Hepatic Uptake Mechanism of Ophiopogonin D Mediated by Organic Anion Transporting Polypeptides
Hepatic Uptake Mechanism of Ophiopogonin D Mediated by Organic Anion Transporting Polypeptides
复制标题
有机阴离子转运多肽介导的麦冬皂苷D的肝摄取机制。
DOI：
10.1007/s13318-016-0384-8
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发表时间：
2017-08-01
影响因子：
1.9
通讯作者：
Xia, Chunhua
中科院分区：
文献类型：
--
作者：
Zhang, Wen;Xiong, Xiaomin;Xia, Chunhua
奥曲肽D（Oppionin D，OPD）是参麦注射液（参麦注射液）的主要活性成分之一，在我国临床应用广泛。我们前期的研究表明OPD可能通过有机阴离子转运多肽（OATPs/oatps）从血液转运到肝脏。为探讨OPD在大鼠和人肝细胞中的摄取机制，采用Oatp 1b 2、Oatp 1a 1和Oatp 1a 4的竞争性抑制剂瑞舒伐他汀、Oatp 1b 2的特异性抑制剂烟酸、Oatp 1a 4的特异性抑制剂地高辛、Oatp 1a 1的特异性抑制剂溴磺酞（BSP）和布洛芬，研究OPD在大鼠肝细胞中的摄取。此外，还研究了OPD在人OATP 1B 1 * 1a-HEK 293 T细胞中的摄取，瑞舒伐他汀、BSP、利福平和烟酸均用作OATP 1B 1的竞争性抑制剂。OPD可在大鼠原代肝细胞中摄取，K（m）（米氏常数）为8.10 μ M，V（max）（最大速度）为54.39 nmol/min/mg蛋白。瑞舒伐他汀和甘草酸可显著抑制大鼠肝细胞摄取OPD。然而，地高辛，BSP和布洛芬对大鼠肝细胞摄取OPD没有影响。OATP 1B 1 * 1a-HEK 293 T细胞也能转运OPD，K（m）为5.50 μ Ie，V（max）为29.07 nmol/min/mg蛋白。与瑞舒伐他汀相比，OPD与OATP 1B 1的亲和力更高，单位时间内转运更快。瑞舒伐他汀、BSP、利福平和烟酸对OATP 1B 1 * 1a-HEK 293 T细胞转运OPD均有一定程度的抑制作用，提示人OATP 1B 1和大鼠OATP 1b 2可能参与OPD的肝脏摄取。
Ophiopogonin D (OPD) is one of the main active ingredients of SMI (Shenmai injection) which is widely used in clinical practice in China. Our previous study indicated that OPD might be transported from blood into liver mediated by organic anion transporting polypeptides (OATPs/oatps). This study aims to explore the hepatic uptake mechanism of OPD in rat and human.Rosuvastatin (a competitive inhibitor of oatp1b2, oatp1a1, and oatp1a4), glycyrrhizic acid (a specific inhibitor of oatp1b2), digoxin (a specific inhibitor of oatp1a4), bromosulfophthalein (BSP), and ibuprofen (a specific inhibitor of oatp1a1) were used to study the uptake of OPD in rat hepatocytes. Furthermore, the uptake of OPD in human OATP1B1*1a-HEK293T cells was also investigated, and rosuvastatin, BSP, rifampin, and glycyrrhizic acid were all used as the competitive inhibitor of OATP1B1.OPD can be taken in rat primary hepatocytes with K (m) (Michaelis Menten constant) of 8.10 mu M and V (max) (maximum velocity) of 54.39 nmol/min/mg protein. The uptake of OPD in rat hepatocytes was inhibited significantly by rosuvastatin and glycyrrhizic acid. However, digoxin, BSP, and ibuprofen had no effect on the uptake of OPD in rat hepatocytes. OPD can also be transported by OATP1B1*1a-HEK293T cells with K (m) of 5.50 mu Ie and V (max) of 29.07 nmol/min/mg protein. Compared with rosuvastatin, OPD has a higher affinity with OATP1B1 and can be transported faster in unit time. Rosuvastatin, BSP, rifampin, and glycyrrhizic acid all exhibited a certain extent inhibitory effect on the transport of OPD in OATP1B1*1a-HEK293T cells.Overall, this study indicates OATP1B1 in human and oatp1b2 in rats might participate in the hepatic uptake of OPD.