Abstract
Flavonoids are found ubiquitously in higher plants and constitute an important component of the majority of peoples' daily diets. The biological activities of flavonoids cover a very broad spectrum, from anticancer and antibacterial activities through to inhibition of bone resorption. In the present paper, the interactions between flavonoids and lipid bilayers as well as biological membranes and their components are reviewed, with special emphasis on the structure-activity relationships and mechanisms underlying the biological activity of flavonoids.
Similar content being viewed by others
Article PDF
Abbreviations
- ABC:
-
ATP binding cassette protein
- ABCB1:
-
P-gp, P-glycoprotein
- ABCC1:
-
MRP1, multidrug resistance-related protein
- ANS:
-
1-anilinonaphthalene-8-sulfonic acid
- C:
-
catechin
- CFTR:
-
cystic fibrosis transmembrane conductance regulator
- DOPC:
-
1,2-dioleoyl-sn-glycero-3-phosphocholine
- DPPC:
-
1,2-dipalmitoyl-sn-glycero-3-phosphocholine
- EC:
-
epicatechin
- ECG:
-
epigallocatechin
- EGCG:
-
epigallocatechin gallate
- EYPC:
-
egg yolk phosphatidylcholine
- GSH:
-
glutathione
- HPLC:
-
high pressure liquid chromatography
- LDL:
-
low density lipoprotein
- MDR:
-
multidrug resistance
- NADH:
-
β-nicotinamide adenine dinucleotide
- NBD:
-
nucleotide binding domain
- NPN:
-
N-phenyl-1-naphthylamine
- POPC:
-
1-palmitoyl-2-oleoyl-sn-glycero-phosphocholine
References
Harborne JB, Williams CA . Advances in flavonoid research since 1992. Phytochemistry 2000; 55: 481–504.
Havsteen BH . The biochemistry and medical significance of the flavonoids. Pharmacol Ther 2002; 96: 67–202.
Heim KE, Tagliaferro AR, Bobilya DJ . Flavonoid antioxidants: chemistry, metabolism and structure-activity relationships. J Nutr Biochem 2002; 13: 572–84.
Barron D, Ibrahim RK, Isoprenylated Flavonoids: A survey. Phytochemistry 1996; 43: 921–82.
Fraschini F, Demartini G, Esposti D . Pharmacology of silymarin. Clin Drug Invest 2002; 22: 51–65.
Brandi ML . Natural and synthetic isoflavones in the prevention and treatment of chronic diseases. Calcif Tissue Int 1997; 61: S5–S8.
Le Marchand L . Cancer preventive effects of flavonoids: a review. Biomed Pharmacother 2002; 56: 296–301.
Mizunuma H, Kanazawa K, Ogura S, Otsuka S, Nagai H . Anticarcinogenic effects of isoflavones may be mediated by genistein in mouse mammary tumor virus-induced breast cancer. Oncology 2002; 62: 78–84.
Kuiper GG, Lemmen JG, Carlsson B, Corton JC, Safe SH, van der Saag PT, et al. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrynology 1998; 139: 4252–63.
Sadzuka Y, Sugiyama T, Shimoi K, Kinae N, Hirota S . Protective effect of flavonoids on doxorubicin-induced cardiotoxicity. Toxicol Lett 1997; 92: 1–7.
Yamaguchi M, Gao YH . Inhibitory effect of genistein on bone resorption in tissue culture. Biochem Pharmacol 1998; 55: 71–6.
Dragsted LO . Antioxidant actions of polyphenols in humans. Int J Vitam Nutr Res 2003; 73: 11–9.
Muscatello U, Alessandrini A, Valdre G, Vannini V, Valdre U . Lipid oxidation deletes the nanodomain organization of artificial membranes. Biochem Biophys Res Commun 2000; 270: 448–52.
Brown DA, London E . Structure and function of sphingolipid-and cholesterol-rich membrane rafts. J Biol Chem 2000; 275: 17221–4.
Edidin M . The state of lipid rafts: from model membranes to cells. Annu Rev Biophys Biomol Struct 2003; 32: 257–83.
