Functional and Pharmacological Comparison of Human, Mouse, and Rat Organic Cation Transporter 1 toward Drug and Pesticide Interaction.
Functional and Pharmacological Comparison of Human, Mouse, and Rat Organic Cation Transporter 1 toward Drug and Pesticide Interaction.
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人类、小鼠和大鼠有机阳离子转运蛋白1对药物和农药相互作用的功能和药理学比较。
DOI：
10.3390/ijms21186871
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发表时间：
2020-09-19
影响因子：
5.6
通讯作者：
Hagos Y
中科院分区：
文献类型：
--
作者：
Floerl S;Kuehne A;Hagos Y
从动物数据到人类数据的推断并不总是可能的，因为几个基本因素，如表达水平、定位以及相关运输蛋白的底物选择性和亲和力，可能因物种而异。在这项研究中，我们研究了药物和杀虫剂与临床相关的有机阳离子转运蛋白hOCT1(SLC22A1)的相互作用，并与来自小鼠和大鼠的同源转运蛋白进行了比较。我们测定了人、小鼠和大鼠OCT1对常用底物1-甲基-4-苯基吡啶(MPP)的Km值(73±7、36±13和57±5µM)和Decynium22的IC50值(12.1±0.8、5.3±0.4和10.5±0.4µM)。我们首次证明了阳离子杀菌剂咪扎利、嘧菌酯、咪鲜胺和杀菌威与人和啮齿动物OCT1的相互作用。酮康唑、可乐定和维拉帕米等药物对人、小鼠和大鼠的OCT1活性显示出显著的抑制潜力。HOCT1与小鼠和大鼠同源基因的相关性分析表明，这三个物种之间存在很强的功能相关性。总之，这种方法表明转运蛋白相互作用的数据在许多情况下是可以在啮齿动物和人类之间转移的，但不能排除其他药物和杀虫剂的潜在物种差异，尽管建议对新的分子实体进行人和啮齿动物转运蛋白的功能比较。
Extrapolation from animal to human data is not always possible, because several essential factors, such as expression level, localization, as well as the substrate selectivity and affinity of relevant transport proteins, can differ between species. In this study, we examined the interactions of drugs and pesticides with the clinically relevant organic cation transporter hOCT1 (SLC22A1) in comparison to the orthologous transporters from mouse and rat. We determined Km-values (73 ± 7, 36 ± 13, and 57 ± 5 µM) of human, mouse and rat OCT1 for the commonly used substrate 1-methyl-4-phenylpyridinium (MPP) and IC50-values of decynium22 (12.1 ± 0.8, 5.3 ± 0.4, and 10.5 ± 0.4 µM). For the first time, we demonstrated the interaction of the cationic fungicides imazalil, azoxystrobin, prochloraz, and propamocarb with human and rodent OCT1. Drugs such as ketoconazole, clonidine, and verapamil showed substantial inhibitory potential to human, mouse, and rat OCT1 activity. A correlation analysis of hOCT1 versus mouse and rat orthologs revealed a strong functional correlation between the three species. In conclusion, this approach shows that transporter interaction data are in many cases transferable between rodents and humans, but potential species differences for other drugs and pesticides could not be excluded, though it is recommendable to perform functional comparisons of human and rodent transporters for new molecular entities.
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影响因子：
2.5
作者：
Faniband MH;Littorin M;Ekman E;Jönsson BA;Lindh CH
通讯作者：
Lindh CH
DOI：
10.1124/jpet.102.044404
发表时间：
2003-02-01
影响因子：
3.5
作者：
Gründemann, DG;Hahne, C;Schömig, E
通讯作者：
Schömig, E
影响因子：
3.6
作者：
Gorboulev, V;Shatskaya, N;Koepsell, H
通讯作者：
Koepsell, H
DOI：
10.1016/j.jchromb.2017.03.004
发表时间：
2017-05-01
影响因子：
3
作者：
Gao, Xue;Tan, Yanglan;Guo, Hao
通讯作者：
Guo, Hao
影响因子：
3.6
作者：
Han, Tianxiang (Kevin);Everett, Ruth S.;Thakker, Dhiren R.
通讯作者：
Thakker, Dhiren R.