Coordinate regulation of systemic and kidney tryptophan metabolism by the drug transporters OAT1 and OAT3.
Coordinate regulation of systemic and kidney tryptophan metabolism by the drug transporters OAT1 and OAT3.
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DOI：
10.1016/j.jbc.2021.100575
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Nigam SK
中科院分区：
文献类型：
--
作者：
Granados JC;Richelle A;Gutierrez JM;Zhang P;Zhang X;Bhatnagar V;Lewis NE;Nigam SK
器官如何感知循环中的代谢物是一个关键问题。在这里，我们展示了药物的多特异性有机阴离子转运体OAT1(SLC22A6或NKT)和OAT3(SLC22A8)在器官感觉中发挥作用。对Oat1和OAT3基因敲除小鼠血清的代谢组学分析显示，参与代谢和信号传递的色氨酸衍生物发生了变化。其中一些代谢物来自肠道微生物组，并被认为是慢性肾脏疾病中的尿毒症毒素。以细胞为基础的转运分析支持与转运体的直接相互作用。为了评估OAT1或OAT3功能丧失对肾脏的影响，肾脏是这些摄取转运蛋白高度表达的器官，敲除转录数据被映射到一个基于“代谢任务”的计算模型，该模型评估了150多个细胞功能。尽管两个基因敲除中的色氨酸代谢物发生了变化，但只有在Oat1基因敲除中，与色氨酸相关的多种细胞功能增加。因此，被剥夺了通过OAT1摄取犬尿氨酸、犬尿酸、邻氨基苯甲酸酯和N-甲酰邻氨基苯甲酸的能力，肾脏通过激活与色氨酸相关的生物合成途径来做出反应。这些结果支持遥感和信号理论，该理论描述了“药物”转运体如何通过促进器官串扰来帮助优化代谢物和信号分子的水平。由于OAT1和OAT3被许多药物抑制，这些数据暗示了药物-代谢物相互作用的可能性。事实上，人类使用丙磺舒治疗，这是一种用于治疗痛风的燕麦抑制剂，循环中的色氨酸代谢物升高。此外，鉴于监管机构建议对药物进行OAT1和OAT3结合或转运测试，因此这些代谢物可以用作内源性生物标志物，以确定候选药物是否与OAT1和/或OAT3相互作用。
How organs sense circulating metabolites is a key question. Here, we show that the multispecific organic anion transporters of drugs, OAT1 (SLC22A6 or NKT) and OAT3 (SLC22A8), play a role in organ sensing. Metabolomics analyses of the serum of Oat1 and Oat3 knockout mice revealed changes in tryptophan derivatives involved in metabolism and signaling. Several of these metabolites are derived from the gut microbiome and are implicated as uremic toxins in chronic kidney disease. Direct interaction with the transporters was supported with cell-based transport assays. To assess the impact of the loss of OAT1 or OAT3 function on the kidney, an organ where these uptake transporters are highly expressed, knockout transcriptomic data were mapped onto a “metabolic task”-based computational model that evaluates over 150 cellular functions. Despite the changes of tryptophan metabolites in both knockouts, only in the Oat1 knockout were multiple tryptophan-related cellular functions increased. Thus, deprived of the ability to take up kynurenine, kynurenate, anthranilate, and N-formylanthranilate through OAT1, the kidney responds by activating its own tryptophan-related biosynthetic pathways. The results support the Remote Sensing and Signaling Theory, which describes how “drug” transporters help optimize levels of metabolites and signaling molecules by facilitating organ cross talk. Since OAT1 and OAT3 are inhibited by many drugs, the data implies potential for drug–metabolite interactions. Indeed, treatment of humans with probenecid, an OAT-inhibitor used to treat gout, elevated circulating tryptophan metabolites. Furthermore, given that regulatory agencies have recommended drugs be tested for OAT1 and OAT3 binding or transport, it follows that these metabolites can be used as endogenous biomarkers to determine if drug candidates interact with OAT1 and/or OAT3.
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