Human metabolic transformation of quercetin blocks its capacity to decrease endothelial nitric oxide synthase (eNOS) expression and endothelin-1 secretion by human endothelial cells

Journal of Agricultural and Food Chemistry

Volumn 61, Issue 36, 2013, Pages 8589-8596

  Tribolo, Sandra ^a   Lodi, Federica ^a,b   Winterbone, Mark S ^a   Saha, Shika ^a   Needs, Paul W ^a   Hughes, David A ^a   Kroon, Paul A ^a  

^a INSTITUTE OF FOOD RESEARCH   (United Kingdom)

^b EUROPEAN FOOD SAFETY AUTHORITY   (Italy)

Author keywords

blood pressure; cardiovascular disease; endothelial function; flavonoids; flavonols; human metabolism; polyphenols

Indexed keywords

CARDIO-VASCULAR DISEASE; ENDOTHELIAL FUNCTION; FLAVONOLS; HUMAN METABOLISMS; POLYPHENOLS;

BIOMOLECULES; BLOOD PRESSURE; ENDOTHELIAL CELLS; GENE EXPRESSION; METABOLISM; METABOLITES; NITRIC OXIDE; PHENOLS; PHYSIOLOGY;

FLAVONOIDS;

ENDOTHELIAL NITRIC OXIDE SYNTHASE; ENDOTHELIN 1; MESSENGER RNA; QUERCETIN;

ADULT; ARTICLE; BLOOD; CELL CULTURE; DRUG EFFECT; ENDOTHELIUM CELL; GENE EXPRESSION; GENETICS; HUMAN; MALE; METABOLISM; SECRETION (PROCESS); UMBILICAL VEIN ENDOTHELIAL CELL;

ADULT; CELLS, CULTURED; ENDOTHELIAL CELLS; ENDOTHELIN-1; GENE EXPRESSION; HUMAN UMBILICAL VEIN ENDOTHELIAL CELLS; HUMANS; MALE; NITRIC OXIDE SYNTHASE TYPE III; QUERCETIN; RNA, MESSENGER;

EID: 84884221597     PISSN: 00218561     EISSN: 15205118     Source Type: Journal    
DOI: 10.1021/jf402511c     Document Type: Article

References (57)

