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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Multidrug Resistance-Associated Protein-1 Functional Activity in Calu-3 Cells

Karen O. Hamilton, Elizabeth Topp, Irwan Makagiansar, Teruna Siahaan, Mehran Yazdanian and Kenneth L. Audus
Journal of Pharmacology and Experimental Therapeutics September 2001, 298 (3) 1199-1205;
Karen O. Hamilton
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Elizabeth Topp
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Irwan Makagiansar
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Teruna Siahaan
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Mehran Yazdanian
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Kenneth L. Audus
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Abstract

The purpose of this work was to determine whether the in vitro bronchiolar epithelial cell model, Calu-3, possesses efflux pump activity by the multidrug resistance-associated protein-1 (MRP1). Reverse transcription-polymerase chain reaction demonstratedMRP1 gene expression in Calu-3 cells. Indirect fluorescence studies showed a basolateral membrane localization of MRP1 compared with P-glycoprotein (Pgp) that was found on the apical side of these cells. An increase in the rate of accumulation of the MRP1 substrate calcein was observed following treatment with the organic anion/MRP1 inhibitor indomethacin, the Pgp inhibitors cyclosporin A (CsA) and vinblastine, as well as conditions of energy depletion. Total calcein efflux was significantly decreased with the MRP1 inhibitors probenecid and indomethacin, while total efflux was unchanged following treatment with CsA. In the latter case, however, intracellular calcein levels postefflux were significantly greater. Probenecid and indomethacin increased calcein net secretion 2.4- and 3.5-fold, respectively. The efflux of etoposide, a known substrate for both Pgp and MRP1, was shown to be mainly Pgp-mediated by using the multidrug-resistant inhibitors quinidine (mixed Pgp/MRP1), CsA (Pgp), and MK571 (MRP1). Together, these data suggest that Calu-3 cells possess MRP1 functional activity that is subordinate to Pgp efflux. We present here kinetic analysis of calcein efflux from Calu-3 cells to support our findings.

Footnotes

  • ↵1 Current address: Boehringer Ingelheim Pharmaceuticals, Inc. Department of Pharmaceutics, Ridgefield, CT 06877.

  • This study was supported by funds from Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT.

  • Abbreviations:
    MRP1
    multidrug resistance-associated protein
    Pgp
    P-glycoprotein
    CFTR
    cystic fibrosis transmembrane regulator
    MDR
    multidrug resistance
    C-AM
    calcein acetoxymethyl ester
    PBS
    phosphate-buffered saline
    CsA
    cyclosporin A
    A
    apical
    B
    basolateral
    RT-PCR
    reverse-transcription polymerase chain reaction
    bp
    base pair
    • Received February 9, 2001.
    • Accepted May 4, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 298 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 298, Issue 3
1 Sep 2001
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Multidrug Resistance-Associated Protein-1 Functional Activity in Calu-3 Cells

Karen O. Hamilton, Elizabeth Topp, Irwan Makagiansar, Teruna Siahaan, Mehran Yazdanian and Kenneth L. Audus
Journal of Pharmacology and Experimental Therapeutics September 1, 2001, 298 (3) 1199-1205;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Multidrug Resistance-Associated Protein-1 Functional Activity in Calu-3 Cells

Karen O. Hamilton, Elizabeth Topp, Irwan Makagiansar, Teruna Siahaan, Mehran Yazdanian and Kenneth L. Audus
Journal of Pharmacology and Experimental Therapeutics September 1, 2001, 298 (3) 1199-1205;
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