Gordon MH . Roedig-Penman A . Antioxidant activity of quercetin and myricetin in liposomes. Chem Phys Lipids 1998; 97: 79–85.
Arora A, Nair MG, Straasburg GM . Antioxidant activities of isoflavones and their biological metabolites in a liposomal system. Arch Biochem Biophys 1998; 356: 133–41.
van Acker SA, van den Berg DJ, Tromp MN, Griffioen DH, van Bennekom WP, van der Vijgh WJ, et al. Structural aspects of antioxidant activity of flavonoids. Free Radic Biol Med 1996; 20: 331–42.
Liao K, Yin M . Individual and combined antioxidant effects of seven phenolic agents in human erythrocyte membrane ghosts and phosphatidylcholine liposome systems: importance of the partition coefficient. J Agric Food Chem 2000; 48: 2266–70.
Madsen HL, Andersen CM, Jorgensen LV, Skibsted LH . Radical scavenging by dietary flavonoids. A kinetic study of antioxidant efficiencies. Eur Food Res Technol 2000; 211: 240–6.
Murota K, Shimizu S, Miyamoto S, Izumi T, Obata A, Kikuchi M, et al. Unique uptake and transport of isoflavone aglycones by human intestinal caco-2 cells: comparison of isoflavonoids and flavonoids. J Nutr 2002; 132: 1956–61.
Yang B, Kotani A, Arai K, Kusu F . Estimation of the antioxidant activities of flavonoids from their oxidation potentials. Anal Sci 2001; 17: 599–604.
Chen ZY, Chan PT, Hoa KY, Funga KP, Wang J . Antioxidant activity of natural flavonoids is governed by number and location of their aromatic hydroxyl groups. Chem Phys Lipids 1996; 79: 157–63.
Galati G, Sabzevari O, Wilson JX, O'Brien PJ . Prooxidant activity and cellular effects of the phenoxyl radicals of dietary flavonoids and other polyphenolics. Toxicology 2002; 177: 91–104.
van Dijk C, Driessen AJ, Recourt K . The uncoupling efficiency and affinity of flavonoids for vesicles. Biochem Pharmacol 2000; 60: 1593–600.
Tammela P, Laitinen L, Galkin A, Wennberg T, Heczko R, Vuorela H, et al. Permeability characteristics and membrane affinity of flavonoids and alkyl gallates in Caco-2 cells and in phospholipid vesicles. Arch Biochem Biophys 2004; 425: 193–9.
Kajiya K, Ichiba M, Kuwabara M, Kumazawa S, Nakayama T . Role of lipophilicity and hydrogen peroxide formation in the cytotoxicity of flavonols. Biosci Biotechnol Biochem 2001; 65: 1227–9.
Movileanu L, Neagoe I, Flonta ML . Interaction of the antioxidant flavonoid quercetin with planar lipid bilayers. Int J Pharm 2000; 205: 135–46.
Saija A, Bonina F, Trombetta D, et al. Flavonoid-biomembrane interactions: a calorimetric study on dipalmitoylphospha-tidylcholine vesicles. Int J Pharm 1995; 124: 1–8.
Saija A, Scalese M, Lanza M, Marzullo D, Bonina F, Castelli F . Flavanoids as antioxidant agents: importance of their interaction with biomembranes. Free Radic Biol Med 1995; 19: 481–6.
Lehtonen JY, Adlercreutz H, Kinnunen PK . Binding of daidzein to liposomes. Biochim Biophys Acta 1996; 1285: 91–100.
Arora A, Byrem TM, Nair MG . Strasburg GM, Modulation of liposomal membrane fluidity by flavonoids and isoflavonoids. Arch Biochem Biophys 2000; 373: 102–9.
Hendrich AB, Malon R, Pola A, Shirataki Y, Motohashi N, Michalak K . Differential interaction of Sophora isoflavonoids with lipid bilayers. Eur J Pharm Sci 2002; 16: 201–8.
