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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Arsenic Induces Expression of the Multidrug Resistance-Associated Protein 2 (MRP2) Gene in Primary Rat and Human Hepatocytes

Laurent Vernhet, Marie-Pascale Séité, Nathalie Allain, André Guillouzo and Olivier Fardel
Journal of Pharmacology and Experimental Therapeutics July 2001, 298 (1) 234-239;
Laurent Vernhet
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Marie-Pascale Séité
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Nathalie Allain
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André Guillouzo
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Olivier Fardel
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Abstract

Metals, such as arsenic or cadmium, have recently been demonstrated to interact with metabolic pathways, including phase I and phase II enzymes and the phase III efflux pump P-glycoprotein. In the present study, we investigated the effects of heavy metals and metalloids on the expression of the multidrug resistance-associated protein 2 (MRP2), a major hepatic transporter. Treatment of primary rat hepatocytes by sodium arsenite [As(III)], sodium arsenate and potassium antimony tartrate, but not cadmium chloride, was shown to markedly increase MRP2 mRNA and protein levels; As(III)-mediated induction was dose- and time-dependent and paralleled a strong increase in MRP2 amounts as assessed by Western blotting. As(III) was also demonstrated to markedly up-regulate MRP2 gene expression in primary human hepatocytes. MRP2 mRNA induction occurring in As(III)-treated rat hepatocytes was fully blocked by actinomycin D, indicating that it required active gene transcription. It was associated with an activation of the c-Jun N-terminal kinase pathway and with a reduction of cellular glutathione levels. Quercetin, a flavonoid compound known to block As(III)-related induction of P-glycoprotein, was also found to prevent up-regulation of MRP2 gene expression in rat hepatocytes exposed to As(III). Such an effect was unlikely to be due to alteration of JNK pathway since quercetin failed to abolish As(III)-induced JNK phosphorylation. It may rather be linked to the increase of cellular glutathione levels by quercetin, thus limiting the depleting effects of As(III) on glutathione amounts. Finally, these results confirm that some metals strongly regulate expression of detoxifying proteins, including biliary drug transporters.

Footnotes

  • This work was supported by the Ligue Nationale contre le Cancer (Comité d'Ille et Vilaine), Rennes, France.

  • Abbreviations:
    GSH
    glutathione
    JNK
    c-Jun N-terminal protein kinases
    mdr
    multidrug resistant/resistance
    MRP2
    multidrug resistance-associated protein 2
    As(III)
    sodium arsenite
    kb
    kilobase(s)
    • Received January 3, 2001.
    • Accepted March 27, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 298 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 298, Issue 1
1 Jul 2001
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Arsenic Induces Expression of the Multidrug Resistance-Associated Protein 2 (MRP2) Gene in Primary Rat and Human Hepatocytes

Laurent Vernhet, Marie-Pascale Séité, Nathalie Allain, André Guillouzo and Olivier Fardel
Journal of Pharmacology and Experimental Therapeutics July 1, 2001, 298 (1) 234-239;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Arsenic Induces Expression of the Multidrug Resistance-Associated Protein 2 (MRP2) Gene in Primary Rat and Human Hepatocytes

Laurent Vernhet, Marie-Pascale Séité, Nathalie Allain, André Guillouzo and Olivier Fardel
Journal of Pharmacology and Experimental Therapeutics July 1, 2001, 298 (1) 234-239;
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