Substrate Selectivity Check of the Ergothioneine Transporter
Substrate Selectivity Check of the Ergothioneine Transporter
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DOI：
10.1124/dmd.118.080440
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发表时间：
2018-06-01
影响因子：
3.9
通讯作者：
Gruendemann, Dirk
中科院分区：
文献类型：
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作者：
Tschirka, Julia;Kreisor, Madlen;Gruendemann, Dirk
候选维生素麦角硫因（ET）是一种独特的抗氧化剂。ET转运体（ETT）（基因符号SLC22A4）在不同细胞中的表达被认为是细胞内ET活性的信号，因为我们之前已经证明ETT对ET具有高度选择性。不幸的是，一些人继续认为ETT是一种相关的药物转运体，使用了具有误导性的功能名称OCTN1，新型有机阳离子转运体。本研究是由最近两份报告引起的，其中宣布了新的ETT底物。令人惊讶的是，saracatinib和一些核苷类药物ETT的转运效率（TEs）与ET的转运效率（TE）一样高。在这里，我们基于293细胞中人类和大鼠ETT的调节表达和液相色谱-质谱定量分析，研究了几种药物的转运。对于核苷类阿糖胞苷、吉西他滨、2′-脱氧胞苷和2′-脱氧腺苷，以及萨拉卡替尼、异丙托品、二甲双胍和奥沙利铂，表达ETT的细胞摄取没有比对照细胞增加。可以检测到ett介导的加巴喷丁摄取，但其TE比麦角硫因的TE低约100倍（50-200 ml/min /毫克蛋白质）。总之，ETT对其生理底物麦角硫因具有高度特异性。我们的结果与其他底物的一些报道相矛盾。ETT不提供多种底物特异性，也不是阳离子药物的转运体。只有在亚结构上与ET相关的化合物（如加巴喷丁、肉碱和tea）才能被转运，但转运效率很低。因此，ETT仍然是ET活性的特定分子指标。
The candidate vitamin ergothioneine (ET) is a unique antioxidant. Expression of the ET transporter (ETT) (gene symbol SLC22A4) in distinct cells is thought to signal intracellular ET activity, since we have previously shown that the ETT is highly selective for ET. Unfortunately, some continue to hold the ETT as a relevant drug transporter, using the misleading functional name OCTN1, novel organic cation transporter. The present study was provoked by two recent reports in which new ETT substrates were declared. Astonishingly, the transport efficiencies (TEs) of ETT for saracatinib and some nucleoside drugs were as high as the TE for ET. Here we examined, based on regulated expression of ETT from human and rat in 293 cells and liquid chromatography-mass spectrometry quantification, the transport of several drugs. With the nucleosides cytarabine, gemcitabine, 2'-deoxycytidine, and 2'-deoxyadenosine, and the drugs saracatinib, ipratropium, metformin, and oxaliplatin, the uptake into cells expressing ETT was not increased over control cells. ETT-mediated uptake of gabapentin was detectable, but the TE was approximately 100-fold lower than the TE for ergothioneine (50-200 ml/min per milligram of protein). In conclusion, the ETT remains highly specific for its physiologic substrate ergothioneine. Our results contradict several reports on additional substrates. The ETT does not provide multiple substrate specificities, and it is not a transporter of cationic drugs. Only compounds that are related to ET in substructure-for example, gabapentin, carnitine, and TEA-can be transported, but with very low efficiency. Thus, ETT persists as a specific molecular indicator of ET activity.