多药耐药蛋白2
下调和上调
化学
流出
内分泌学
内科学
药理学
运输机
生物
ATP结合盒运输机
生物化学
医学
基因
作者
Hisamitsu Hayashi,Tadahaya Mizuno,Reiko Horikawa,Hironori Nagasaka,Takashi Yabuki,Hajime Takikawa,Yuichi Sugiyama
标识
DOI:10.1016/j.jhep.2011.11.021
摘要
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. 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. 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. 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. 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.
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