Basic biochemical mechanisms behind the health benefits of polyphenols.

Polyphenols and consequently many flavonoids have several beneficial actions on human health. However, the actual molecular interactions of polyphenols with biological systems remain mostly speculative. This review addresses the potential mechanisms of action that have been so far identified, as well as the feasibility that they could occur in vivo. Those mechanisms include: i) non specific actions, based on chemical features common to most polyphenols, e.g. the presence of a phenol group to scavenge free radicals; and ii) specific mechanisms; based on particular structural and conformational characteristics of select polyphenols and the biological target, e.g. proteins, or defined membrane domains. A better knowledge about the nature and biological consequences of polyphenol interactions with cell components will certainly contribute to develop nutritional and pharmacological strategies oriented to prevent the onset and/or the consequences of human disease.

[1]  Y. Fujimura,et al.  The 67kDa laminin receptor as a primary determinant of anti-allergic effects of O-methylated EGCG. , 2007, Biochemical and biophysical research communications.

[2]  C. Fraga,et al.  Procyanidin dimer B2 [epicatechin-(4beta-8)-epicatechin] in human plasma after the consumption of a flavanol-rich cocoa. , 2002, The American journal of clinical nutrition.

[3]  Derek Stewart,et al.  The inhibitory effects of berry polyphenols on digestive enzymes , 2005, BioFactors.

[4]  Y. Shirataki,et al.  Differential interaction of Sophora isoflavonoids with lipid bilayers. , 2002, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[5]  J. Laranjinha,et al.  Dietary polyphenols generate nitric oxide from nitrite in the stomach and induce smooth muscle relaxation. , 2009, Toxicology.

[6]  E. Kaxiras,et al.  Complexation of flavonoids with iron: structure and optical signatures. , 2008, The journal of physical chemistry. B.

[7]  T. Miyase,et al.  Relationship between the biological activities of methylated derivatives of (-)-epigallocatechin-3-O-gallate (EGCG) and their cell surface binding activities. , 2007, Journal of agricultural and food chemistry.

[8]  Helgi I. Ingólfsson,et al.  The inhibitory effect of (-)-epigallocatechin gallate on activation of the epidermal growth factor receptor is associated with altered lipid order in HT29 colon cancer cells. , 2007, Cancer research.

[9]  A. Imberty,et al.  Interactions between flavan-3-ols and poly(L-proline) studied by isothermal titration calorimetry: effect of the tannin structure. , 2007, Journal of agricultural and food chemistry.

[10]  S. Cole,et al.  Fruit and vegetable intake and risk of cardiovascular disease: the Women's Health Study. , 2000, The American journal of clinical nutrition.

[11]  J. Slotte,et al.  Characterization of flavonoid--biomembrane interactions. , 2002, Archives of biochemistry and biophysics.

[12]  Koji Yamada,et al.  Lipid raft‐associated catechin suppresses the FcϵRI expression by inhibiting phosphorylation of the extracellular signal‐regulated kinase1/2 , 2004, FEBS letters.

[13]  B. Holub,et al.  Supplementation with quercetin markedly increases plasma quercetin concentration without effect on selected risk factors for heart disease in healthy subjects. , 1998, The Journal of nutrition.

[14]  M. Nair,et al.  Structure-activity relationships for antioxidant activities of a series of flavonoids in a liposomal system. , 1998, Free radical biology & medicine.

[15]  K. Uchino,et al.  Hesperidin as an inhibitor of lipases from porcine pancreas and Pseudomonas. , 1997, Bioscience, biotechnology, and biochemistry.

[16]  D. Lombardo,et al.  In vitro polyphenol effects on activity, expression and secretion of pancreatic bile salt-dependent lipase. , 2005, Biochimica et biophysica acta.

[17]  B. Aggarwal,et al.  Caffeic acid phenethyl ester is a potent and specific inhibitor of activation of nuclear transcription factor NF-kappa B. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[18]  E. Feskens,et al.  Cocoa intake, blood pressure, and cardiovascular mortality: the Zutphen Elderly Study. , 2006, Archives of internal medicine.

[19]  J. Laranjinha,et al.  Diffusion of nitric oxide through the gastric wall upon reduction of nitrite by red wine: physiological impact. , 2010, Nitric oxide : biology and chemistry.

