Up-regulation of basolateral multidrug resistance protein 3 (Mrp3) in cholestatic rat liver

Authors

  • Markus Georg Donner,

    1. Division of Tumor Biochemistry, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
    Current affiliation:
    1. Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universität Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany. E-mail: markus.donner@uni-duesseldorf.de
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  • Dietrich Keppler

    Corresponding author
    1. Division of Tumor Biochemistry, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
    • Division of Tumor Biochemistry, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. fax: (49) 6221-422402
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Abstract

Cholestasis induces down-regulation of multidrug resistance protein 2 (Mrp2, symbol Abcc2), which is localized to the canalicular membrane. Given the overlapping substrate specificities of Mrp2 and multidrug resistance protein 3 (Mrp3, symbol Abcc3), we examined the hypothesis of a different subcellular and lobular localization of these members of the Mrp family in rat liver after bile duct ligation. We raised a polyclonal antibody against rat Mrp3 and detected this protein in the basolateral plasma membrane of hepatocytes surrounding the central veins and of cholangiocytes. The Mrp3 protein level was less than 2% of the expression observed after 72 hours of obstructive cholestasis. After 48 hours of bile duct ligation, the Mrp3 protein was increased and was further enhanced after 72 hours. In 72-hour-cholestatic rat liver Mrp3 was expressed, in addition, in periportal hepatocytes. However, there was a preponderance of Mrp3 in the pericentral area of the liver lobule. In Mrp2-deficient mutant rat liver, the Mrp3 protein expression was most enhanced and its zonation was lost. The Mrp3 immunostaining of cholangiocytes was preserved in cholestatic and in Mrp2-deficient mutant liver. Canalicular Mrp2 decreased and amounted to 34% of normal after bile duct ligation for 72 hours. We conclude that the hepatocellular up-regulation of Mrp3 in cholestasis together with cholangiocellular Mrp3 may compensate for the biliary obstruction and impaired canalicular Mrp2 function by clearing cholephilic anionic substances into the blood.

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