Smith A J, de Vree J M, Ottenhoff R, Oude Elferink R P, Schinkel A H, Borst P
Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam.
Hepatology. 1998 Aug;28(2):530-6. doi: 10.1002/hep.510280234.
Mice homozygous for a disruption in the Mdr2 gene (Mdr2 (-/-) mice) lack the Mdr2 P-glycoprotein (P-gp) in the canalicular membrane of the hepatocyte and are unable to excrete phosphatidylcholine into the bile. These mice develop a nonsuppurative cholestatic liver disease, presumably caused by the high concentrations of free cytotoxic bile acids in bile. We generated transgenic mice that express the human homolog of Mdr2, MDR3, specifically in the liver by the use of an albumin promoter. In these mice the MDR3 P-gp is exclusively located in the canalicular membrane of hepatocytes and phospholipid excretion into bile is restored. Mice that contain the same amount of MDR3 P-gp as that of Mdr2 P-gp in wild-type mice, also excrete the same amount of phospholipids. No histopathological abnormalities were observed in the livers of these mice. In mice that express MDR3 at a higher or lower level, the phospholipid excretion correlated with the amount of MDR3 P-gp. We conclude that the human MDR3 P-gp is functionally homologous to the murine Mdr2 P-gp and that it can fully replace this P-gp in Mdr2 (-/-) mice, restoring the excretion of phospholipids into the bile. The phospholipid excretion is limited by the amount of MDR3 or Mdr2 P-gp. The excretion of cholesterol is not tightly coupled to the excretion of phospholipids in these mice, because a very low phospholipid excretion level is sufficient to give almost wild-type cholesterol excretion into the bile.
多药耐药蛋白2基因缺失的纯合子小鼠（Mdr2(-/-)小鼠）在肝细胞胆小管膜中缺乏多药耐药蛋白2 P-糖蛋白（P-gp），并且无法将磷脂酰胆碱排泄到胆汁中。这些小鼠会发展出一种非化脓性胆汁淤积性肝病，推测是由胆汁中高浓度的游离细胞毒性胆汁酸引起的。我们通过使用白蛋白启动子，培育出了在肝脏中特异性表达人多药耐药蛋白2同源物MDR3的转基因小鼠。在这些小鼠中，MDR3 P-gp仅位于肝细胞的胆小管膜中，并且恢复了磷脂向胆汁中的排泄。含有与野生型小鼠中Mdr2 P-gp量相同的MDR3 P-gp的小鼠，也排泄相同量的磷脂。在这些小鼠的肝脏中未观察到组织病理学异常。在表达MDR3水平较高或较低的小鼠中，磷脂排泄与MDR3 P-gp的量相关。我们得出结论，人MDR3 P-gp在功能上与鼠Mdr2 P-gp同源，并且它可以在Mdr2(-/-)小鼠中完全替代这种P-gp，恢复磷脂向胆汁中的排泄。磷脂排泄受MDR3或Mdr2 P-gp量的限制。在这些小鼠中，胆固醇的排泄与磷脂的排泄没有紧密关联，因为非常低的磷脂排泄水平就足以使胆汁中的胆固醇排泄几乎达到野生型水平。
