pH-dependent transport kinetics of the human organic anion-transporting polypeptide 1A2
pH-dependent transport kinetics of the human organic anion-transporting polypeptide 1A2
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DOI：
10.1016/j.dmpk.2019.12.002
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发表时间：
2020-04-01
影响因子：
2.1
通讯作者：
Ohtani, Hisakazu
中科院分区：
文献类型：
--
作者：
Morita, Tokio;Akiyoshi, Takeshi;Ohtani, Hisakazu
有机阴离子转运多肽（OATP）1A 2表达于肠和肾上皮细胞的顶侧，被认为参与药物的肠吸收和肾重吸收。尽管认为OATP 1A 2的转运活性具有pH依赖性，但pH对其动力学参数和OATP 1A 2抑制剂效价的影响尚未阐明。已知一些OATP具有多个结合位点（MBS），但仍不清楚OATP 1A 2是否具有MBS。在本研究中，我们使用表达OATP 1A 2的HEK 293细胞评价了pH值对OATP 1A 2介导的雌酮3-硫酸酯摄取的影响。HEK 293-OATP 1A 2细胞对0.3 μ M雌酮3-硫酸盐的摄取具有pH依赖性。OATP 1A 2在pH 6.3和7.4下表现出双峰饱和动力学。与在pH 6.3（5.62 μ M）下观察到的相比，在pH 7.4（43.2 μ M）下，高亲和力位点的Km值高8倍。此外，pH值对抑制剂效力的影响在所检查的抑制剂中各不相同。这些结果表明，OATP 1A 2在较低pH值条件下的转运特性（如在小肠粘膜和远端小管微环境中发现的转运特性）与在中性pH值条件下观察到的转运特性不同。(C)2019年日本异生物学研究学会。由爱思唯尔有限公司出版。保留所有权利。
Organic anion-transporting polypeptide (OATP) 1A2 is expressed on the apical sides of intestinal and renal epithelial cells and considered to be involved in the intestinal absorption and renal reabsorption of drugs. Although the transport activity of OATP1A2 is considered to be pH-dependent, the effects of pH on its kinetic parameters and on the potency of OATP1A2 inhibitors are yet to be elucidated. Some OATP are known to have multiple binding sites (MBS), but it remains unclear whether OATP1A2 has MBS. In the present study, we evaluated the influence of pH on the OATP1A2-mediated uptake of estrone 3-sulfate using OATP1A2-expressing HEK293 cells. The uptake of 0.3 mu M estrone 3-sulfate by HEK293-OATP1A2 cells was pH-dependent. OATP1A2 exhibited bimodal saturation kinetics at pH 6.3 and 7.4. Compared with that seen at pH 6.3 (5.62 mu M), the K-m value of the high-affinity site was 8-fold higher at pH 7.4 (43.2 mu M). In addition, the influence of pH on the potency of inhibitors varied among the examined inhibitors. These results suggest that the transport properties of OATP1A2 under lower pH conditions, such as those found in the microenvironments of the small intestinal mucosa and distal tubules, differ from those seen under neutral pH conditions. (C) 2019 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.