[20]  J. Vita,et al.  Grapes and cardiovascular disease. , 2009, The Journal of nutrition.

[21]  I. Yamazaki,et al.  ESR spin-trapping studies on the reaction of Fe2+ ions with H2O2-reactive species in oxygen toxicity in biology. , 1990, The Journal of biological chemistry.

[22]  C. Fraga,et al.  Antioxidant actions of flavonoids: thermodynamic and kinetic analysis. , 2010, Archives of biochemistry and biophysics.

[23]  M Carlquist,et al.  Structure of the ligand‐binding domain of oestrogen receptor beta in the presence of a partial agonist and a full antagonist , 1999, The EMBO journal.

[24]  J. Salonen,et al.  Flavonoid intake and the risk of ischaemic stroke and CVD mortality in middle-aged Finnish men: the Kuopio Ischaemic Heart Disease Risk Factor Study , 2008, British Journal of Nutrition.

[25]  M. Couturier,et al.  Chain-breaking activity of resveratrol and piceatannol in a linoleate micellar model. , 2008, Chemistry and physics of lipids.

[26]  C. Fraga,et al.  Epicatechin in human plasma: in vivo determination and effect of chocolate consumption on plasma oxidation status. , 2000, The Journal of nutrition.

[27]  N. J. Baxter,et al.  Multiple interactions between polyphenols and a salivary proline-rich protein repeat result in complexation and precipitation. , 1997, Biochemistry.

[28]  L. Klotz,et al.  Protein modification elicited by oxidized low-density lipoprotein (LDL) in endothelial cells: protection by (-)-epicatechin. , 2007, Free radical biology & medicine.

[29]  J. M. Delfino,et al.  Dimeric procyanidins are inhibitors of NF-kappaB-DNA binding. , 2009, Biochemical pharmacology.

[30]  S. Martinez,et al.  Cyclic Voltammetry Investigation of the Phenolic Content of Croatian Wines , 2004, American Journal of Enology and Viticulture.

[31]  C. Fraga,et al.  Antioxidant and membrane effects of procyanidin dimers and trimers isolated from peanut and cocoa. , 2005, Journal of agricultural and food chemistry.

[32]  R. F. D. Souza,et al.  Antioxidant properties of complexes of flavonoids with metal ions. , 2004 .

[33]  Koji Yamada,et al.  A difference between epigallocatechin‐3‐gallate and epicatechin‐3‐gallate on anti‐allergic effect is dependent on their distinct distribution to lipid rafts , 2004, BioFactors.

[34]  Ramaroson Andriantsitohaina,et al.  Estrogen Receptor Alpha as a Key Target of Red Wine Polyphenols Action on the Endothelium , 2010, PloS one.

[35]  D. Peterson,et al.  Epicatechin carbonyl-trapping reactions in aqueous maillard systems: Identification and structural elucidation. , 2006, Journal of agricultural and food chemistry.

[36]  H. Frierson,et al.  Enhanced gamma-glutamyl transpeptidase expression and selective loss of CuZn superoxide dismutase in hepatic iron overload. , 1998, Free radical biology & medicine.

[37]  C. Fraga,et al.  Cocoa, Chocolate, and Cardiovascular Disease , 2009, Journal of cardiovascular pharmacology.

[38]  Kai Simons,et al.  Lipid Rafts As a Membrane-Organizing Principle , 2010, Science.

[39]  P. Plastina,et al.  Structure-activity relationships of resveratrol and derivatives in breast cancer cells. , 2009, Molecular nutrition & food research.

[40]  W. Ling,et al.  Anthocyanin Prevents CD40-Activated Proinflammatory Signaling in Endothelial Cells by Regulating Cholesterol Distribution , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[41]  D. Das,et al.  Grapes, Wines, Resveratrol, and Heart Health , 2009, Journal of cardiovascular pharmacology.

[42]  M. Messina A brief historical overview of the past two decades of soy and isoflavone research. , 2010, The Journal of nutrition.

[43]  E. Weitzberg,et al.  Nonenzymatic nitric oxide production in humans. , 1998, Nitric oxide : biology and chemistry.

[44]  E. Feskens,et al.  Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study , 1993, The Lancet.

[45]  G. Batta,et al.  Inhibitory effects of tannin on human salivary α-amylase , 2004 .