1. Brown, A. A.; Hu, F. B. Dietary modulation of endothelial function: implications for cardiovascular disease Am. J. Clin. Nutr. 2001, 73, 673-686
2. Corder, R.; Douthwaite, J. A.; Lees, D. M.; Khan, N. Q.; Viseu dos Santos, A. C.; Wood, E. G.; Carrier, M. J. Health: endothelin-1 synthesis reduced by red wine Nature 2001, 414, 863-864
3. Moncada, S.; Higgs, A. The l -arginine-nitric oxide pathway N. Engl. J. Med. 1993, 329, 2002-2012
4. Ross, R. Atherosclerosis-an inflammatory disease N. Engl. J. Med. 1999, 340, 115-126
5. Stoclet, J. C.; Chataigneau, T.; Ndiaye, M.; Oak, M. H.; El Bedoui, J.; Chataigneau, M.; Schini-Kerth, V. B. Vascular protection by dietary polyphenols Eur. J. Pharmacol. 2004, 500, 299-313
6. Hooper, L.; Kroon, P. A.; Rimm, E. B.; Cohn, J. S.; Harvey, I.; Le Cornu, K. A.; Ryder, J. J.; Hall, W. L.; Cassidy, A. Flavonoids, flavonoid-rich foods, and cardiovascular risk: a meta-analysis of randomized controlled trials Am. J. Clin. Nutr. 2008, 88, 38-50
7. Mursu, J.; Nurmi, T.; Tuomainen, T. P.; Salonen, J. T.; Pukkala, E.; Voutilainen, S. Intake of flavonoids and risk of cancer in Finnish men: The Kuopio Ischaemic Heart Disease Risk Factor Study Int. J. Cancer 2008, 123, 660-663
8. Hertog, M. G.; Hollman, P. C.; Katan, M. B.; Kromhout, D. Intake of potentially anticarcinogenic flavonoids and their determinants in adults in The Netherlands Nutr. Cancer 1993, 20, 21-29
9. Egert, S.; Bosy-Westphal, A.; Seiberl, J.; Kurbitz, C.; Settler, U.; Plachta-Danielzik, S.; Wagner, A. E.; Frank, J.; Schrezenmeir, J.; Rimbach, G.; Wolffram, S.; Muller, M. J. Quercetin reduces systolic blood pressure and plasma oxidised low-density lipoprotein concentrations in overweight subjects with a high-cardiovascular disease risk phenotype: a double-blinded, placebo-controlled cross-over study Br. J. Nutr. 2009, 102, 1065-1074
10. Edwards, R. L.; Lyon, T.; Litwin, S. E.; Rabovsky, A.; Symons, J. D.; Jalili, T. Quercetin reduces blood pressure in hypertensive subjects J. Nutr. 2007, 137, 2405-2411
11. Loke, W. M.; Hodgson, J. M.; Proudfoot, J. M.; McKinley, A. J.; Puddey, I. B.; Croft, K. D. Pure dietary flavonoids quercetin and (-)-epicatechin augment nitric oxide products and reduce endothelin-1 acutely in healthy men Am. J. Clin. Nutr. 2008, 88, 1018-1025
12. Duarte, J.; Perez-Palencia, R.; Vargas, F.; Ocete, M. A.; Perez-Vizcaino, F.; Zarzuelo, A.; Tamargo, J. Antihypertensive effects of the flavonoid quercetin in spontaneously hypertensive rats Br. J. Pharmacol. 2001, 133, 117-124
13. Galisteo, M.; Garcia-Saura, M. F.; Jimenez, R.; Villar, I. C.; Zarzuelo, A.; Vargas, F.; Duarte, J. Effects of chronic quercetin treatment on antioxidant defence system and oxidative status of deoxycorticosterone acetate-salt- hypertensive rats Mol. Cell. Biochem. 2004, 259, 91-99
14. Jalili, T.; Carlstrom, J.; Kim, S.; Freeman, D.; Jin, H.; Wu, T. C.; Litwin, S. E.; David Symons, J. Quercetin-supplemented diets lower blood pressure and attenuate cardiac hypertrophy in rats with aortic constriction J. Cardiovasc. Pharmacol. 2006, 47, 531-541
15. Sanchez, M.; Galisteo, M.; Vera, R.; Villar, I. C.; Zarzuelo, A.; Tamargo, J.; Perez-Vizcaino, F.; Duarte, J. Quercetin downregulates NADPH oxidase, increases eNOS activity and prevents endothelial dysfunction in spontaneously hypertensive rats J. Hypertens. 2006, 24, 75-84
16. Loke, W. M.; Proudfoot, J. M.; Hodgson, J. M.; McKinley, A. J.; Hime, N.; Magat, M.; Stocker, R.; Croft, K. D. Specific dietary polyphenols attenuate atherosclerosis in apolipoprotein E-knockout mice by alleviating inflammation and endothelial dysfunction Arterioscler. Thromb. Vasc. Biol. 2010, 30, 749-757
17. Taubert, D.; Berkels, R.; Klaus, W.; Roesen, R. Nitric oxide formation and corresponding relaxation of porcine coronary arteries induced by plant phenols: essential structural features J. Cardiovasc. Pharmacol. 2002, 40, 701-713
18. Perez-Vizcaino, F.; Ibarra, M.; Cogolludo, A. L.; Duarte, J.; Zaragoza-Arnaez, F.; Moreno, L.; Lopez-Lopez, G.; Tamargo, J. 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
19. Khoo, N. K.; White, C. R.; Pozzo-Miller, L.; Zhou, F.; Constance, C.; Inoue, T.; Patel, R. P.; Parks, D. A. Dietary flavonoid quercetin stimulates vasorelaxation in aortic vessels Free Radical Biol. Med. 2010, 49, 339-347
