Interactions of gallic acid, resveratrol, quercetin and aspirin at the platelet cyclooxygenase-1 level Functional and modelling studies

Marilena Crescente; Gisela Jessen; Stefania Momi; Hans-Dieter Höltje; Paolo Gresele; Chiara Cerletti; Giovanni de Gaetano

doi:10.1160/TH09-01-0057

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2009; 102(02): 336-346
DOI: 10.1160/TH09-01-0057

Platelets and Blood Cells

Schattauer GmbH

Interactions of gallic acid, resveratrol, quercetin and aspirin at the platelet cyclooxygenase-1 level Functional and modelling studies

Marilena Crescente

¹Research Laboratories, “John Paul II” Center for High Technology Research and Education in Biomedical Sciences, Catholic University, Campobasso, Italy

,

Gisela Jessen

²Institut für Pharmazeutische und Medizinische Chemie, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany

,

Stefania Momi

³Department of Internal Medicine, Division of Internal and Cardiovascular Medicine, University of Perugia, Perugia, Italy

,

Hans-Dieter Höltje

²Institut für Pharmazeutische und Medizinische Chemie, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany

,

Paolo Gresele

³Department of Internal Medicine, Division of Internal and Cardiovascular Medicine, University of Perugia, Perugia, Italy

,

Chiara Cerletti

¹Research Laboratories, “John Paul II” Center for High Technology Research and Education in Biomedical Sciences, Catholic University, Campobasso, Italy

,

Giovanni de Gaetano

¹Research Laboratories, “John Paul II” Center for High Technology Research and Education in Biomedical Sciences, Catholic University, Campobasso, Italy

› Author Affiliations

Abstract

Summary

While resveratrol and quercetin possess antiplatelet activity, little is known on the effect of gallic acid on platelets.We studied the interactions of these three different polyphenols among themselves and with aspirin, at the level of platelet cyclooxygenase-1 (COX-1). Both functional (in vitro and in vivo) and molecular modelling approaches were used. All three polyphenols showed comparable antioxidant activity (arachidonic acid [AA]-induced intraplatelet ROS production); however, resveratrol and quercetin, but not gallic acid, inhibited AA-induced platelet aggregation. Gallic acid, similarly to salicylic acid, the major aspirin metabolite, prevented inhibition of AA-induced platelet function by aspirin but, at variance with salicylic acid, also prevented inhibition by the other two polyphenols. Molecular modelling studies, performed by in silico docking the polyphenols into the crystal structure of COX-1, suggested that all compounds form stable complexes into the COX-1 channel, with slightly different but functionally relevant interaction geometries. Experiments in mice showed that gallic acid administered before aspirin, resveratrol or quercetin fully prevented their inhibitory effect on serum TxB2. Finally, a mixture of resveratrol, quercetin and gallic acid, at relative concentrations similar to those contained in most red wines, did not inhibit platelet aggregation, but potentiated sub-inhibitory concentrations of aspirin. Gallic acid interactions with other polyphenols or aspirin at the level of platelet COX-1 might partly explain the complex,and possibly contrasting, effects of wine and other components of the Mediterranean diet on platelets and on the pharmacologic effect of lowdose aspirin.

Keywords

Platelets - aspirin - dietary polyphenols - COX-1 inhibition - fooddrug interaction