[46]  S. Daniels,et al.  Summary of American Heart Association Diet and Lifestyle Recommendations Revision 2006 , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[47]  W. Bors,et al.  Reactions of linoleic acid peroxyl radicals with phenolic antioxidants: a pulse radiolysis study. , 1987, International journal of radiation biology and related studies in physics, chemistry, and medicine.

[48]  C. Fraga,et al.  Procyanidins protect Caco-2 cells from bile acid- and oxidant-induced damage. , 2006, Free radical biology & medicine.

[49]  J. Vaya,et al.  The relation between the chemical structure of flavonoids and their estrogen-like activities. , 2004, Current medicinal chemistry.

[50]  W. Koppenol,et al.  Reactions of iron(II) nucleotide complexes with hydrogen peroxide , 1990 .

[51]  J. Cillard,et al.  Involvement of phenoxyl radical intermediates in lipid antioxidant action of myricetin in iron-treated rat hepatocyte culture. , 1998, Biochemical pharmacology.

[52]  J. Kyle,et al.  Plant polyphenols: are they the new magic bullet? , 2003, Proceedings of the Nutrition Society.

[53]  S. Yusuf,et al.  Dietary Patterns and the Risk of Acute Myocardial Infarction in 52 Countries: Results of the INTERHEART Study , 2008, Circulation.

[54]  J. M. Delfino,et al.  Epicatechin, catechin, and dimeric procyanidins inhibit PMA‐induced NF‐κB activation at multiple steps in Jurkat T cells , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[55]  N. Hollenberg,et al.  (-)-Epicatechin mediates beneficial effects of flavanol-rich cocoa on vascular function in humans. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[56]  C. Fraga,et al.  (-)-Epicatechin and related procyanidins modulate intracellular calcium and prevent oxidation in Jurkat T cells , 2008, Free radical research.

[57]  S A van Acker,et al.  Structural aspects of antioxidant activity of flavonoids. , 1996, Free radical biology & medicine.

[58]  M. Thompson,et al.  Stability of flavonoid complexes of copper(II) and flavonoid antioxidant activity. , 1976, Analytica chimica acta.

[59]  H. Sies,et al.  (-)-Epicatechin elevates nitric oxide in endothelial cells via inhibition of NADPH oxidase. , 2007, Biochemical and biophysical research communications.

[60]  W. Alrefai,et al.  Green tea catechin EGCG inhibits ileal apical sodium bile acid transporter ASBT. , 2010, American journal of physiology. Gastrointestinal and liver physiology.

[61]  A. Driessen,et al.  The uncoupling efficiency and affinity of flavonoids for vesicles. , 2000, Biochemical pharmacology.

[62]  Q. Guo,et al.  Studies on protective mechanisms of four components of green tea polyphenols against lipid peroxidation in synaptosomes. , 1996, Biochimica et biophysica acta.

[63]  O. Kwon,et al.  Inhibition of the intestinal glucose transporter GLUT2 by flavonoids , 2007, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[64]  Nathan R. Perron,et al.  A Review of the Antioxidant Mechanisms of Polyphenol Compounds Related to Iron Binding , 2009, Cell Biochemistry and Biophysics.

[65]  G. Bray,et al.  A clinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group. , 1997, The New England journal of medicine.

[66]  M. Armand Lipases and lipolysis in the human digestive tract: where do we stand? , 2007, Current opinion in clinical nutrition and metabolic care.

[67]  Chi-Tang Ho,et al.  Trapping reactions of reactive carbonyl species with tea polyphenols in simulated physiological conditions. , 2006, Molecular nutrition & food research.

[68]  Donna Spiegelman,et al.  Fruit and vegetable intake and risk of major chronic disease. , 2004, Journal of the National Cancer Institute.

[69]  Olga Pechanova,et al.  Hypertension, nitric oxide, oxidants, and dietary plant polyphenols. , 2010, Current pharmaceutical biotechnology.

[70]  C. Fraga,et al.  Flavonoid-membrane Interactions: A Protective Role of Flavonoids at the Membrane Surface? , 2005, Clinical & developmental immunology.

[71]  J. Sunamoto,et al.  Interaction of flavonoids with 1,1-diphenyl-2-picrylhydrazyl free radical, liposomal membranes and soybean lipoxygenase-1. , 1988, Biochemical pharmacology.

