Hepatic uptake of cholecystokinin octapeptide by organic anion-transporting polypeptides OATP4 and OATP8 of rat and human liver
Hepatic uptake of cholecystokinin octapeptide by organic anion-transporting polypeptides OATP4 and OATP8 of rat and human liver
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DOI：
10.1053/gast.2001.28704
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发表时间：
2001-11-01
期刊：
影响因子：
29.4
通讯作者：
Kullak-Ublick, GA
中科院分区：
文献类型：
--
作者：
Ismair, MG;Stieger, B;Kullak-Ublick, GA
背景与目的：胆囊收缩素（CCK）是一种主要的胃肠道肽激素，餐后从小肠释放，对胆囊和胃肠道运动产生显着影响。较小的亚型 CCK-8 和 CCK-4 迅速被肝细胞吸收、代谢并排泄到胆汁中。我们的目的是鉴定和表征肝细胞 CCK-8 摄取系统。方法：在表达大鼠肝脏（Oatp1、Oatp2、Oatp3 或 Oatp4）和人肝脏（OATP-A、OATP-B、OATP-C 或 OATP8）有机阴离子转运多肽的非洲爪蟾卵母细胞以及原代培养的大鼠肝细胞中测量 CCK-8 摄取。结果。大鼠Oatp4和人OATP8有效介导卵母细胞中CCK-8的摄取，米氏常数(K-m)值分别为14.9+/-2.9μmol/L和11.1+/-2.9μmol/L。肝细胞对CCK-8的摄取也达到饱和，K-m为6.7+/-2.1μmol/L。大鼠肝细胞中的 K-m 值与 Oatp4 介导的转运一致。结论：CCK-8由大鼠Oatp4和人OATP8选择性转运，两者均仅表达于肝细胞基底外侧膜。这两种转运蛋白是 CCK-8 的第一个且可能是主要的肝脏摄取系统，并且可能对于这种激素从循环中的快速清除至关重要。
Background & Aims: Cholecystokinin (CCK) is a major gastrointestinal peptide hormone that is released postprandially from the small intestine and exerts marked effects on gallbladder and gastrointestinal motility. The smaller isoforms CCK-8 and CCK-4 are rapidly taken up into hepatocytes, metabolized, and excreted into bile. Our aim was to identify and characterize the hepatocellular CCK-8 uptake system. Methods: CCK-8 uptake was measured in Xenopus laevis oocytes expressing the organic anion-transporting polypeptides of rat liver (Oatp1,, Oatp2, Oatp3, or Oatp4) and of human liver (OATP-A, OATP-B, OATP-C, or OATP8) and in primary cultured rat hepatocytes. Results. Rat Oatp4 and human OATP8 efficiently mediated CCK-8 uptake in oocytes, with Michaelis constant (K-m) values of 14.9 +/- 2.9 mu mol/L and 11.1 +/- 2.9 mu mol/L, respectively. CCK-8 uptake by hepatocytes was also saturable, with a K-m of 6.7 +/- 2.1 mu mol/L. The K-m value in rat hepatocytes is consistent with Oatp4-mediated transport. Conclusions: CCK-8 is selectively transported by rat Oatp4 and human OATP8, both of which are exclusively expressed at the basolateral membrane of hepatocytes. These 2 transporters are the first and probably the predominant hepatic uptake systems for CCK-8 and may be critical for the rapid clearance of this hormone from the circulation.