Department of Pediatrics, University of California San Diego, La Jolla, California 92093, USA.
J Biol Chem. 2011 Sep 9;286(36):31522-31. doi: 10.1074/jbc.M111.272534. Epub 2011 Jul 12.
The main kidney transporter of many commonly prescribed drugs (e.g. penicillins, diuretics, antivirals, methotrexate, and non-steroidal anti-inflammatory drugs) is organic anion transporter-1 (OAT1), originally identified as NKT (Lopez-Nieto, C. E., You, G., Bush, K. T., Barros, E. J., Beier, D. R., and Nigam, S. K. (1997) J. Biol. Chem. 272, 6471-6478). Targeted metabolomics in knockouts have shown that OAT1 mediates the secretion or reabsorption of many important metabolites, including intermediates in carbohydrate, fatty acid, and amino acid metabolism. This observation raises the possibility that OAT1 helps regulate broader metabolic activities. We therefore examined the potential roles of OAT1 in metabolic pathways using Recon 1, a functionally tested genome-scale reconstruction of human metabolism. A computational approach was used to analyze in vivo metabolomic as well as transcriptomic data from wild-type and OAT1 knock-out animals, resulting in the implication of several metabolic pathways, including the citric acid cycle, polyamine, and fatty acid metabolism. Validation by in vitro and ex vivo analysis using Xenopus oocyte, cell culture, and kidney tissue assays demonstrated interactions between OAT1 and key intermediates in these metabolic pathways, including previously unknown substrates, such as polyamines (e.g. spermine and spermidine). A genome-scale metabolic network reconstruction generated some experimentally supported predictions for metabolic pathways linked to OAT1-related transport. The data support the possibility that the SLC22 and other families of transporters, known to be expressed in many tissues and primarily known for drug and toxin clearance, are integral to a number of endogenous pathways and may be involved in a larger remote sensing and signaling system (Ahn, S. Y., and Nigam, S. K. (2009) Mol. Pharmacol. 76, 481-490, and Wu, W., Dnyanmote, A. V., and Nigam, S. K. (2011) Mol. Pharmacol. 79, 795-805). Drugs may alter metabolism by competing for OAT1 binding of metabolites.
许多常用处方药（如青霉素、利尿剂、抗病毒药、甲氨蝶呤和非甾体抗炎药）的主要肾脏转运蛋白是有机阴离子转运蛋白-1（OAT1），最初被鉴定为 NKT（Lopez-Nieto，C. E.，You，G.，Bush，K. T.，Barros，E. J.，Beier，D. R.，和 Nigam，S. K.（1997）J. Biol. Chem. 272，6471-6478）。敲除动物的靶向代谢组学研究表明，OAT1 介导许多重要代谢物的分泌或重吸收，包括碳水化合物、脂肪酸和氨基酸代谢的中间产物。这一观察结果提出了 OAT1 有助于调节更广泛代谢活动的可能性。因此，我们使用经过功能测试的人类代谢全基因组重建 Recon 1 来研究 OAT1 在代谢途径中的潜在作用。一种计算方法用于分析野生型和 OAT1 敲除动物的体内代谢组学和转录组学数据，结果表明几种代谢途径的作用，包括柠檬酸循环、多胺和脂肪酸代谢。使用 Xenopus oocyte、细胞培养和肾脏组织测定的体外和离体分析验证表明，OAT1 与这些代谢途径中的关键中间产物相互作用，包括以前未知的底物，如多胺（如精胺和亚精胺）。全基因组代谢网络重建生成了一些与 OAT1 相关转运相关的代谢途径的实验支持预测。数据支持这样一种可能性，即 SLC22 和其他家族的转运蛋白，已知在许多组织中表达，主要用于清除药物和毒素，是许多内源性途径的组成部分，可能参与更大的远程传感和信号系统（Ahn，S. Y.，和 Nigam，S. K.（2009）Mol. Pharmacol. 76，481-490，和 Wu，W.，Dnyanmote，A. V.，和 Nigam，S. K.（2011）Mol. Pharmacol. 79，795-805）。药物可能通过与 OAT1 结合代谢物竞争来改变代谢。
