Influence of Omeprazole on Multidrug Resistance Protein 3 Expression in Human Liver

  1. Monika Hitzl1,
  2. Kathrin Klein1,
  3. Ulrich M. Zanger1,
  4. Peter Fritz2,
  5. Andreas K. Nüssler3,
  6. Peter Neuhaus3 and
  7. Martin F. Fromm1,4
  1. 1Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany (M.H., K.K., U.M.Z., M.F.F.); 2Department of Pathology, Robert-Bosch-Hospital, Stuttgart, Germany (P.F.); 3Department of Surgery, Charité, Campus Virchow-Clinic, Humboldt University, Berlin, Germany (A.K.N., P.N.); and 4Institute of Experimental an Clinical Pharmacology and Toxicology, University of Erlangen-Nuremberg, Erlangen, Germany (M.F.F.)
  1. Dr. Martin F. Fromm, Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstr. 112, 70376 Stuttgart, Germany. E-mail:martin.fromm{at}ikp-stuttgart.de

Abstract

Multidrug resistance protein (MRP) 3 transports bile salts and conjugated xenobiotics from cells (hepatocytes and enterocytes) into the blood. Hepatic MRP3 expression is low under normal conditions but is markedly up-regulated during cholestasis. Since little is known about additional factors increasing human hepatic MRP3 expression, we investigated the variability of MRP3 expression in a large collection of human livers and factors contributing to variable MRP3 expression in liver and HepG2 cells. MRP3 was measured in 62 human livers from patients with and without omeprazole treatment and in HepG2 cells with and without omeprazole or β-naphthoflavone treatment. Livers of patients treated with omeprazole showed 4.8-fold (P< 0.0001) higher MRP3 protein expression compared with the remainder of the population. Accordingly, MRP3 mRNA and protein were induced 2.4- and 1.8-fold, respectively (P < 0.01 andP < 0.05), in HepG2 cells treated with omeprazole. Finally, MRP3 was induced in HepG2 cells by β-naphthoflavone. In summary, treatment with omeprazole and β-naphthoflavone is a determinant of variable human hepatic MRP3 expression.

Footnotes

  • Supported by the Deutsche Forschungsgemeinschaft (Bonn, FR 1298/2-1), Grant 01 GG 9846 from the German Federal Ministry of Education and Science, and the Robert Bosch Foundation (Stuttgart, Germany).

  • DOI: 10.1124/jpet.102.043547

  • Abbreviations:
    HIV
    human immunodeficiency virus
    MRP
    multidrug resistance protein
    PCR
    polymerase chain reaction
    TBS
    Tris-buffered saline
    TBS-T
    Tris-buffered saline/Tween 20
    DMSO
    dimethyl sulfoxide
    RT-PCR
    reverse transcription polymerase chain reaction
    a.u.
    arbitrary units
    • Received August 27, 2002.
    • Accepted October 3, 2002.
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  1. doi: 10.1124/jpet.102.043547 JPET February 1, 2003 vol. 304 no. 2 524-530
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