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Research ArticleArticle

Mechanisms and Interaction of Vinblastine and Reduced Glutathione Transport in Membrane Vesicles by the Rabbit Multidrug Resistance Protein Mrp2 Expressed in Insect Cells

Rémon A. M. H. Van Aubel, Jan B. Koenderink, Janny G. P. Peters, Carel H. Van Os and Frans G. M. Russel
Molecular Pharmacology October 1999, 56 (4) 714-719;
Rémon A. M. H. Van Aubel
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Jan B. Koenderink
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Janny G. P. Peters
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Carel H. Van Os
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Frans G. M. Russel
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Abstract

The present study examined how the multidrug resistance protein (MRP) 2, which is an ATP-dependent anionic conjugate transporter, also mediates transport of the chemotherapeutic cationic drug vinblastine (VBL). We show that ATP-dependent [3H]VBL (0.2 μM) uptake into membrane vesicles from Sf9 cells infected with a baculovirus encoding rabbit Mrp2 (Sf9-Mrp2) was similar to vesicles from mock-infected Sf9 cells (Sf9-mock) but could be stimulated by reduced glutathione (GSH) with a half-maximum stimulation of 1.9 ± 0.1 mM. At 5 mM GSH, initial ATP-dependent [3H]VBL uptake rates were saturable with an apparentKm of 1.5 ± 0.3 μM. The inhibitory effect of VBL on Mrp2-mediated ATP-dependent transport of the anionic conjugate [3H]leukotriene C4 was potentiated by increasing GSH concentrations. Membrane vesicles from Sf9-Mrp2 cells exhibited a ∼7-fold increase in initial GSH uptake rates compared with membrane vesicles from Sf9-mock cells. Uptake of [3H]GSH was osmotically sensitive, independent of ATP, and was trans-inhibited by GSH. The anionic conjugates estradiol-17β-d-glucuronide and leukotriene C4cis-inhibited [3H]GSH uptake but only in the presence of ATP. Whereas ATP-dependent [3H]VBL uptake was stimulated by GSH, VBL did not affect [3H]GSH uptake. Our results show that GSH is required for Mrp2-mediated ATP-dependent VBL transport and that Mrp2 transports GSH independent of VBL.

Footnotes

  • Send reprint requests to: Dr. F. G. M. Russel, University of Nijmegen, Department of Pharmacology and Toxicology 233, P.O. Box 9101, 6500 HB Nijmegen, the Netherlands. E-mail:F.Russel{at}farm.kun.nl

  • J.B.K. is supported by the Netherlands Organization for Scientific Research through Grant 805-05.041.

  • Abbreviations:
    MRP
    multidrug resistance protein
    LTC4
    leukotriene C4
    VBL
    vinblastine
    VCR
    vincristine
    GSH
    reduced glutathione
    E217βG
    estradiol-17β-d-glucuronide
    DNP-SG
    S-dinitrophenyl-glutathione
    EHBR
    Eisai hyperbilirubinemic rat strain
    DTT
    dithiothreitol
    MK571
    3-([{3-(2-[7-chloro-2-quinolinyl]ethenyl)phenyl}-{(3-dimethyl-amino-3-oxopropyl)-thio}-methyl]thio)propanoic acid
    YCF1
    yeast cadmium factor-1
    • Received January 20, 1999.
    • Accepted May 21, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 56 (4)
Molecular Pharmacology
Vol. 56, Issue 4
1 Oct 1999
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Research ArticleArticle

Mechanisms and Interaction of Vinblastine and Reduced Glutathione Transport in Membrane Vesicles by the Rabbit Multidrug Resistance Protein Mrp2 Expressed in Insect Cells

Rémon A. M. H. Van Aubel, Jan B. Koenderink, Janny G. P. Peters, Carel H. Van Os and Frans G. M. Russel
Molecular Pharmacology October 1, 1999, 56 (4) 714-719;

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Research ArticleArticle

Mechanisms and Interaction of Vinblastine and Reduced Glutathione Transport in Membrane Vesicles by the Rabbit Multidrug Resistance Protein Mrp2 Expressed in Insect Cells

Rémon A. M. H. Van Aubel, Jan B. Koenderink, Janny G. P. Peters, Carel H. Van Os and Frans G. M. Russel
Molecular Pharmacology October 1, 1999, 56 (4) 714-719;
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