20. Appeldoorn, M. M.; Venema, D. P.; Peters, T. H.; Koenen, M. E.; Arts, I. C.; Vincken, J. P.; Gruppen, H.; Keijer, J.; Hollman, P. C. Some phenolic compounds increase the nitric oxide level in endothelial cells in vitro J. Agric. Food Chem. 2009, 57, 7693-7699
21. Nicholson, S. K.; Tucker, G. A.; Brameld, J. M. Physiological concentrations of dietary polyphenols regulate vascular endothelial cell expression of genes important in cardiovascular health Br. J. Nutr. 2010, 103, 1398-1403
22. Day, A. J.; Mellon, F.; Barron, D.; Sarrazin, G.; Morgan, M. R.; Williamson, G. Human metabolism of dietary flavonoids: identification of plasma metabolites of quercetin Free Radical Res. 2001, 35, 941-952
23. Kroon, P. A.; Clifford, M. N.; Crozier, A.; Day, A. J.; Donovan, J. L.; Manach, C.; Williamson, G. How should we assess the effects of exposure to dietary polyphenols in vitro? Am. J. Clin. Nutr. 2004, 80, 15-21
24. Sesink, A. L. A.; O'Leary, K. A.; Hollman, P. C. H. Quercetin gluouronides but not glucosides are present in human plasma after consumption of quercetin-3-glucoside or quercetin-4′-glucoside J. Nutr. 2001, 131, 1938-1941
25. Perez-Vizcaino, F.; Duarte, J.; Santos-Buelga, C. The flavonoid paradox: conjugation and deconjugation as key steps for the biological activity of flavonoids J. Sci. Food Agric. 2012, 92, 1822-1825
26. Tribolo, S.; Lodi, F.; Connor, C.; Suri, S.; Wilson, V. G.; Taylor, M. A.; Needs, P. W.; Kroon, P. A.; Hughes, D. A. Comparative effects of quercetin and its predominant human metabolites on adhesion molecule expression in activated human vascular endothelial cells Atherosclerosis 2008, 197, 50-56
27. Suri, S.; Liu, X. H.; Rayment, S.; Hughes, D. A.; Kroon, P. A.; Needs, P. W.; Taylor, M. A.; Tribolo, S.; Wilson, V. G. Quercetin and its major metabolites selectively modulate cyclic GMP-dependent relaxations and associated tolerance in pig isolated coronary artery Br. J. Pharmacol. 2010, 159, 566-575
28. Winterbone, M. S.; Tribolo, S.; Needs, P. W.; Kroon, P. A.; Hughes, D. A. Physiologically relevant metabolites of quercetin have no effect on adhesion molecule or chemokine expression in human vascular smooth muscle cells Atherosclerosis 2009, 202, 431-438
29. Rus, H. G.; Niculescu, F.; Vlaicu, R. Tumor necrosis factor-α in human arterial wall with atherosclerosis Atherosclerosis 1991, 89, 247-254
30. Needs, P. W.; Kroon, P. A. Convenient syntheses of metabolically important quercetin glucuronides and sulfates Tetrahedron 2006, 62, 6862-6868
31. Naseem, K. M. The role of nitric oxide in cardiovascular diseases Mol. Aspects Med. 2005, 26, 33-65
32. Douglas, G.; Channon, K. M. The pathogenesis of atherosclerosis Medicine 2010, 38, 397-402
33. Yen, G. C.; Duh, P. D.; Tsai, H. L.; Huang, S. L. Pro-oxidative properties of flavonoids in human lymphocytes Biosci., Biotechnol., Biochem. 2003, 67, 1215-1522
34. Choi, E. J.; Chee, K. M.; Lee, B. H. Anti- and prooxidant effects of chronic quercetin administration in rats Eur. J. Pharmacol. 2003, 482, 281-285
35. Zhao, L.; Wu, J.; Wang, Y.; Yang, J.; Wei, J.; Gao, W.; Guo, C. Cholesterol metabolism is modulated by quercetin in rats J. Agric. Food Chem. 2011, 59, 1104-1108
36. Chiesi, M.; Schwaller, R. Inhibition of constitutive endothelial nosynthase activity by tannin and quercetin Biochem. Pharmacol. 1995, 49, 495-501
37. Jackson, S. J.; Venema, R. C. Quercetin inhibits eNOS, microtubule polymerization, and mitotic progression in bovine aortic endothelial cells J. Nutr. 2006, 136, 1178-1184
38. 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 Radical Biol. Med. 1999, 26, 107-116
39. Cao, G.; Sofic, E.; Prior, R. L. Antioxidant and prooxidant behavior of flavonoids: structure-activity relationships Free Radical Biol. Med. 1997, 22, 749-760
40. Tan, J.; Wang, B.; Zhu, L. DNA binding and oxidative DNA damage induced by a quercetin copper(II) complex: potential mechanism of its antitumor properties J. Biol. Inorg. Chem. 2009, 14, 727-739
41. Lodi, F.; Jimenez, R.; Menendez, C.; Needs, P. W.; Duarte, J.; Perez-Vizcaino, F. Glucuronidated metabolites of the flavonoid quercetin do not auto-oxidise, do not generate free radicals and do not decrease nitric oxide bioavailability Planta Med. 2008, 74, 741-746
