Role of breast cancer resistance protein (Bcrp1/Abcg2) in the extrusion of glucuronide and sulfate conjugates from enterocytes to intestinal lumen
Role of breast cancer resistance protein (Bcrp1/Abcg2) in the extrusion of glucuronide and sulfate conjugates from enterocytes to intestinal lumen
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DOI：
10.1124/mol.104.007393
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发表时间：
2005-03-01
影响因子：
3.6
通讯作者：
Sugiyama, Y
中科院分区：
文献类型：
--
作者：
Adachi, Y;Suzuki, H;Sugiyama, Y
本研究的目的是探讨小肠外排转运体将葡萄糖醛酸苷(G)和硫酸(S)结合物挤出肠腔的意义。从这一点出发，我们利用卫材高胆红素血症大鼠(EHBRs)进行了原位肠道灌流实验，在EHBRs中，多药耐药蛋白2(MRP2/Abcc2)是遗传缺陷的乳腺癌耐药蛋白(Bcrp1/ABCG2)基因敲除小鼠。在EHBRs和Bcrp1(-/-)小鼠的肠腔内灌流含有4-甲基伞形酮(4MU)和E3040[6-hydroxy-5，7-dimethyl-2-methylamino4-(3-pyridilmethyl)苯并噻唑的培养液，以测定代谢物流出到肠腔的情况。E3040-葡萄糖醛酸苷(G)在EHBRs中的外流明显低于正常大鼠。而4MU-G、4MU-硫酸盐(S)和E3040-S的外流在EHBRs大鼠和正常大鼠之间没有显著差异。而Bcrp1(-/-)小鼠细胞内形成的4MU-G、4MU-S和E3040-G的外排能力明显低于正常小鼠。因此，Bcrp1在将肠细胞中形成的葡萄糖醛酸苷和硫酸盐结合物挤出到肠腔中起重要作用，而MRp2负责某些葡萄糖醛酸偶联物的外流。
The purpose of this study is to examine the significance of efflux transporters in the small intestine to extrude glucuronide (G) and sulfate (S) conjugates into the intestinal lumen. From this standpoint, we performed in situ intestinal perfusion experiments by using Eisai hyperbilirubinemic rats ( EHBRs) in which the multidrug resistance protein 2 (Mrp2/Abcc2) is hereditarily defective and breast cancer resistance protein (Bcrp1/Abcg2) knockout mice. The intestinal lumen of EHBRs and Bcrp1 (-/-) mice was perfused with medium containing 4-methylumbelliferone ( 4MU) and E3040 [6-hydroxy-5,7-dimethyl-2-methylamino4-(3-pyridilmethyl) benzothiazole] to determine the efflux of metabolites into the outflow. The efflux of E3040-glucuronide ( G) in EHBRs was significantly lower compared with that in normal rats. However, no significant difference was observed for the efflux of 4MU-G, 4MU-sulfate (S), and E3040-S between EHBRs and normal rats. In contrast, the efflux of intracellularly formed 4MU-G, 4MU-S, and E3040-G in Bcrp1 (-/-) mice was significantly lower than that in normal mice. Therefore, Bcrp1 has an important role in extruding glucuronide and sulfate conjugates formed in enterocytes into the intestinal lumen, whereas Mrp2 is responsible for the efflux of some glucuronide conjugates.