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

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• 作者：Hisamitsu Hayashi¹ ; ^{hayapi@mol.f.u-tokyo.ac.jp} ; Tadahaya Mizuno¹ ; Reiko Horikawa² ; Hironori Nagasaka³ ; Takashi Yabuki¹ ; Hajime Takikawa⁴ ; Yuichi Sugiyama¹ ; ^{sugiyama@mol.f.u-tokyo.ac.jp}
• 关键词：MRP2/Mrp2 ; human/rat isoforms of multidrug resistance-associated protein 2 ; BSEP/Bsep ; human/rat isoforms of the bile salt export pump ; DJS ; Dubin&ndash ; Johnson Syndrome ; TR&minus ; transport deficient rat ; EHBR ; Eisai hyperbilirubinemic rat ; 4PBA ; 4-phen
• 刊名：Journal of Hepatology
• 出版年：2012
• 期刊代码：162_01688278
• 类别：med
• 出版时间：May, 2012
• 卷：56
• 期：5
• 页码：1136-1144
• 文件大小：1269 K

摘要

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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.