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

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.

• Authors: Hisamitsu Hayashi, Tadahaya Mizuno, Reiko Horikawa, Hironori Nagasaka, Takashi Yabuki, Hajime Takikawa, Yuichi Sugiyama
• Journal: Journal of hepatology (J Hepatol) Vol. 56 Issue 5 Pg. 1136-1144 (May 2012) ISSN: 1600-0641 [Electronic] Netherlands
• PMID: 22245901 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Chemical References

• ABCC2 protein, human
• Multidrug Resistance-Associated Protein 2
• Multidrug Resistance-Associated Proteins
• Phenylbutyrates
• 4-phenylbutyric acid
• Bilirubin

Topics

• Adult
• Animals
• Bilirubin (blood)
• Carcinoma, Hepatocellular (metabolism, pathology)
• Cell Line
• Cell Membrane (drug effects, metabolism)
• Child, Preschool
• Dogs
• Female
• Humans
• Infant
• Kidney (drug effects, metabolism, pathology)
• Liver (drug effects, metabolism, pathology)
• Liver Neoplasms (metabolism, pathology)
• Male
• Models, Animal
• Multidrug Resistance-Associated Protein 2
• Multidrug Resistance-Associated Proteins (metabolism)
• Ornithine Carbamoyltransferase Deficiency Disease (drug therapy, metabolism)
• Phenylbutyrates (pharmacology, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Ubiquitination (drug effects)
• Up-Regulation (drug effects)