Huh NW, Porter NA, McIntosh TJ, Simon SA . The interaction of polyphenols with bilayers: conditions for increasing bilayer adhesion. Biophys J 1996; 71: 3261–77.
Kato R, Kajiya K, Tokumoto H, Kumazawa S, Nakayama T . Affinity of isoflavonoids for lipid bilayers evaluated with liposomal systems. Biofactors 2003; 19: 179–87.
Ollila F, Halling K, Vuorela P, Vuorela H, Slotte JP . Characterization of flavonoid-biomembrane interactions. Arch Biochem Biophys 2002; 399: 103–8.
Lenne-Gouverneur AF, Lobstein A, Haan-Archipoff G, Duportail G, Anton R, Kuhry JG . Interactions of the monomeric and dimeric flavones apigenin and amentoflavone with the plasma membrane of L929 cells; a fluorescence study. Mol Membr Biol 1999; 16: 157–65.
Pawlikowska-Pawlêga B, Gruszecki WI, Misiak LE, Gawron A . The study of the quercetin action on human erythrocyte membranes. Biochem Pharmacol 2003; 66: 605–12.
Wójtowicz K, Pawlikowska-Pawlêga B, Gawron A, Misiak LE, Gruszecki WI . Modifying effect of quercetin on the lipid membrane. Folia Histochem Cytobiol 1996; 34: 49–50.
Scheidt HA, Pampel A, Nissler L, Gebhardt R, Huster D . Investigation of the membrane localization and distribution of flavonoids by high-resolution magic angle spinning NMR spectroscopy. Biochim Biophys Acta 2004; 1663: 97–107.
Tsuchiya H, Iinuma M . Reduction of membrane fluidity by antibacterial sophoraflavanone G isolated from Sophora exigua. Phytomedicine 2000; 7: 161–5.
Morel C, Stermitz FR, Tegos G, Lewis K . Isoflavones as potentiators of antibacterial activity. J Agric Food Chem 2003; 10: 5677–9.
Tsuchiya H, Nagayama M, Tanaka T, Furusawa M, Kashimata M, Takeuchi H . Membrane-rigidifying effects of anti-cancer dietary factors. Biofactors 2003; 16: 45–56.
Furusawa M, Tsuchiya H, Nagayama M, Tanaka T, Nakaya K, Iinuma M . Anti-platelet and membrane-rigidifying flavonoids in brownish scale of onion. J Health Sci 2003; 49: 475–80.
Simon SA, McIntosh TJ . Interdigitated hydrocarbon chain packing causes the biphasic transition behavior in lipid/alcohol suspension. Biochim Biophys Acta 1984; 773: 169–72.
Bondar OP, Pivovarenko VG, Rowe ES . Flavonols: new fluorescent membrane probes for studying the interdigitation of lipid bilayers. Biochim Biophys Acta 1998; 1369: 119–30.
Nakayama T, Ono K, Hashimoto K . Affinity of antioxidative polyphenols for lipid bilayers evaluated with a liposome system. Biosci Biotech Biochem 1998; 62: 1005–7.
Wang H, Provan GJ, Helliwell K . Tea favonoids: their functions, utilisation and analysis. Trends Food Sci Technol 2000; 11: 152–60.
Hashimoto T, Kumazawa S, Nanjo F, Hara Y, Nakayama T . Interaction of tea catechins with lipid bilayers investigated with liposome systems. Biosci Biotechnol Biochem 1999; 63: 2252–5.
Tsuchiya H . Effects of green tea catechins on membrane fluidity. Pharmacology 1999; 59: 34–44.
Verstraeten SV, Keen CL, Schmitz HH, Fraga CG, Oteiza PI . Flavan-3–ols and procyanidins protect liposomes against lipid oxidation and disruption of the bilayer structure. Free Radic Biol Med 2003; 34: 84–92.
Kajiya K, Kumazawa S, Nakayama T . Steric effects on interaction of tea catechins with lipid bilayers. Biosci Biotechnol Biochem 2001; 65: 2638–43.
