4-Phenylbutyrate modulates ubiquitination of hepatocanalicular MRP2 and reduces serum total bilirubin concentration

J Hepatol. 2012 May;56(5):1136-1144. doi: 10.1016/j.jhep.2011.11.021. Epub 2012 Jan 13.

Abstract

Background & aims: Multidrug resistance-associated protein 2 (in humans, MRP2; in rodents, Mrp2) mediates biliary excretion of bilirubin glucuronides. Therefore, upregulation of MRP2/Mrp2 expression may improve hyperbilirubinemia. We investigated the effects of 4-phenylbutyrate (4PBA), a drug used to treat ornithine transcarbamylase deficiency (OTCD), on the cell surface expression and transport function of MRP2/Mrp2 and serum T-Bil concentration.

Methods: MRP2-expressing MDCKII (MRP2-MDCKII) cells and rats were studied to explore the change induced by 4PBA treatment in the cell surface expression and transport function of MRP2/Mrp2 and its underlying mechanism. Serum and liver specimens from OTCD patients were analyzed to examine the effect of 4PBA on hepatic MRP2 expression and serum T-Bil concentration in humans.

Results: In MRP2-MDCKII cells and the rat liver, 4PBA increased the cell surface expression and transport function of MRP2/Mrp2. In patients with OTCD, hepatic MRP2 expression increased and serum T-Bil concentration decreased significantly after 4PBA treatment. In vitro studies designed to explore the mechanism underlying this drug action suggested that cell surface-resident MRP2/Mrp2 is degraded via ubiquitination-mediated targeting to the endosomal/lysosomal degradation pathway and that 4PBA inhibits the degradation of cell surface-resident MRP2/Mrp2 by reducing its susceptibility to ubiquitination.

Conclusions: 4PBA activates MRP2/Mrp2 function through increased expression of MRP2/Mrp2 at the hepatocanalicular membrane by modulating its ubiquitination, and thereby decreases serum T-Bil concentration. 4PBA has thus therapeutic potential for improving hyperbilirubinemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Bilirubin / blood*
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Cell Line
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Child, Preschool
  • Dogs
  • Female
  • Humans
  • Infant
  • Kidney / drug effects
  • Kidney / metabolism
  • Kidney / pathology
  • Liver / drug effects
  • Liver / metabolism*
  • Liver / pathology
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Male
  • Models, Animal
  • Multidrug Resistance-Associated Proteins / metabolism*
  • Ornithine Carbamoyltransferase Deficiency Disease / drug therapy
  • Ornithine Carbamoyltransferase Deficiency Disease / metabolism*
  • Phenylbutyrates / pharmacology*
  • Phenylbutyrates / therapeutic use
  • Rats
  • Rats, Sprague-Dawley
  • Ubiquitination / drug effects*
  • Up-Regulation / drug effects

Substances

  • Multidrug Resistance-Associated Proteins
  • Phenylbutyrates
  • multidrug resistance-associated protein 2
  • 4-phenylbutyric acid
  • Bilirubin