Expression of thirty-six drug transporter genes in human intestine, liver, kidney, and organotypic cell lines
Expression of thirty-six drug transporter genes in human intestine, liver, kidney, and organotypic cell lines
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DOI：
10.1124/dmd.107.014902
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发表时间：
2007-08-01
影响因子：
3.9
通讯作者：
Karlsson, Johan
中科院分区：
文献类型：
--
作者：
Hilgendorf, Constanze;Ahlin, Gustav;Karlsson, Johan
本研究旨在定量评估人空肠、结肠、肝脏和肾脏中36种重要药物转运蛋白的mRNA表达。将这些转运蛋白在人体器官中的表达与源自这些器官的常用细胞系（Caco-2、HepG 2和Caki-1）中的表达进行比较，以评估其作为体外转运蛋白系统模型的价值，还将其与从文献中获得的大鼠组织中表达的数据进行比较，以评估种属差异。在肠道中高表达的转运蛋白包括HPT 1、PEPT 1、BCRP、MRP 2和MDR 1，而在肝脏中，OCT 1、MRP 2、OATP-C、NTCP和BSEP是主要的转运蛋白。在肾脏中，OAT 1的表达水平最高，其次是OAT 3、OAT 4、MCT 5、MDR 1、MRP 2、OCT 2和OCT N 2。对于人空肠和Caco-2细胞，观察到人体组织和代表性细胞系之间的最佳一致性。肝和肾直系同源细胞系中的表达与相关组织中的表达不相关。与大鼠转运蛋白基因表达的比较显示了显着的物种差异。我们的研究结果允许一个全面的定量比较药物转运蛋白在人体肠道，肝脏和肾脏的表达。我们认为，这将是有益的预测药代动力学研究，重点是最高表达的转运蛋白。我们希望我们对大鼠和人体组织的比较将有助于解释在体内模型中观察到的物种差异，增加对主动转运过程对药代动力学和分布的影响的理解，并提高从动物研究到人类的预测质量。
This study was designed to quantitatively assess the mRNA expression of 36 important drug transporters in human jejunum, colon, liver, and kidney. Expression of these transporters in human organs was compared with expression in commonly used cell lines (Caco-2, HepG2, and Caki-1) originating from these organs to assess their value as in vitro transporter system models, and was also compared with data obtained from the literature on expression in rat tissues to assess species differences. Transporters that were highly expressed in the intestine included HPT1, PEPT1, BCRP, MRP2, and MDR1, whereas, in the liver, OCT1, MRP2, OATP-C, NTCP and BSEP were the main transporters. In the kidney, OAT1 was expressed at the highest levels, followed by OAT3, OAT4, MCT5, MDR1, MRP2, OCT2, and OCTN2. The best agreement between human tissue and the representative cell line was observed for human jejunum and Caco-2 cells. Expression in liver and kidney ortholog cell lines was not correlated with that in the associated tissue. Comparisons with rat transporter gene expression revealed significant species differences. Our results allowed a comprehensive quantitative comparison of drug transporter expression in human intestine, liver, and kidney. We suggest that it would be beneficial for predictive pharmacokinetic research to focus on the most highly expressed transporters. We hope that our comparison of rat and human tissue will help to explain the observed species differences in in vivo models, increase understanding of the impact of active transport processes on pharmacokinetics and distribution, and improve the quality of predictions from animal studies to humans.