Effect of flavonoids on MRP1-mediated transport in Panc-1 cells.
The purpose of this study was to identify the effects of dietary flavonoids, which are present in fruits, vegetables, and plant-derived beverages, on the transport of daunomycin (DNM) and vinblastine (VBL) in Panc-1 cells. Panc-1 is a human pancreatic adenocarcinoma cell line, which expresses Multidrug Resistance-Associated Protein1 (MRP1). The 2-h accumulation of (3)H-DNM and (3)H-VBL was determined in the presence and absence of 22 flavonoids. Biochanin-A, genistein, quercetin, chalcone, silymarin, phloretin, morin, and kaempferol, at 100 microM concentrations, all significantly increased the accumulation of both DNM and VBL in Panc-1 cells, with morin increasing DNM and VBL accumulation by 546 +/- 50% (mean +/- SE, n = 9) and 553 +/- 37% (n = 9), respectively. Fisetin treatment significantly decreased the accumulation of both DNM and VBL. Concentration-dependent studies demonstrated significant effects on VBL accumulation at 50 microM, but not at 10 microM concentrations, except for chalcone that was effective at a 10 microM concentration. Following a 24-h incubation, there were no changes in MRP1 membrane expression or glutathione-S-transferase activity in cells. Cellular glutathione (GSH) concentrations were significantly decreased following a 2-h incubation with biochanin A, chalcone, genistein, phloretin, quercetin, and silymarin, and following a 24-h incubation with biochanin A, chalcone, genistein, and phloretin. These results therefore indicate that the flavonoids morin, chalcone, silymarin, phloretin, genistein, quercetin, biochanin A, and kaempferol can inhibit MRP1-mediated drug transport, effects that may involve binding interactions with MRP1, as well as modulation of GSH concentrations.
Nguyen
Hang
H
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, 517 Hochstetter Hall, Amherst, New York 14260-1200, USA.
Zhang
Shuzhong
S
Morris
Marilyn E
ME
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis; D000903:Antibiotics, Antineoplastic / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism; D001693:Biological Transport, Active; D015153:Blotting, Western; D019742:Chemokines, CC / Q000378:metabolism*; D003630:Daunorubicin / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D009363:Neoplasm Proteins / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D019742:Chemokines, CC; D005419:Flavonoids; D009363:Neoplasm Proteins; C070959:Ccl6 protein, mouse; D014747:Vinblastine; D005982:Glutathione Transferase; D005978:Glutathione; D003630:Daunorubicin