Regional Expression Levels of Drug Transporters and Metabolizing Enzymes along the Pig and Human Intestinal Tract and Comparison with Caco-2 Cells
Regional Expression Levels of Drug Transporters and Metabolizing Enzymes along the Pig and Human Intestinal Tract and Comparison with Caco-2 Cells
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DOI：
10.1124/dmd.116.072231
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发表时间：
2017-02
影响因子：
3.9
通讯作者：
S. Vaessen;M. V. van Lipzig;R. Pieters;C. Krul;H. Wortelboer;E. van de Steeg
中科院分区：
文献类型：
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作者：
S. Vaessen;M. V. van Lipzig;R. Pieters;C. Krul;H. Wortelboer;E. van de Steeg
肠道转运蛋白和代谢酶在多种药物的口服吸收中起着至关重要的作用。本研究的目的是通过比较猪肠、人肠和Caco-2细胞之间这些蛋白质和酶的表达水平来表征更好的可用肠体外模型。因此，我们测定了猪肠道（十二指肠、空肠、回肠; N = 4）、人肠道（空肠; N = 9）和Caco-2细胞中19种药物转运蛋白的绝对蛋白表达和12种代谢酶沿着的mRNA表达。所包括的转运蛋白和酶的表达在猪和人肠组织之间大体相当，尽管乳腺癌耐药蛋白、单羧酸转运蛋白5、多药耐药蛋白（MRP）1、MRP 1、MRP 3（102倍）和有机阴离子转运多肽（OATP）4A 1（106倍）在猪空肠中的表达高于人空肠。或者，Caco-2细胞中相关转运蛋白（葡萄糖转运蛋白1、OATP 4A 1、MRP 2、MRP 1和OATP 2B 1）的表达水平显著高于人空肠（3- 130倍）。此外，所有检查的CYP均显示，与人空肠相比，Caco-2细胞中的基因表达至少低5倍，CYP 1A 1和CYP 3A 5的差异最小，CYP 3A 4的差异最大（与Caco-2细胞相比，人空肠中的表达高871倍）。总之，提供了猪和人肠道组织和Caco-2细胞中临床相关转运蛋白和代谢酶的表达水平的全面概述，这可能有助于决定最合适的模型，以进一步提高我们对确定化合物肠道吸收过程的理解。
Intestinal transporter proteins and metabolizing enzymes play a crucial role in the oral absorption of a wide variety of drugs. The aim of the current study was to characterize better available intestinal in vitro models by comparing expression levels of these proteins and enzymes between porcine intestine, human intestine, and Caco-2 cells. We therefore determined the absolute protein expression of 19 drug transporters and the mRNA expression of 12 metabolic enzymes along the pig intestinal tract (duodenum, jejunum, ileum; N = 4), in human intestine (jejunum; N = 9), and Caco-2 cells. Expression of the included transporters and enzymes was in general well comparable between porcine and human intestinal tissue, although breast cancer resistance protein, monocarboxylate transporter 5, multidrug resistance protein (MRP) 1, MRP1, MRP3 (∼2-fold), and organic anion-transporting polypeptide (OATP) 4A1 (∼6-fold) was higher expressed in pig compared with human jejunum. Alternatively, expression level of relevant transporter proteins (glucose transporter 1, OATP4A1, MRP2, MRP1, and OATP2B1) was significantly higher (3- to 130-fold) in Caco-2 cells compared with human jejunum. Moreover, all examined CYPs showed at least a fivefold lower gene expression in Caco-2 cells compared with human jejunum, with the smallest differences for CYP1A1 and CYP3A5 and the largest difference for CYP3A4 (871-fold higher expression in human jejunum compared with Caco-2 cells). In conclusion, a comprehensive overview is provided of the expression levels of clinically relevant transporter proteins and metabolic enzymes in porcine and human intestinal tissue and Caco-2 cells, which may assist in deciding upon the most suitable model to further improve our understanding of processes that determine intestinal absorption of compounds.