[72]  W. Bors,et al.  Flavonoids as antioxidants: determination of radical-scavenging efficiencies. , 1990, Methods in enzymology.

[73]  C. Fraga Plant polyphenols: How to translate their in vitro antioxidant actions to in vivo conditions , 2007, IUBMB life.

[74]  G. Williamson,et al.  Dietary intake and bioavailability of polyphenols. , 2000, The Journal of nutrition.

[75]  Q Xie,et al.  Structure-activity relationships for a large diverse set of natural, synthetic, and environmental estrogens. , 2001, Chemical research in toxicology.

[76]  P. Oteiza,et al.  Modulation of transcription factor NF-κB in Hodgkin's lymphoma cell lines: Effect of (−)-epicatechin , 2006, Free radical research.

[77]  C. Fraga,et al.  Flavan-3-ols and procyanidins protect liposomes against lipid oxidation and disruption of the bilayer structure. , 2003, Free radical biology & medicine.

[78]  M. Guo,et al.  Iron-binding and anti-Fenton properties of baicalein and baicalin. , 2009, Journal of inorganic biochemistry.

[79]  J. Steinberger,et al.  Fruit and vegetable consumption and its relation to markers of inflammation and oxidative stress in adolescents. , 2009, Journal of the American Dietetic Association.

[80]  A. Crozier,et al.  Dietary Flavonoids and Phenolic Compounds , 2009 .

[81]  S. Jaganathan,et al.  Antiproliferative Effects of Honey and of Its Polyphenols: A Review , 2009, Journal of biomedicine & biotechnology.

[82]  R. Lamuela-Raventós,et al.  Matrix effects on the bioavailability of resveratrol in humans , 2010 .

[83]  Dongmin Liu,et al.  Green tea catechins and cardiovascular health: an update. , 2008, Current medicinal chemistry.

[84]  M. Ligumsky,et al.  The stomach as a "bioreactor": when red meat meets red wine. , 2008, Journal of agricultural and food chemistry.

[85]  G. Schuler,et al.  Effect of cocoa products on blood pressure: systematic review and meta-analysis. , 2010, American journal of hypertension.

[86]  E. Middleton,et al.  The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. , 2000, Pharmacological reviews.

[87]  Frank Hu,et al.  The Effect of Fruit and Vegetable Intake on Risk for Coronary Heart Disease , 2001, Annals of Internal Medicine.

[88]  T. Lüscher,et al.  Cocoa and Cardiovascular Health , 2009, Circulation.

[89]  H. Sakai,et al.  (-)-Epigallocatechin gallate inhibits growth and activation of the VEGF/VEGFR axis in human colorectal cancer cells. , 2010, Chemico-biological interactions.

[90]  B. Frei,et al.  Dietary flavonoids attenuate tumor necrosis factor alpha-induced adhesion molecule expression in human aortic endothelial cells. Structure-function relationships and activity after first pass metabolism. , 2006, The Journal of biological chemistry.

[91]  G. Rimbach,et al.  Activity of monomeric, dimeric, and trimeric flavonoids on NO production, TNF‐α secretion, and NF‐κB‐dependent gene expression in RAW 264.7 macrophages , 2000 .

[92]  J. Corton,et al.  Interaction of Estrogenic Chemicals and Phytoestrogens with Estrogen Receptor β. , 1998, Endocrinology.

[93]  P. Oteiza,et al.  Dimeric procyanidin B2 inhibits constitutively active NF-kappaB in Hodgkin's lymphoma cells independently of the presence of IkappaB mutations. , 2008, Biochemical pharmacology.

[94]  B. Murray,et al.  Effects of tea polyphenols on emulsification of olive oil in a small intestine model system. , 2006, Journal of agricultural and food chemistry.

[95]  Souad Bousserouel,et al.  Apple procyanidins activate apoptotic signaling pathway in human colon adenocarcinoma cells by a lipid-raft independent mechanism. , 2009, Biochemical and biophysical research communications.

[96]  C. Fraga,et al.  TNFalpha-induced NF-kappaB activation and cell oxidant production are modulated by hexameric procyanidins in Caco-2 cells. , 2008, Archives of biochemistry and biophysics.

[97]  A. Sum,et al.  Molecular binding of catechins to biomembranes: relationship to biological activity. , 2009, Journal of agricultural and food chemistry.