Tsuchiya H . Stereospecificity in membrane effects of catechins. Chem Biol Interact 2001; 134: 41–54.
Caturla N, Vera-Samper E, Villalain J, Mateo CR, Micol V . The relationship between the antioxidant and the antibacterial properties of galloylated catechins and the structure of phospholipid model membranes. Free Radic Biol Med 2003; 34: 648–62.
Ikigai H, Nakae T, Hara Y, Shimamura T . Bactericidal catechins damage the lipid bilayer. Biochim Biophys Acta 1993; 1147: 132–6.
Kajiya K, Kumazawa S, Nakayama T . Effects of external factors on the interaction of tea catechins with lipid bilayers. Biosci Biotechnol Biochem 2002; 66: 2330–5.
Kitano K, Nam KY, Kimura S, Fujiki H, Imanishi Y . Sealing effects of (-) - epigallocatechin gallate on protein kinase C and protein phosphatase 2A. Biophys Chem 1997; 65: 157–64.
Ford JM, Hait WN . Pharmacology of drugs that alter multidrug resistance in cancer. Pharmacol Rev 1990; 42: 155–99.
Krishna R, Mayer LD . Multidrug resistance (MDR) in cancer. Mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anti-cancer drugs. Eur J Pharm Sci 2000; 11: 265–83.
Gottesman MM, Pastant I, Ambudkar SV . P-glycoprotein and multidrug resistance. Curr Opinion Genet Devel 1996; 6: 610–7.
Blackmore CG, McNaughton PA, van Veen HW . Multidrug trans-porters in prokaryotic and eukaryotic cells: physiological functions and transport mechanisms. Mol Membr Biol 2001; 18: 97–103.
Sugimoto Y, Tsukahara S, Ishikawa E, Mitsuhashi J . Breast cancer resistance protein: Molecular traget for anticancer drug resistance and pharmacokinetics/pharmacodynamics. Cancer Sci 2005; 96: 457–65.
Eytan GD, Regev R, Oren G, Assaraf YG . The role of passive transbilayer drug movement in multidrug resistance and its modulation. J Biol Chem 1996; 271: 12897–902.
Eytan GD, Kuchel PW . Mechanism of action of P-glycoprotein in relation to passive membrane permeation. Int Rev Cytol 1999; 190: 175–250.
Frezard F, Garnier-Suillerot A . Comparison of the membrane transport of anthracycline derivatives in drug-resistant and drug-sensitive K562 cells. Eur J Biochem 1991; 196: 483–91.
Sinicrope FA, Dudeja PK, Bissonnette BM, Safa AR, Brasitus TA . Modulation of P-glycoprotein-mediated drug transport by alterations in lipid fluidity of rat liver canalicular membrane vesicles. J Biol Chem 1992; 267: 24995–5002.
Dudeja PK, Anderson KM, Harris SH, Buckingham L, Coon JS . Reversal of multidrug resistance phenotype by surfactants: relationship to membrane lipid fluidity. Arch Biochem Biophys 1995; 319: 309–15.
Romsicki Y, Sharom FJ . The membrane lipid environment modulates drug interactions with the P-glycoprotein multidrug transporter. Biochemistry 1999; 38: 6887–96.
Hendrich AB, Michalak K . Lipids as a target for drugs modulating multidrug resistance of cancer cells. Curr Drug Targ 2003; 4: 23–30.
Ford JM . Experimental reversal of P-glycoprotein-mediated multidrug resistance by pharmacological chemosensitisers. Eur J Cancer 1996; 32A: 991–1001.
Tsuruo T, Iida H, Tsukagoshi S, Sakurai Y . Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil. Cancer Res 1981; 41: 1967–72.
Critchfield JW, Welsh CL, Phang JM, Yeh GC . Modulation of adriamycin accumulation and efflux by flavonoids in CHT-15 colon cells. Biochem Pharmacol 1994; 48: 1437–45.
Zhang S, Morris ME . Effects of the flavonoids biochanin A, morin, phloretin, and silymarin on P-glycoprotein-mediated transport. J Pharmacol Exp Ther 2003; 304: 1258–67.
