Interactions of glycyrrhizin with organic anion transporting polypeptides of rat and human liver
Interactions of glycyrrhizin with organic anion transporting polypeptides of rat and human liver
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DOI：
10.1016/s1386-6346(03)00154-2
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发表时间：
2003-08-01
影响因子：
4.2
通讯作者：
Kullak-Ublick, GA
中科院分区：
文献类型：
--
作者：
Ismair, MG;Stanca, C;Kullak-Ublick, GA
在日本，甘草酸（GL）用于治疗慢性丙型肝炎。静脉给药后，GL主要通过排泄至胆汁中消除。肝细胞摄取GL是一种载体介导的过程，其特征类似于有机阴离子转运多肽（OATP，溶质载体基因家族SLC 21 A）。因此，我们研究了GL是否是大鼠和人肝脏OATP的潜在转运底物。由于无法直接测量GL的转运，因此在注射编码OATP的cRNA的非洲爪蟾卵母细胞中，对GL介导的[H-3]雌酮-3-硫酸酯或[S-35]溴磺酞摄取的顺式抑制进行了动力学分析。在表达大鼠Oatp 4、人OATP-C或人OATP 8（主要在肝细胞中表达的OATP 1B亚家族成员）的卵母细胞中，GL抑制[H-3]雌酮-3-硫酸盐摄取75-100%。狄克逊图显示非竞争性抑制，Ki值分别为6.1、15.9和12.5 μ mol/l。相比之下，大鼠Oatp 1、Oatp 2和Oatp 3以及人OATP-A和OATP-B的GL抑制仅在0 - 53%之间。总之，GL是一种抑制剂，因此可能是大鼠和人肝脏特异性OATP的转运底物。GL被肝脏摄取的速率可能取决于这些肝细胞OATP的功能和表达水平。(C)2003 Elsevier Science B. V.保留所有权利。
Glycyrrhizin (GL) is used in Japan for the treatment of chronic hepatitis C. Following intravenous administration, GL is eliminated mainly by excretion into bile. Hepatocyte uptake of GL is a carrier-mediated process with characteristics resembling the organic anion transporting polypeptides (OATPs, solute carrier gene family SLC21A). We, therefore, studied whether GL is a potential transport substrate of the OATPs of rat and human liver. Because transport of GL could not be measured directly, GL-mediated cis-inhibition of [H-3]estrone-3-sulfate or [S-35]bromosulfophthalein uptake was analyzed kinetically in Xenopus laevis oocytes injected with cRNA coding for OATPs. GL inhibited [H-3]estrone-3-sulfate uptake by 75-100% in oocytes expressing rat Oatp4, human OATP-C or human OATP8, members of the OATP1B subfamily that are expressed predominantly in hepatocytes. Dixon plots indicated a non-competitive type of inhibition, with Ki values of 6.1, 15.9 and 12.5 mumol/l, respectively. In contrast, GL inhibition of rat Oatp1, Oatp2 and Oatp3 and human OATP-A and OATP-B was only between 0 and 53%. In conclusion, GL is an inhibitor and, therefore, potentially a transport substrate of the liver-specific OATPs in rat and man. The rate at which GL is taken up into the liver may depend upon the function and expression levels of these hepatocellular OATPs. (C) 2003 Elsevier Science B.V. All rights reserved.