有机阴离子转运蛋白OAT1(SLC22A6)和OAT3(SLC22A8)是在肾脏中表达的药物转运蛋白,在药物和内源性代谢物的体内运输中具有公认的作用。这些药物转运蛋白的相对未开发的潜在功能是它们对天然产物(NP)的体内调节及其对内源性代谢的影响的贡献。这对于评估在转运蛋白位点处与其他化合物的潜在NP相互作用是重要的。这里,我们分析了亚洲几个完善的数据库中存在的NP(中国,印度阿育吠陀)和其他传统。小鼠敲除中OAT1和OAT3的丢失导致许多NP的血清改变,包括类黄酮,维生素,还有吲哚.基于化学性质的多变量分析,OAT1-和OAT3依赖性NP在很大程度上是可分离的。使用体外转运测定和蛋白质结合测定确认与转运蛋白的直接结合。我们的体内和体外结果,在以前的数据的背景下考虑,证明OAT1和OAT3在处理非合成小分子天然产物中起着关键作用,NP衍生的抗氧化剂,植物化学物质,和营养素(例如,泛酸,硫胺素)。正如遥感和信号理论所描述的,药物转运蛋白通过调节内源性抗氧化剂和营养物质在器官和生物体之间的运动来帮助调节氧化还原状态。我们的结果表明,膳食抗氧化剂和其他NPs可能会进入这些器官间和生物体间途径。
The organic anion
transporters OAT1 (SLC22A6) and OAT3 (SLC22A8) are drug
transporters that are expressed in the kidney, with well-established roles in the in vivo transport of drugs and endogenous metabolites. A comparatively unexplored potential function of these drug
transporters is their contribution to the in vivo regulation of natural products (NPs) and their effects on endogenous metabolism. This is important for the evaluation of potential NP interactions with other compounds at the transporter site. Here, we have analyzed the NPs present in several well-established databases from Asian (Chinese, Indian Ayurvedic) and other traditions. Loss of OAT1 and OAT3 in murine knockouts caused serum alterations of many NPs, including flavonoids, vitamins, and indoles. OAT1- and OAT3-dependent NPs were largely separable based on a multivariate analysis of chemical properties. Direct binding to the transporter was confirmed using in vitro transport assays and protein binding assays. Our in vivo and in vitro results, considered in the context of previous data, demonstrate that OAT1 and OAT3 play a pivotal role in the handling of non-synthetic small molecule natural products, NP-derived antioxidants, phytochemicals, and nutrients (e.g., pantothenic acid, thiamine). As described by remote sensing and signaling theory, drug
transporters help regulate redox states by meditating the movement of endogenous antioxidants and nutrients between organs and organisms. Our results demonstrate how dietary antioxidants and other NPs might feed into these inter-organ and inter-organismal pathways.