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Variability in human hepatic MRP4 expression: influence of cholestasis and genotype

The Pharmacogenomics Journal volume 8, pages 42–52 (2008)Cite this article

Abstract

The multidrug resistance protein 4 (MRP4) is an efflux transporter involved in the transport of endogenous substrates and xenobiotics. We measured MRP4 mRNA and protein expression in human livers and found a 38- and 45-fold variability, respectively. We sequenced 2 kb of the 5′-flanking region, all exons and intron/exon boundaries of the MRP4 gene in 95 patients and identified 74 genetic variants including 10 non-synonymous variations, seven of them being located in highly conserved regions. None of the detected polymorphisms was significantly associated with changes in the MRP4 mRNA or protein expression. Immunofluorescence microscopy indicated that none of the non-synonymous variations affected the cellular localization of MRP4. However, in cholestatic patients the MRP4 mRNA and protein expression both were significantly upregulated compared to non-cholestatic livers (protein: 299±138 vs 100±60a.u., P<0.001). Taken together, human hepatic MRP4 expression is highly variable. Genetic variations were not sufficient to explain this variability. In contrast, cholestasis is one major determinant of human hepatic MRP4 expression.

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Acknowledgements

Supported by the DFG (Bonn, FR 1298/2-4), the grant 0313080D (HepatoSys, to UMZ) from the German Federal Ministry of Education and Science, the HW & J Hector Foundation (Mannheim) and by the Robert Bosch Foundation (Stuttgart), Germany.

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Authors and Affiliations

  1. Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nuremberg, Erlangen, Germany

    U Gradhand, H Glaeser, I Bachmakov & M F Fromm

  2. Institute of Pharmacology, University of Mainz, Mainz, Germany

    T Lang

  3. Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tuebingen, Tuebingen, Germany

    E Schaeffeler, H Tegude, K Klein, U M Zanger, M Eichelbaum & M Schwab

  4. Department of Pathology, Robert-Bosch-Hospital, Stuttgart Tuebingen, Tuebingen, Germany

    P Fritz

  5. Department of Pharmacology, Ernst Moritz Arndt University Greifswald, Greifswald, Germany

    G Jedlitschky & H K Kroemer

  6. Epidauros Biotechnology, Pharmacogenetics Laboratory, Am Neuland 1, Bernried, Germany

    B Anwald & R Kerb

  7. Department of Clinical Pharmacology, University Hospital Tuebingen, Tuebingen, Germany

    M Schwab

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Correspondence to M F Fromm.

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Gradhand, U., Lang, T., Schaeffeler, E. et al. Variability in human hepatic MRP4 expression: influence of cholestasis and genotype. Pharmacogenomics J 8, 42–52 (2008). https://doi.org/10.1038/sj.tpj.6500451

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  • DOI: https://doi.org/10.1038/sj.tpj.6500451

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