Efflux of dietary flavonoid quercetin 4'-beta-glucoside across human intestinal Caco-2 cell monolayers by apical multidrug resistance-associated protein-2.

Although there is strong evidence to suggest that flavonoid consumption is beneficial to human health, the extent to which flavonoids are absorbed and the mechanisms involved are controversial. Contrary to common dogma, we previously demonstrated that quercetin 4'-beta-glucoside, the predominant form of the most abundant dietary flavonoid, quercetin, was not absorbed across Caco-2 cell monolayers. The aim of this study was to test the hypothesis that a specific efflux transporter is responsible for this lack of absorption. Transport of quercetin 4'-beta-glucoside, alone or with inhibitors, was examined with Caco-2 cell monolayers. In addition, subcellular localization of the multidrug resistance-associated proteins MRP1 and MRP2 was examined by immunofluorescent confocal microscopy. Efflux of quercetin 4'-beta-glucoside, a saturable process, was not altered by verapamil, a P-glycoprotein inhibitor, but was competitively inhibited by MK-571, an MRP inhibitor. These data in combination with immunofluorescent localization of MRP2 to the apical membrane support a role for MRP2 in the intestinal transcellular efflux of quercetin 4'-beta-glucoside. These results suggest a role for MRP2 in the transport of a new class of agents, dietary glucosides.

[1]  D. Keppler,et al.  Conjugate export pumps of the multidrug resistance protein (MRP) family: localization, substrate specificity, and MRP2-mediated drug resistance. , 1999, Biochimica et biophysica acta.

[2]  T. Walle,et al.  Transport of the flavonoid chrysin and its conjugated metabolites by the human intestinal cell line Caco-2. , 1999, Biochemical pharmacology.

[3]  C. Manach,et al.  Part of quercetin absorbed in the small intestine is conjugated and further secreted in the intestinal lumen. , 1999, The American journal of physiology.

[4]  G. Hooiveld,et al.  Glutathione S-conjugate transport in hepatocytes entering the cell cycle is preserved by a switch in expression from the apical MRP2 to the basolateral MRP1 transporting protein. , 1999, Journal of cell science.

[5]  R. Walgren,et al.  Transport of quercetin and its glucosides across human intestinal epithelial Caco-2 cells. , 1998, Biochemical pharmacology.

[6]  M. Kool,et al.  Drug export activity of the human canalicular multispecific organic anion transporter in polarized kidney MDCK cells expressing cMOAT (MRP2) cDNA. , 1998, The Journal of clinical investigation.

[7]  J. Terao,et al.  Inhibition of mammalian 15-lipoxygenase-dependent lipid peroxidation in low-density lipoprotein by quercetin and quercetin monoglucosides. , 1998, Archives of biochemistry and biophysics.

[8]  P. Hollman,et al.  Relative bioavailability of the antioxidant flavonoid quercetin from various foods in man , 1997, FEBS letters.

[9]  M. Kool,et al.  Analysis of expression of cMOAT (MRP2), MRP3, MRP4, and MRP5, homologues of the multidrug resistance-associated protein gene (MRP1), in human cancer cell lines. , 1997, Cancer research.

[10]  A. Aromaa,et al.  Dietary flavonoids and the risk of lung cancer and other malignant neoplasms. , 1997, American journal of epidemiology.

[11]  H. Adlercreutz,et al.  Flavonoids, dietary-derived inhibitors of cell proliferation and in vitro angiogenesis. , 1997, Cancer research.

[12]  J. Pelling,et al.  Induction of p21/WAF1 and G1 cell‐cycle arrest by the chemopreventive agent apigenin , 1997, Molecular carcinogenesis.

[13]  O. Texier,et al.  Bioavailability of rutin and quercetin in rats , 1997, FEBS letters.

[14]  J. Bacon,et al.  Effect of storage and domestic processing on the content and composition of flavonol glucosides in onion (Allium cepa) , 1997 .

[15]  G. Weber,et al.  Increased signal transduction activity and down-regulation in human cancer cells. , 1996, Anticancer research.

[16]  D. Keppler,et al.  cDNA Cloning of the Hepatocyte Canalicular Isoform of the Multidrug Resistance Protein, cMrp, Reveals a Novel Conjugate Export Pump Deficient in Hyperbilirubinemic Mutant Rats* , 1996, The Journal of Biological Chemistry.

[17]  M. Flens,et al.  Tissue distribution of the multidrug resistance protein. , 1996, The American journal of pathology.

[18]  E. Feskens,et al.  Dietary Flavonoids, Antioxidant Vitamins, and Incidence of Stroke: The Zutphen Study , 1996 .

[19]  O. Texier,et al.  Bioavailability, metabolism and physiological impact of 4-oxo-flavonoids , 1996 .

[20]  Paul Knekt,et al.  Flavonoid intake and coronary mortality in Finland: a cohort study , 1996, BMJ.

[21]  P. Hollman,et al.  Absorption of dietary quercetin glycosides and quercetin in healthy ileostomy volunteers. , 1995, The American journal of clinical nutrition.

[22]  T. Walle,et al.  Quercetin, a potent and specific inhibitor of the human P-form phenosulfotransferase. , 1995, Biochemical pharmacology.

[23]  P. Borst,et al.  Overexpression of the gene encoding the multidrug resistance-associated protein results in increased ATP-dependent glutathione S-conjugate transport. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[24]  D. Keppler,et al.  The MRP gene encodes an ATP-dependent export pump for leukotriene C4 and structurally related conjugates. , 1994, The Journal of biological chemistry.

[25]  D. Keppler,et al.  ATP-dependent transport of glutathione S-conjugates by the multidrug resistance-associated protein. , 1994, Cancer research.

[26]  H. Gelboin,et al.  Isozyme- and species-specific susceptibility of cDNA-expressed CYP1A P-450s to different flavonoids. , 1994, Biochimica et biophysica acta.

[27]  S. Barnes,et al.  Genistein, daidzein, and their .beta.-glycoside conjugates: antitumor isoflavones in soybean foods from American and Asian diets , 1993 .

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

[29]  P. Artursson,et al.  Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells. , 1991, Biochemical and biophysical research communications.

[30]  I. Hirono,et al.  Metabolic fate of [14C] quercetin in the ACI rat. , 1983, The Japanese journal of experimental medicine.

[31]  I. H. Segel.  Enzyme Kinetics: Behavior and Analysis of Rapid Equilibrium and Steady-State Enzyme Systems , 1975 .

[32]  L. Griffiths,et al.  Metabolism of flavonoid compounds in germ-free rats. , 1972, The Biochemical journal.

[33]  R. Walgren,et al.  Transport of genistein-7-glucoside by human intestinal CACO-2 cells: potential role for MRP2. , 1999, Research communications in molecular pathology and pharmacology.

[34]  T. Fossen,et al.  Flavonoids from red onion (Allium cepa) , 1998 .

[35]  K. Tew,et al.  ATP-dependent uptake of natural product cytotoxic drugs by membrane vesicles establishes MRP as a broad specificity transporter. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[36]  R. Goldbohm,et al.  Consumption of onions and a reduced risk of stomach carcinoma , 1996 .

[37]  G. Wong,et al.  The effect of dietary quercetin and rutin on AOM-induced acute colonic epithelial abnormalities in mice fed a high-fat diet. , 1993, Nutrition and cancer.

[38]  W. Pierpoint.  Flavonoids in the human diet. , 1986, Progress in clinical and biological research.