Full Text

References

References
1 de Lorgeril M, Salen P, Martin J-L. et al. Wine Drinking and Risks of Cardiovascular Complications After Recent Acute Myocardial Infarction. Circulation 2002; 106: 1465-1469.
2 Di Castelnuovo A, Rotondo S, Iacoviello L. et al. Meta-analysis of wine and beer consumption in relation to vascular risk. Circulation 2002; 105: 2836-2844.
3 Huxley RR, Neil HA. The relation between dietary flavonol intake and coronary heart disease mortality: a meta-analysis of prospective cohort studies. Eur J Clin Nutr 2003; 57: 904-908.
4 Kuriyama S, Shimazu T, Ohmori K. et al. Green tea consumption and mortality due to cardiovascular disease, cancer, and all causes in Japan: the Ohsaki study. J Am Med Assoc 2006; 296: 1255-1265.
5 di Giuseppe R, Di Castelnuovo A, Centritto F. et al. Regular consumption of dark chocolate is associated with low serum concentrations of C-reactive protein in a healthy Italian population. J Nutr 2008; 138: 1939-1945.
6 Sofi F, Cesari F, Abbate R. et al. Adherence to Mediterranean diet and health status: meta-analysis. Br Med J 2008; 337: a1344.
7 Manach C, Williamson G, Morand C. et al. Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am J Clin Nutr 2005; 81: 230S-242S.
8 Flammer AJ, Hermann F, Sudano I. et al. Dark chocolate improves coronary vasomotion and reduces platelet reactivity. Circulation 2007; 116: 2376-2382.
9 Pace-Asciak CR, Hahn S, Diamandis EP. et al. The red wine phenolics trans-resveratrol and quercetin block human platelet aggregation and eicosanoid synthesis: implications for protection against coronary heart disease. Clin Chim Acta 1995; 235: 207-219.
10 Rotondo S, Rotilio D, Cerletti C. et al. Red wine, aspirin and platelet function. Thromb Haemost 1996; 76: 818-819.
11 Janssen K, Mensink RP, Cox FJ. et al. Effects of the flavonoids quercetin and apigenin on hemostasis in healthy volunteers: results from an in vitro and a dietary supplement study. Am J Clin Nutr 1998; 67: 255-262.
12 Pignatelli P, Pulcinelli FM, Celestini A. et al. The flavonoids quercetin and catechin synergistically inhibit platelet function by antagonizing the intracellular production of hydrogen peroxide. Am J Clin Nutr 2000; 72: 1150-1155 Erratum in Am J Clin Nutr 2001;73: 360.
13 Freedman JE, Parker 3rd C, Li L. et al. Select flavonoids and whole juice from purple grapes inhibit platelet function and enhance nitric oxide release. Circulation 2001; 103: 2792-2798.
14 Shen MY, Hsiao G, Liu CL. et al. Inhibitory mechanisms of resveratrol in platelet activation: pivotal roles of p38 MAPK and NO/cyclic GMP. Br J Haematol 2007; 139: 475-485.
15 Olas B, Saluk-Juszczak J, Wachowicz B. D-glucaro 1,4-lactone and resveratrol as antioxidants in blood platelets. Cell Biol Toxicol 2008; 24: 189-199.
16 Cerletti C, Livio M, de Gaetano G. Non-steroidal anti-inflammatory drugs react with two sites on platelet cyclo-oxygenase. Evidence from “in vivo” drug interaction studies in rats. Biochim Biophys Acta 1982; 714: 122-128.
17 de Gaetano G, Cerletti C, Dejana E. et al. Pharmacology of platelet inhibition in humans: implications of the salicylate-aspirin interaction. Circulation 1985; 72: 1185-1193.
18 Loll PJ, Picot D, Garavito RM. The structural basis of aspirin activity inferred from the cristal structure of inactivated prostaglandin H2 synthase. Nat Struct Biol 1995; 02: 637-643.
19 Appeldoorn CC, Bonnefoy A, Lutters BC. et al. Gallic acid antagonizes P-selectin-mediated plateletleukocyte interactions: implications for the French paradox. Circulation 2005; 111: 106-112.
20 Burns J, Gardner PT, O’Neil J. et al. Relationship among antioxidant activity, vasodilation capacity, and phenolic content of red wines. J Agric Food Chem 2000; 48: 220-230.
21 Burow S, Valet G. Flow-cytometric characterization of stimulation, free radical formation, peroxidase activity and phagocytosis of human granulocytes with 2,7-dichlorofluorescein (DCF). Eur J Cell Biol 1987; 43: 128-133.
22 Maresca M, Colao C, Leoncini G. Generation of hydrogen peroxide in resting and activated platelets. Cell Biochem Funct 1992; 10: 79-85.
23 Krötz F, Sohn HY, Pohl U. Reactive oxygen species: players in the platelet game. Arterioscler Thromb Vasc Biol 2004; 24: 1988-1996.
24 Born GVR, Cross MJ. The aggregation of blood platelets. J Physiol 1963; 168: 178-195.
25 Pampuch A, Cerletti C, de Gaetano G. Comparison of VASP-phosphorylation assay to light-transmission aggregometry in assessing inhibition of the platelet ADP P2Y12 receptor. Thromb Haemost 2006; 96: 767-773.
