The Isoquinolone Derived Prolyl Hydroxylase Inhibitor ICA Is a Potent Substrate of the Organic Anion Transporters 1 and 3
The Isoquinolone Derived Prolyl Hydroxylase Inhibitor ICA Is a Potent Substrate of the Organic Anion Transporters 1 and 3
复制标题
异喹诺酮衍生的脯氨酰羟化酶抑制剂 ICA 是有机阴离子转运蛋白 1 和 3 的有效底物
作者：
Schulz K;Hagos Y;Schley G;Burzlaff N;Willam C;Burckhardt BC
低氧诱导因子（hypoxia-inducible factor，HIF）是一种转录因子复合物，它介导了许多细胞对低氧的反应。HIF稳定性由称为HIF脯氨酰羟化酶（PHD）的双加氧酶家族控制。异喹啉酮衍生的PHD抑制剂，如2-（1-氯-4-羟基异喹啉-3-甲酰胺基）乙酸酯（伊卡），其稳定细胞内HIF-α已被认为是治疗与缺血相关的疾病的潜在有益的治疗策略。为了稳定HIF-α，伊卡必须通过有机阴离子转运蛋白1、2或3（OAT 1、OAT 2或OAT 3）之一穿过基底外侧膜被近端小管细胞（PCT）摄取。OAT 4可能介导伊卡通过管腔膜释放到尿液中。方法以人OAT 1、OAT 2、OAT 3和OAT 4稳定转染HEK 293细胞，以对氨基马尿酸（PAH）、环鸟苷酸（cGMP）和雌酮-3-硫酸酯（ES）为参比底物，结果伊卡对转染OAT 1和OAT 3的HEK 293细胞摄取PAH和ES均有抑制作用，半数抑制值分别为0.29±0.05和2.58±0.16 μ M。OAT 2对伊卡的敏感性较低。外排实验将伊卡鉴定为OAT 1和OAT 3底物。用伊卡预加载OAT 4转染的HEK 293细胞，刺激ES摄取18.3± 3.8%。结论伊卡主要通过OAT 1跨PCT基底外侧膜摄取，并通过OAT 4外排至管腔。
ObjectiveMany cellular responses to hypoxia are mediated by the transcription factor complex hypoxia-inducible factor (HIF). HIF stability is governed by a family of dioxygenases called HIF prolyl hydroxylases (PHDs). Isoquinolone-derived PHD inhibitors, like 2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetate (ICA), which stabilize the intracellular HIF-α have been suggested as a potentially beneficial therapeutic strategy for the treatment of disorders associated with ischemia. To stabilize HIF-α, ICA has to be taken up into proximal tubule cells (PCTs) across the basolateral membrane by one of the organic anion transporters 1, 2 or 3 (OAT1, OAT2 or OAT3). The release into the urine across the luminal membrane may be mediated by OAT4.MethodTo demonstrate interaction of ICA with human OAT1, OAT2, OAT3 and OAT4, ICA was tested on these transporters stably transfected in HEK293 cells by using p-aminohippurate (PAH), cGMP and estrone-3-sulfate (ES) as reference substrates, respectively.ResultsUptakes of PAH and ES in OAT1-and OAT3-transfected HEK293 cells were inhibited by ICA with half-maximal inhibition values of 0.29±0.05 and 2.58±0.16 µ M, respectively. OAT2 was less sensitive to ICA. Efflux experiments identified ICA as an OAT1 and OAT3 substrate. Preloading OAT4-transfected HEK293 cells with ICA stimulated ES uptake by 18.3±3.8%.ConclusionThe uptake of ICA across the basolateral membrane of PCTs occurs mainly by OAT1 and the efflux into the tubular lumen by OAT4.
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影响因子：
6.6
作者：
V. Selvaraju;N. Parinandi;R. Adluri;Joshua W Goldman;N. Hussain;J. A. Sánchez;N. Maulik
通讯作者：
V. Selvaraju;N. Parinandi;R. Adluri;Joshua W Goldman;N. Hussain;J. A. Sánchez;N. Maulik
影响因子：
6
作者：
Schley, Gunnar;Klanke, Bernd;Wiliam, Carsten
通讯作者：
Wiliam, Carsten
转运蛋白参与 N-氨基甲酰谷氨酸的肾脏排泄，这是一种治疗先天性 N-乙酰谷氨酸合酶缺乏症的孤儿药。
DOI：
--
发表时间：
2014
期刊：
AJP - Renal Physiology
影响因子：
--
作者：
Elisabeth Schwob;Y. Hagos;G. Burckhardt;B. Burckhardt
通讯作者：
B. Burckhardt
影响因子：
5.8
作者：
Pelis, Ryan M.;Wright, Stephen H.
通讯作者：
Wright, Stephen H.