez R, Andriambeloson E, Duarte J, Andriantsitohaina R, Jimenez J, Perez-Vizcaino F. et al . Involvement of thromboxane A2 in the endothelium-dependent contractions induced by myricetin in rat isolated aorta. Br J Pharmacol. 1999; 127 1539-44
Prof. Francisco Pérez Vizcaino
Department of Pharmacology
School of Medicine
Universidad Complutense
28040 Madrid
Spain
Phone: +34-91-394-1477
Fax: +34-91-394-1465
Email: fperez@med.ucm.es