26 Lill G, Voit S, Schrör K. et al. Complex effects of different green tea catechins on human platelets. FEBS Lett 2003; 546: 265-270.
27 Rarey M, Kramer B, Lengauer T. et al. A fast flexible docking method using an incremental construction algorithm. J Mol Biol 1996; 261: 470-489.
28 Lindhal E, Hess B, van der Spoel D. GROMACS 3.0: a package for molecular simulation and trajectory analysis. J Mol Model 2001; 07: 306-317.
29 Hohlfeld T, Zimmermann N, Weber AA. et al. Pyrazolinone analgesics prevent the antiplatelet effect of aspirin and preserve human platelet thromboxane synthesis. J Thromb Haemost 2008; 06: 166-173.
30 Momi S, Pitchford SC, Alberti PF. et al. Nitroaspirin plus clopidogrel versus aspirin plus clopidogrel against platelet thromboembolism and intimal thickening in mice. Thromb Haemost 2005; 93: 535-543.
31 Roth GJ, Stanford N, Majerus PW. Acetylation of prostaglandin synthase by aspirin. Proc Natl Acad Sci USA 1975; 72: 3073-3076.
32 Livio M, Del Maschio A, Cerletti C. et al. Indomethacin prevents the long-lasting inhibitory effect of aspirin on human platelet cyclo-oxygenase activity. Prostaglandins 1982; 23: 787-796.
33 Cerletti C, Livio M, Doni MG. et al. Salicylate fails to prevent the inhibitory effect of 5,8,11,14-eicosatetraynoic acid on human platelet cyclo-oxygenase and lipoxygenase activities. Biochim Biophys Acta 1983; 759: 125-127.
34 Crescente M, Cerletti C, de Gaetano G. Gallic acid, a dietary polyphenolic component, blunts the inhibition of platelet COX-1 by aspirin: preliminary in-vitro findings. Thromb Haemost 2007; 97: 1054-1056.
35 Picot D, Loll PJ, Garavito RM. The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1. Nature 1994; 367: 243-249.
36 Handler N, Brunhofer G, Studenik C. et al. ‘Bridged’ stilbene derivatives as selective cyclooxygenase-1 inhibitors. Bioorg Med Chem 2007; 15: 6109-6118.
37 Shahrzad S, Aoyagi K, Winter A. et al. Pharmacokinetics of gallic acid and its relative bioavailability from tea in healthy humans. J Nutr 2001; 131: 1207-1210.
38 Meng X, Maliakal P, Lu H. et al. Urinary and plasma levels of resveratrol and quercetin in humans, mice, and rats after ingestion of pure compounds and grape juice. J Agric Food Chem 2004; 52: 935-942.
39 Walle T, Hsieh F, DeLegge MH. et al. High absorption but very low bioavailability of oral resveratrol in humans. Drug Metab Dispos 2004; 32: 1377-1382.
40 Seeram NP, Lee R, Heber D. Bioavailability of ellagic acid in human plasma after consumption of ellagitannins from pomegranate (Punica granatum L.) juice. Clin Chim Acta 2004; 348: 63-68.
41 Labieniec M, Gabryelak T. Interactions of tannic acid and its derivatives (ellagic and gallic acid) with calf thymus DNA and bovine serum albumin using spectroscopic method. J Photochem Photobiol B 2006; 82: 72-78.
42 Ciccarone E, Di Castelnuovo A, Salcuni M. et al. A high-score Mediterranean dietary pattern is associated with a reduced risk of peripheral arterial disease in Italian patients with Type 2 diabetes. J Thromb Haemost 2003; 01: 1744-1752.
43 Trichopoulou A, Costacou T, Bamia C. et al. Adherence to a Mediterranean diet and survival in a Greek population. N Engl J Med 2003; 348: 2599-2608.
44 Martínez-González MA, Fuente-Arrillaga CD, Nunez-Cordoba JM. et al. Adherence to Mediterranean diet and risk of developing diabetes: prospective cohort study. Br Med J 2008; 336: 1348-1351.
45 Gambino MC, Passaghe S, Chen ZM. et al. Selectivity of oral aspirin as an inhibitor of platelet vs vascular cyclooxygenase activity is reduced by portacaval shunt in rats. J Pharmacol Exp Ther 1988; 245: 287-290.
46 Konishi Y, Hitomi Y, Yoshioka E. Intestinal absorption of p-coumaric and gallic acids in rats after oral administration. J Agric Food Chem 2004; 52: 2527-2532.
47 Heptinstall S, May J, Fox S. et al. Cocoa flavanols and platelet and leukocyte function: recent in vitro and ex vivo studies in healthy adults. J Cardiovasc Pharmacol 2006; 47 (Suppl. 02) S197-205.
48 Maree AO, Fitzgerald DJ. Variable platelet response to aspirin and clopidogrel in atherothrombotic disease. Circulation 2007; 115: 2196-2207.
49 Zimmermann N, Hohlfeld T. Clinical implications of aspirin resistance. Thromb Haemost 2008; 100: 379-390.
50 MacDonald TM, Wei L. Effect of ibuprofen on cardioprotective effect of aspirin. Lancet 2003; 361: 573-574.