Functional Characterization of Multidrug Resistance-Associated Protein 3 (Mrp3/Abcc3) in the Basolateral Efflux of Glucuronide Conjugates in the Mouse Small Intestine
Functional Characterization of Multidrug Resistance-Associated Protein 3 (Mrp3/Abcc3) in the Basolateral Efflux of Glucuronide Conjugates in the Mouse Small Intestine
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DOI：
10.1124/jpet.109.156943
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发表时间：
2010-02-01
影响因子：
3.5
通讯作者：
Sugiyama, Yuichi
中科院分区：
文献类型：
--
作者：
Kitamura, Yoshiaki;Kusuhara, Hiroyuki;Sugiyama, Yuichi
肠道表达代谢酶和转运蛋白，并作为口服异生素的屏障。本研究旨在利用野生型和 Mrp3(-/-) 小鼠研究多药耐药相关蛋白 3 (Mrp3/Abcc3) 在肠道内形成的葡萄糖醛酸结合物浆膜流出中的重要性。将外翻的肠囊与4-甲基伞形酮(4MU)一起孵育，并测定细胞内形成的4MU(4MUG)的葡萄糖醛酸结合物进入粘膜和浆膜侧的流出率。野生型小鼠中 4MUG 跨浆膜膜的渗透性表面积乘积 (PSserosal) 在十二指肠中最大，其次是空肠、回肠和结肠。除了结肠外，Mrp3(-/-) 小鼠的相应参数均显着降低（约为野生型小鼠的 33%），其中 4MUG 的 PS 浆膜在野生型和 Mrp3(-/-) 小鼠之间相似。野生型和Mrp3(-/-)小鼠之间全肠段4MUG的PS粘膜没有差异。除4MUG外，与野生型小鼠相比，Mrp3(-/-)小鼠空肠外翻囊中7-乙基-10-羟基喜树碱(SN-38)和对乙酰氨基酚的葡萄糖醛酸苷缀合物的PS浆膜也显着降低。野生型和Mrp3(-/-)小鼠之间外排转运蛋白的mRNA和蛋白表达没有差异。这些结果表明，Mrp3 在小肠中各种葡萄糖醛酸结合物与未知转运蛋白一起从小肠中的肠细胞到门静脉血的流出转运中起主要作用，但在结肠中，Mrp3 对 4MUG 的基底外侧流出的贡献可以忽略不计。
The intestine expresses metabolic enzymes and transporters and functions as a barrier to orally administered xenobiotics. This study aimed to examine the importance of multidrug resistance- associated protein 3 (Mrp3/Abcc3) in the serosal efflux of glucuronide conjugates formed in the intestine using wild-type and Mrp3(-/-) mice. The everted sacs of the intestine were incubated with 4-methylumbelliferone (4MU), and the efflux rates of intracellularly formed glucuronide conjugate of 4MU (4MUG) into the mucosal and serosal sides were determined. The permeability-surface area product across the serosal membrane (PSserosal) of 4MUG in wild-type mice was greatest in the duodenum followed by the jejunum, ileum, and colon. The corresponding parameters were significantly reduced in Mrp3(-/-) mice (approximately 33% of that in wild-type mice) except for the colon where the PSserosal of 4MUG was similar between wild-type and Mrp3(-/-) mice. There was no difference in the PSmucosal of 4MUG in whole segments of the intestine between wild-type and Mrp3(-/-) mice. In addition to 4MUG, the PSserosal of the glucuronide conjugates of 7-ethyl-10-hydroxycamptothecin (SN-38) and acetaminophen in the jejunal everted sacs were also significantly reduced in Mrp3(-/-) mice compared with wild-type mice. There was no difference in the mRNA and protein expression of efflux transporters between wild-type and Mrp3(-/-) mice. These results suggest that Mrp3 plays major roles in the efflux transport of various glucuronide conjugates from the enterocytes to the portal blood in the small intestine together with unknown transporter(s), but the contribution of Mrp3 to the basolateral efflux of 4MUG was negligible in the colon.