Effect of flavonoids on MRP1-mediated transport in Panc-1 cells

Authors

  • Hang Nguyen,

    1. 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
    Current affiliation:
    1. Groton Laboratories, Pfizer Inc., Eastern Point Road 8220-2356, Groton, CT 06340.
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  • Shuzhong Zhang,

    1. 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
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  • Marilyn E. Morris

    Corresponding author
    1. 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
    • 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. Telephone: 716- 645-2842, ext. 230; Fax: 716-645-3693
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Abstract

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 3H-DNM and 3H-VBL was determined in the presence and absence of 22 flavonoids. Biochanin-A, genistein, quercetin, chalcone, silymarin, phloretin, morin, and kaempferol, at 100 μM 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 μM, but not at 10 μM concentrations, except for chalcone that was effective at a 10 μM 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. © 2003 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 92:250–257, 2003

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