Ischemia/Reperfusion-inducible protein modulates the function of organic cation transporter 1 and multidrug and toxin extrusion 1.
Ischemia/Reperfusion-inducible protein modulates the function of organic cation transporter 1 and multidrug and toxin extrusion 1.
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缺血/再灌注诱导蛋白调节有机阳离子转运蛋白 1 和多药物和毒素排出 1 的功能。
DOI：
10.1021/mp400013t
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发表时间：
2013-07-01
影响因子：
4.9
通讯作者：
Shu Y
中科院分区：
文献类型：
--
作者：
Li Q;Yang H;Peng X;Guo D;Dong Z;Polli JE;Shu Y
最近发现的缺血/再灌注诱导蛋白（IRIP）已被报道负调节细胞培养系统中的几种转运蛋白的活性。本研究的目的是确定IRIP是否调节OCT 1和MATE 1的活性，从而调节其底物二甲双胍（一种治疗糖尿病和其他肥胖相关综合征的药物）的体内分布。在有和没有OCT 1或MATE 1的情况下，在过表达IRIP的人胚肾293细胞中进行的摄取研究中，发现IRIP过表达可显著抑制OCT 1或MATE 1介导的1-甲基-4-苯基吡啶鎓的摄取。相反，通过小发夹RNA（shRNA）敲低IRIP增加了体外转运活性。IRIP过表达减少了转运蛋白的膜定位，而细胞中的转录水平没有任何变化。通过在小鼠肝脏中通过水动力学尾静脉注射过表达IRIP，我们证明了IRIP表达的增加可以导致二甲双胍在肝脏中的蓄积显著减少（P < 0.01）。此外，我们观察到，与同窝出生的瘦小鼠相比，ob/ob小鼠中IRIP的表达约为一半（P < 0.01），肝脏Oct 1蛋白表达和二甲双胍蓄积显著增加。总之，IRIP负性调节细胞中OCT 1和MATE 1的功能。重要的是，我们提供了体内证据，这种调制可能会导致药物处置的改变。IRIP对转运蛋白活性的调节可能发生在转录后水平，需要进一步的研究来表征确切的机制。
The recently identified ischemia/reperfusion-inducible protein (IRIP) has been reported to negatively modulate the activities of several transporters in cell culture systems. The goal of this study is to determine whether IRIP regulates the activities of OCT1 and MATE1, and hence the disposition in vivo of their substrate metformin, a therapeutic drug for diabetes and other obesity-related syndromes. In the uptake studies in the human embryonic kidney 293 cells overexpressing IRIP with and without OCT1 or MATE1, IRIP overexpression was found to significantly inhibit the uptake of 1-methyl-4-phenylpyridinium mediated by OCT1 or MATE1. In contrast, knockdown of IRIP by small hairpin RNA (shRNA) increased the transporter activities in vitro. IRIP overexpression decreased the membrane localization of transporter proteins without any changes in transcript levels in cells. By overexpressing IRIP in mouse liver via hydrodynamic tail vein injection, we demonstrated that increased IRIP expression could cause a significant reduction in hepatic accumulation of metformin (P < 0.01). In addition, we observed that the expression of IRIP was approximately half (P < 0.01) in ob/ob mice when compared to their lean littermates, with significant increases in hepatic Oct1 protein expression and metformin accumulation. In conclusion, IRIP negatively modulates the function of OCT1 and MATE1 in cells. Importantly, we provide in vivo evidence for such modulation that may cause an alteration in drug disposition. The regulation by IRIP on transporter activities likely occurs at a post-transcriptional level, and future studies are needed to characterize the exact mechanism.
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影响因子：
3.2
作者：
Gangale, Maria F.;Miele, Luca;Apa, Rosanna
通讯作者：
Apa, Rosanna
影响因子：
82.9
作者：
Lin, HZ;Yang, SQ;Diehl, AM
通讯作者：
Diehl, AM
影响因子：
3.9
作者：
Higgins, J. William;Bedwell, David W.;Zamek-Gliszczynski, Maciej J.
通讯作者：
Zamek-Gliszczynski, Maciej J.
影响因子：
3.6
作者：
Errasti-Murugarren, Ekaitz;Fernandez-Calotti, Paula;Pastor-Anglada, Marcal
通讯作者：
Pastor-Anglada, Marcal
影响因子：
2.6
作者：
Christensen, Mette M. H.;Brasch-Andersen, Charlotte;Brosen, Kim
通讯作者：
Brosen, Kim