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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Structural Requirements for Functional Interaction of Glutathione Tripeptide Analogs with the Human Multidrug Resistance Protein 1 (MRP1)

Elaine M. Leslie, Raymond J. Bowers, Roger G. Deeley and Susan P. C. Cole
Journal of Pharmacology and Experimental Therapeutics February 2003, 304 (2) 643-653; DOI: https://doi.org/10.1124/jpet.102.044073
Elaine M. Leslie
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Raymond J. Bowers
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Roger G. Deeley
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Susan P. C. Cole
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This article has a correction. Please see:

  • Correction to “Structural Requirements for Functional Interaction of Glutathione Tripeptide Analogs with the Human Multidrug Resistance Protein 1 (MRP1)” - May 01, 2003

Abstract

The human multidrug resistance protein 1 (MRP1) is a primary active transporter of reduced (GSH) and oxidized glutathione, as well as GSH-, glucuronate-, and sulfate-conjugated organic anions. In addition, the transport of certain MRP1 substrates is stimulated by the presence of GSH. To evaluate the structural features of GSH required for interaction with the protein, we investigated the ability of a series of GSH analogs to enhance GSH stimulatable transport of [3H]estrone 3-sulfate (E1SO4). We found that substitution of the γ-Glu residue with Gly, β-Asp, and α-Glu resulted in complete loss of transport stimulation. In contrast, substitution of Gly with Glu or β-Ala resulted in only a partial loss of stimulatory activity. E1SO4transport activity surpassed GSH-stimulated levels in the presence of tripeptides in which Cys was substituted with the hydrophobic amino acids Leu, Phe, and homo-Phe. Moreover, polar substitutions of Cys did not enhance transport to the same extent as nonpolar substitutions of comparable size. γ-Glu-Leu-Gly was 1.6-fold more effective than GSH in stimulating E1SO4 uptake, and kinetic analysis indicated this was due to an increasedVmax. In addition, this tripeptide was shown to be a competitive inhibitor of apigenin-stimulated GSH transport (Ki value of 14 μM), confirming that it either interacts with the same site on MRP1 as GSH or that the binding of the two tripeptides is mutually exclusive. These data provide insight into the architecture of the GSH binding domain of MRP1.

Footnotes

  • This work was supported by Grant MOP-10519 from the Canadian Institutes of Health Research. E.M.L. is the recipient of a Canadian Institutes of Health Research Doctoral Award. R.G.D. is the Stauffer Cancer Research Professor of Queen's University, and S.P.C.C. is a Canada Research Chair in Cancer Biology.

  • DOI: 10.1124/jpet.102.044073

  • Abbreviations:
    GSH
    glutathione
    GST
    glutathioneS-transferase
    MRP1
    multidrug resistance protein 1
    E1SO4
    estrone 3-sulfate
    NNAL
    4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol
    Abu
    aminobutyrate
    DTT
    dithiothreitol
    • Received September 4, 2002.
    • Accepted October 16, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 304 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 304, Issue 2
1 Feb 2003
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Structural Requirements for Functional Interaction of Glutathione Tripeptide Analogs with the Human Multidrug Resistance Protein 1 (MRP1)

Elaine M. Leslie, Raymond J. Bowers, Roger G. Deeley and Susan P. C. Cole
Journal of Pharmacology and Experimental Therapeutics February 1, 2003, 304 (2) 643-653; DOI: https://doi.org/10.1124/jpet.102.044073

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Structural Requirements for Functional Interaction of Glutathione Tripeptide Analogs with the Human Multidrug Resistance Protein 1 (MRP1)

Elaine M. Leslie, Raymond J. Bowers, Roger G. Deeley and Susan P. C. Cole
Journal of Pharmacology and Experimental Therapeutics February 1, 2003, 304 (2) 643-653; DOI: https://doi.org/10.1124/jpet.102.044073
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