Murray Michael, Zhou Fanfan
Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, School of Medical Sciences, The University of Sydney, NSW, 2006, Australia.
Faculty of Pharmacy, The University of Sydney, NSW, 2006, Australia.
Br J Pharmacol. 2017 Jul;174(13):1908-1924. doi: 10.1111/bph.13785. Epub 2017 Apr 24.
Organic anion transporters (OATs) and organic anion-transporting polypeptides (OATPs), encoded by a number of solute carrier (SLC)22A and SLC organic anion (SLCO) genes, mediate the absorption and distribution of drugs and other xenobiotics. The regulation of OATs and OATPs is complex, comprising both transcriptional and post-translational mechanisms. Plasma membrane expression is required for cellular substrate influx by OATs/OATPs. Thus, interest in post-translational regulatory processes, including membrane targeting, endocytosis, recycling and degradation of transporter proteins, is increasing because these are critical for plasma membrane expression. After being synthesized, transporters undergo N-glycosylation in the endoplasmic reticulum and Golgi apparatus and are delivered to the plasma membrane by vesicular transport. Their expression at the cell surface is maintained by de novo synthesis and recycling, which occurs after clathrin- and/or caveolin-dependent endocytosis of existing protein. Several studies have shown that phosphorylation by signalling kinases is important for the internalization and recycling processes, although the transporter protein does not appear to be directly phosphorylated. After internalization, transporters that are targeted for degradation undergo ubiquitination, most likely on intracellular loop residues. Epigenetic mechanisms, including methylation of gene regulatory regions and transcription from alternate promoters, are also significant in the regulation of certain SLC22A/SLCO genes. The membrane expression of OATs/OATPs is dysregulated in disease, which affects drug efficacy and detoxification. Several transporters are expressed in the cytoplasmic subcompartment in disease states, which suggests that membrane targeting/internalization/recycling may be impaired. This article focuses on recent developments in OAT and OATP regulation, their dysregulation in disease and the significance for drug therapy.
有机阴离子转运体（OATs）和有机阴离子转运多肽（OATPs）由多个溶质载体（SLC）22A和SLC有机阴离子（SLCO）基因编码，介导药物及其他外源性物质的吸收和分布。OATs和OATPs的调节机制复杂，包括转录和翻译后机制。OATs/OATPs介导细胞摄取底物需要质膜表达。因此，对翻译后调节过程的关注日益增加，这些过程包括转运蛋白的膜靶向、内吞、再循环和降解，因为它们对质膜表达至关重要。转运体合成后，在内质网和高尔基体中进行N-糖基化，并通过囊泡运输递送至质膜。它们在细胞表面的表达通过从头合成和再循环得以维持，再循环发生在现有蛋白的网格蛋白和/或小窝蛋白依赖性内吞作用之后。多项研究表明，信号激酶磷酸化对内化和再循环过程很重要，尽管转运蛋白似乎不会被直接磷酸化。内化后，靶向降解的转运体会发生泛素化，最有可能发生在细胞内环残基上。表观遗传机制，包括基因调控区域的甲基化和来自交替启动子的转录，在某些SLC22A/SLCO基因的调节中也很重要。疾病状态下OATs/OATPs的膜表达失调，这会影响药物疗效和解毒作用。在疾病状态下，一些转运体在细胞质亚区室中表达，这表明膜靶向/内化/再循环可能受损。本文重点介绍OAT和OATP调节的最新进展、它们在疾病中的失调情况以及对药物治疗的意义。
