Disruption of multidrug and toxin extrusion MATE1 potentiates cisplatin-induced nephrotoxicity
Disruption of multidrug and toxin extrusion MATE1 potentiates cisplatin-induced nephrotoxicity
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DOI：
10.1016/j.bcp.2010.08.019
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发表时间：
2010-12-01
影响因子：
5.8
通讯作者：
Inui, Ken-ichi
中科院分区：
文献类型：
--
作者：
Nakamura, Takanori;Yonezawa, Atsushi;Inui, Ken-ichi
多药毒素排泄物1(MATE1/SLC47A1)表达于肾小管刷状缘膜上，介导阳离子药物的外流。本研究在体内研究了MATE1在顺铂肾毒性中的作用，并在体外给野生型(Mate1(+/+))和Mate1基因敲除(Mate1(-/-))小鼠腹腔注射顺铂(15 mg/kg)，发现Mate1(-/-)小鼠的寿命明显短于Mate1(+/+)小鼠。顺铂给药3天后，Mate1(+/+)和Mate 1(-/-)小鼠的血肌酐和血尿素氮(BUN)水平均较赋形剂对照组升高，内生肌酐清除率降低，此外，与Mate1(+/+)小鼠相比，顺铂治疗Mate1(-/-)小鼠的血肌酐和BUN水平显著升高。药代动力学分析表明，顺铂在Mate1(-/-)小鼠体内的血药浓度和肾组织中的蓄积量均高于Mate1(+/+)小鼠。此外，体外实验中，选择性Mate抑制剂乙胺嘧啶与顺铂联合应用时，与单独应用顺铂相比，肌酐和尿素氮水平也明显升高。综上所述，MATE1介导顺铂的外流，并参与顺铂引起的肾毒性。(C)2010 Elsevier Inc.版权所有
Multidrug and toxin extrusion 1 (MATE1/SLC47A1) is expressed in the brush-border membrane of renal proximal tubules and mediates the efflux of cationic drugs In the present study, the role of MATE1 in the nephrotoxicity of cisplatin was investigated in vivo and in vitro Cisplatin (15 mg/kg) was administered intraperitoneally to wild-type (Mate1(+/+)) and Mate1 knockout (Mate1(-/-)) mice Lifespan was significantly shorter in Mate1(-/-) mice than Mate1(+/+) mice. Three days after the administration of cisplatin, plasma creatinine and blood urea nitrogen (BUN) levels were increased in both Mate1 (+/+) and Mate 1 (-/-) mice compared with vehicle-treated controls, and creatinine clearance was decreased Moreover, a significant rise in creatinine and BUN levels was observed in cisplatin-treated Mate1(-/-) mice in comparison to Mate1 (+/+) mice. A pharmacokinetic analysis revealed the plasma concentration and renal accumulation of cisplatin to be higher in Mate1(-/-) mice than Mate1(+/+) mice 1 h after a single intravenous administration of cisplatin (0 5 mg/kg) Furthermore, the combination of a selective MATE inhibitor, pyrimethamine, with cisplatin also elevated creatinine and BUN levels compared to cisplatin alone In experiments in vitro, the cellular uptake of cisplatin was stimulated by the expression of mouse MATE1 as well as organic cation transporters OCT1 and OCT2. In conclusion, MATE1 mediates the efflux of cisplatin and is involved in cisplatin-induced nephrotoxicity. (C) 2010 Elsevier Inc All rights reserved