Department of Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8019, USA.
Drug Metab Dispos. 2010 Oct;38(10):1673-8. doi: 10.1124/dmd.110.034512. Epub 2010 Jul 2.
Breast cancer resistance protein (Bcrp) is a member of the ATP-binding cassette membrane transporter family, which is expressed apically in liver, kidney, and intestine epithelium. Recent reports suggest that in addition to xenobiotics, porphyrins, and food toxins, Bcrp can also transport bile acids and, therefore, may participate in the adaptive response to cholestasis. Bile duct ligation (BDL), an experimental model of obstructive cholestasis, was performed in male wild-type (WT) and Bcrp knockout (KO) mice. An initial time course of 3, 7, and 14 days of BDL in WT mice revealed that Bcrp expression was significantly reduced in liver but increased in ileum by 7 days. Subsequent experiments using 7-day BDL in WT and Bcrp KO mice demonstrated that there was no difference in liver necrosis, serum glutamic pyruvate aminotransferase, bilirubin, or bile acid levels in serum, hepatic tissue, bile, urine, or feces between the two groups. Protein expression levels for liver organic solute transporter (Ost) α and multidrug resistance protein 1 and kidney multidrug resistance-associated protein (Mrp) 2, Mrp3, and Mrp4 were significantly greater in the sham Bcrp KO versus sham WT mice. The expression of Mrp2 and Mrp4 in KO kidneys was further increased after BDL. In contrast, the adaptive response of transporters to BDL in the liver was similar in KO and WT BDL mice, including Ostα and Ostβ expression, which increased in liver and kidney but decreased in the ileum. These findings suggest that Bcrp does not have a significant role in the adaptive response to cholestasis in the liver but may be more important for solute export in the kidney and intestine.
乳腺癌耐药蛋白（Bcrp）是 ATP 结合盒膜转运蛋白家族的成员，在肝脏、肾脏和肠道上皮细胞中表达于顶侧。最近的报告表明，除了外源性物质、卟啉和食物毒素外，Bcrp 还可以转运胆汁酸，因此可能参与胆汁淤积的适应性反应。胆管结扎（BDL）是一种梗阻性胆汁淤积的实验模型，在雄性野生型（WT）和 Bcrp 敲除（KO）小鼠中进行。WT 小鼠的 BDL 初始时间过程为 3、7 和 14 天，结果表明 Bcrp 在肝脏中的表达显著降低，但在 7 天时在回肠中增加。随后在 WT 和 Bcrp KO 小鼠中进行的为期 7 天的 BDL 实验表明，两组之间的肝脏坏死、血清谷氨酸丙酮酸氨基转移酶、胆红素或胆汁酸水平在血清、肝组织、胆汁、尿液或粪便中均无差异。肝脏有机溶质转运蛋白（Ost）α和多药耐药蛋白 1 以及肾脏多药耐药相关蛋白（Mrp）2、Mrp3 和 Mrp4 的蛋白表达水平在假手术 Bcrp KO 小鼠中明显高于假手术 WT 小鼠。BDL 后 KO 肾脏中的 Mrp2 和 Mrp4 表达进一步增加。相比之下，KO 和 WT BDL 小鼠肝脏对 BDL 的转运体适应性反应相似，包括 Ostα 和 Ostβ 的表达，在肝脏和肾脏中增加，但在回肠中减少。这些发现表明，Bcrp 在肝脏对胆汁淤积的适应性反应中没有重要作用，但可能对肾脏和肠道中的溶质外排更为重要。