42. Lopez-Lopez, G.; Moreno, L.; Cogolludo, A.; Galisteo, M.; Ibarra, M.; Duarte, J.; Lodi, F.; Tamargo, J.; Perez-Vizcaino, F. Nitric oxide (NO) scavenging and NO protecting effects of quercetin and their biological significance in vascular smooth muscle Mol. Pharmacol. 2004, 65, 851-859
43. Lodi, F.; Jimenez, R.; Moreno, L.; Kroon, P. A.; Needs, P. W.; Hughes, D. A.; Santos-Buelga, C.; Gonzalez-Paramas, A.; Cogolludo, A.; Lopez-Sepulveda, R.; Duarte, J.; Perez-Vizcaino, F. Glucuronidated and sulfated metabolites of the flavonoid quercetin prevent endothelial dysfunction but lack direct vasorelaxant effects in rat aorta Atherosclerosis 2009, 204, 34-39
44. Chan, G. C.; Fish, J. E.; Mawji, I. A.; Leung, D. D.; Rachlis, A. C.; Marsden, P. A. Epigenetic basis for the transcriptional hyporesponsiveness of the human inducible nitric oxide synthase gene in vascular endothelial cells J. Immunol. 2005, 175, 3846-3861
45. Zhao, X.; Gu, Z.; Attele, A. S.; Yuan, C. S. Effects of quercetin on the release of endothelin, prostacyclin and tissue plasminogen activator from human endothelial cells in culture J. Ethnopharmacol. 1999, 67, 279-285
46. Donnini, S.; Finetti, F.; Lusini, L.; Morbidelli, L.; Cheynier, V.; Barron, D.; Williamson, G.; Waltenberger, J.; Ziche, M. Divergent effects of quercetin conjugates on angiogenesis Br. J. Nutr. 2006, 95, 1016-1023
47. Matsuura, A.; Yamochi, W.; Hirata, K.; Kawashima, S.; Yokoyama, M. Stimulatory interaction between vascular endothelial growth factor and endothelin-1 on each gene expression Hypertension 1998, 32, 89-95
48. Mullen, W.; Edwards, C. A.; Crozier, A. Absorption, excretion and metabolite profiling of methyl-, glucuronyl-, glucosyl- and sulpho-conjugates of quercetin in human plasma and urine after ingestion of onions Br. J. Nutr. 2006, 96, 107-116
49. Lee, J.; Ebeler, S. E.; Zweigenbaum, J. A.; Mitchell, A. E. UHPLC-(ESI)QTOF MS/MS profiling of quercetin metabolites in human plasma postconsumption of applesauce enriched with apple peel and onion J. Agric. Food Chem. 2012, 60, 8510-8520
50. Canali, R.; Ambra, R.; Stelitano, C.; Mattivi, F.; Scaccini, C.; Virgili, F. A novel model to study the biological effects of red wine at the molecular level Br. J. Nutr. 2007, 97, 1053-1058
51. Loke, W. M.; Proudfoot, J. M.; Stewart, S.; McKinley, A. J.; Needs, P. W.; Kroon, P. A.; Hodgson, J. M.; Croft, K. D. Metabolic transformation has a profound effect on anti-inflammatory activity of flavonoids such as quercetin: lack of association between antioxidant and lipoxygenase inhibitory activity Biochem. Pharmacol. 2008, 75, 1045-1053
52. Loke, W. M.; Proudfoot, J. M.; McKinley, A. J.; Needs, P. W.; Kroon, P. A.; Hodgson, J. M.; Croft, K. D. Quercetin and its in vivo metabolites inhibit neutrophil-mediated low-density lipoprotein oxidation J. Agric. Food Chem. 2008, 56, 3609-3615
53. O'Leary, K. A.; Day, A. J.; Needs, P. W.; Sly, W. S.; O'Brien, N. M.; Williamson, G. Flavonoid glucuronides are substrates for human liver β-glucuronidase FEBS Lett. 2001, 503, 103-106
54. Shimoi, K.; Saka, N.; Nozawa, R.; Sato, M.; Amano, I.; Nakayama, T.; Kinae, N. Deglucuronidation of a flavonoid, luteolin monoglucuronide, during inflammation Drug Metab. Dispos. 2001, 29, 1521-1524
55. Kawai, Y.; Nishikawa, T.; Shiba, Y.; Saito, S.; Murota, K.; Shibata, N.; Kobayashi, M.; Kanayama, M.; Uchida, K.; Terao, J. Macrophage as a target of quercetin glucuronides in human atherosclerotic arteries: implication in the anti-atherosclerotic mechanism of dietary flavonoids J. Biol. Chem. 2008, 283, 9424-9434
56. Menendez, C.; Duenas, M.; Galindo, P.; Gonzalez-Manzano, S.; Jimenez, R.; Moreno, L.; Zarzuelo, M. J.; Rodriguez-Gomez, I.; Duarte, J.; Santos-Buelga, C.; Perez-Vizcaino, F. Vascular deconjugation of quercetin glucuronide: the flavonoid paradox revealed? Mol. Nutr. Food Res. 2011, 55, 1780-1790
57. Al-Shalmani, S.; Suri, S.; Hughes, D. A.; Kroon, P. A.; Needs, P. W.; Taylor, M. A.; Tribolo, S.; Wilson, V. G. Quercetin and its principal metabolites, but not myricetin, oppose lipopolysaccharide-induced hyporesponsiveness of the porcine isolated coronary artery Br. J. Pharmacol. 2011, 162, 1485-1497