Shapiro AB, Ling V . Effect of quercetin on Hoechst 33342 transport by purified and reconstituted P-glycoprotein. Biochem Pharmacol 1997; 53: 587–96.
Di Pietro A, Conseil G, Perez-Victoria JM, Dayan G, Baubichon-Cortay H, Trompier D, et al. Modulation by flavonoids of cell multidrug resistance mediated by P-glycoprotein and related ABC transporters. Cell Mol Life Sci 2002; 59: 307–22.
Boumendjel A, Di Pietro A, Dumontet C, Barron D . Recent advances in the discovery of flavonoids and analogs with high-affnity binding to P-glycoprotein responsible for cancer cell multidrug resistance. Med Res Rev 2002; 22: 512–29.
Hipfner DR, Deeley RG, Cole SP . Structural, mechanistic and clinical aspects of MRP1. Biochim Biophys Acta 1999; 1461: 359–76.
Loe DW, Almquist KC, Deeley RG, Cole SP . Multidrug resistance protein (MRP)-mediated transport of leukotriene C4 and che-motherapeutic agents in membrane vesicles. Demonstration of glutathione-dependent vincristine transport. J Biol Chem 1996; 271: 9675–82.
Leslie EM, Mao Q, Oleschuk CJ, Deeley RG, Cole SP . Modulation of multidrug resistance protein 1 (MRP1/ABCC1) transport and ATPase activities by interaction with dietary flavonoids. Mol Pharmacol 2001; 59: 1171–80.
Leslie EM, Deeley RG, Cole SP . Bioflavonoid stimulation of glutathione transport by the 190–kDa multidrug resistance protein 1 (MRP1). Drug Metab Dispos 2003; 31: 11–5.
Nguyen H, Zhang S, Morris ME . Effect of flavonoids on MRP1–mediated transport in Panc-1 cells. J Pharm Sci 2003; 92: 250–7.
van Zanden JJ, Wortelboer HM, Bijlsma S, Punt A, Usta M, Bladeren PJ, et al. Quantitative structure-activity relationship studies on the flavonoid mediated inhibition of multidrug resistance proteins 1 and 2. Biochem Pharmacol 2005; 69: 699–708.
Rychlik B, Pulaski L, Sokal A, Soszyñski M, Bartosz G . Transport of organic anions by multidrug resistance-associated protein in the erythrocyte. Acta Biochim Polon 2000; 47: 763–72.
Rychlik B, Balcerczyk A, Klimczak A, Bartosz G . The role of multidrug resistance protein 1 (MRP1) in transport of fluorescent anions across the human erythrocyte membrane. J Membr Biol 2003; 193: 79–90.
Bobrowska-Hagerstrand M, Wrobel A, Rychlik B, Bartosz G, Soderstrom T, Shirataki Y, et al. Monitoring of MRP-like activity in human erythrocytes: inhibitory effect of isoflavones. Blood Cells Molec Dis 2001; 27: 894–900.
Bobrowska-Hägerstrand M, Wróbel A, Mrówczyñska L, Söderström T, Hägerstrand H . Modulation of MRP1–like efflux activity in human erythrocytes caused by membrane perturbing agents. Mol Membr Biol 2003; 20: 255–9.
Trompier D, Baubichon-Cortay H, Chang XB, Maitrejean M, Barron D, Riordon JR, et al. Multiple flavonoid-binding sites within multidrug resistance protein MRP1. Cell Mol Life Sci 2003; 60: 2164–77.
Hooijberg JH, Broxterman HJ, Heijn M, Fles DL, Lankelma J, Pinedo HM . Modulation by (iso)flavonoids of the ATPase activity of the multidrug resistance protein. FEBS Lett 1997; 413: 344–8.
Conseil G, Baubichon-Cortay H, Dayan G, Jault JM, Barron D, Di Pietro A . Flavonoids: a class of modulators with bifunctional interactions at vicinal ATP- and steroid-binding sites on mouse P-glycoprotein. Proc Natl Acad Sci USA 1998; 95: 9831–6.
Wang EJ, Barecki-Roach M, Johnson WW . Elevation of P-glycoprotein function by a catechin in green tea. Biochem Biophys Res Commun 2002; 297: 412–8.
Andersen OS, Finkelstein A, Katz I, Cass A . Effect of phloretin on the permeability of thin lipid membranes. J Gen Physiol 1976; 67: 749–71.
Okamoto F, Okabe K, Kajiya H . Genistein, a soybean isoflavone, inhibits inward rectifier K(+) channels in rat osteoclasts. Jpn J Physiol 2001; 51: 501–9.
Chiang CE, Luk HN, Chen LL, Wang TM, Ding PY . Genistein inhibits the inward rectifying potassium current in guinea pig ventricular myocytes. J Biomed Sci 2002; 9: 321–6.
Cermak R, Kuhn G, Wolffram S . The flavonol quercetin activates basolateral K(+) channels in rat distal colon epithelium. Br J Pharmacol 2002; 135: 1183–90.
Cermak R, Follmer U, Wolffram S . Dietary flavonol quercetin induces chloride secretion in rat colon. Am J Physiol 1998; 275: 1166–72.
Lee EH, Meissner G, Kim DH . Effects of quercetin on single Ca2+ release channel behavior of skeletal muscle. Biophys J 2002; 82: 1266–77.
Bulteau-Pignoux L, Derand R, Metaye T, Joffre M, Becq F . Genistein modifies the activation kinetics and magnitude of phosphorylated wild-type and G551D-CFTR chloride currents. J Membr Biol 2002; 188: 175–82.
Illek B, Fischer H, Santos GF, Widdicombe JH, Machen TE, Reenstra WW . cAMP-independent activation of CTFR C1 channels by the tyrosine kinase inhibitor genistein. Am J Physiol 1995; 268: C886–93.
Lansdell KA, Cai Z, Kidd JF, Sheppard DN . Two mechanisms of genistein inhibition of cystic fibrosis transmembrane conductance regulator C1- channels expressed in murine cell line. J Physiol 2000; 524: 317–30.
Randak C, Auerswald EA, Assfalg-Machleidt I, Reenstra WW, Machleidt W . Inhibition of ATPase, GTPase and adenylate kinase activities of the second nucleotide-binding fold of the cystic fibrosis transmembrane conductance regulator by genistein. Biochem J 1999; 340: 227–35.
Author information
Authors and Affiliations
Corresponding author
Additional information
Project supported by grant from the Ministry of Science and Information Society Technologies of Poland (2 P05A 090 20).
Rights and permissions
About this article
Cite this article
Hendrich, A. Flavonoid-membrane interactions: possible consequences for biological effects of some polyphenolic compounds. Acta Pharmacol Sin 27, 27–40 (2006). https://doi.org/10.1111/j.1745-7254.2006.00238.x
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1111/j.1745-7254.2006.00238.x
Keywords
This article is cited by
-
Role of Mediterranean diet in endocrine diseases: a joint overview by the endocrinologist and the nutritionist
Journal of Endocrinological Investigation (2023)
-
Dose-dependent effect of H2O2 on hairy roots of Scutellaria baicalensis: growth, composition of fatty acids, and flavones
Plant Cell, Tissue and Organ Culture (PCTOC) (2023)
-
Classic Phytochemical Antioxidant and Lipoxygenase Inhibitor, Nordihydroguaiaretic Acid, Activates Phospholipase D through Oxidant Signaling and Tyrosine Phosphorylation Leading to Cytotoxicity in Lung Vascular Endothelial Cells
Cell Biochemistry and Biophysics (2023)
-
Myconoside interacts with the plasma membranes and the actin cytoskeleton and provokes cytotoxicity in human lung adenocarcinoma A549 cells
Journal of Bioenergetics and Biomembranes (2022)
-
Interaction of 4′-methylflavonoids with biological membranes, liposomes, and human albumin
Scientific Reports (2021)