Differential contribution of organic cation transporters, OCT2 and MATE1, in platinum agent-induced nephrotoxicity
Differential contribution of organic cation transporters, OCT2 and MATE1, in platinum agent-induced nephrotoxicity
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DOI：
10.1016/j.bcp.2007.03.004
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发表时间：
2007-08-01
影响因子：
5.8
通讯作者：
Inui, Ken-Ichi
中科院分区：
文献类型：
--
作者：
Yokoo, Sachiko;Yonezawa, Atsushi;Inui, Ken-Ichi
顺铂引起严重肾毒性的机制尚不完全清楚，但卡铂、奥沙利铂和奈达铂的作用机制尚不清楚。研究了铂类药物在大鼠体内的肾脏蓄积和随后的肾毒性。4种药物中，只有顺铂在给药后2天出现肾毒性。顺铂组大鼠尿N-乙酰-β-D-氨基葡萄糖苷酶活性、肾损伤分子-1mRNA和骨桥蛋白表达明显增强。尽管奈达铂对某些标志物有影响，但仅观察到轻微的组织学改变。顺铂在肾脏中的蓄积量远大于其他药物。在体外研究中，大鼠(R)OCT2的表达刺激顺铂和奥沙利铂的细胞蓄积。奥沙利铂也可通过rOCT3转运。H+/有机阳离子逆向转运蛋白rMATE1(多药毒素排泄)以及人(H)MATE1和hMATE2-K可刺激奥沙利铂的H+依赖的逆向转运，但不能刺激顺铂的H+依赖的逆向转运。卡铂和奈达铂不被这些转运蛋白转运。总之，铂类药物的肾毒性与其肾脏蓄积密切相关，这是由OCT和Mate家族的底物专一性决定的。(C)2007 Elsevier Inc.保留所有权利。
The mechanism of severe nephrotoxicity caused by cisplatin, but not carboplatin, oxaliplatin, and nedaplatin, is not fully understood. The renal accumulation and subsequent nephrotoxicity of platinum agents were examined in rats. Among these four drugs, only cisplatin induced nephrotoxicity at 2 days after its intraperitoneal administration. The urinary activity of N-acetyl-beta-D-glucosaminidase and expression of kidney injury molecule-1 mRNA and osteopontin were markedly enhanced in the cisplatin-treated rats. Although some markers were affected in the rats administered nedaplatin, only minor histological change was observed. The renal accumulation of cisplatin was much greater than that of the other drugs. In the in vitro study, the cellular accumulation of cisplatin and oxaliplatin was stimulated by the expression of rat (r) OCT2. Oxaliplatin was also transported by rOCT3. A luminal H+/organic cation antiporter, rMATE1 (multidrug and toxin extrusion) as well as human (h) MATE1 and hMATE2-K, stimulated the H+-gradient-dependent antiport of oxaliplatin, but not of cisplatin. Carboplatin and nedaplatin were not transported by these transporters. In conclusion, the nephrotoxicity of platinum agents was closely associated with their renal accumulation, which is determined by the substrate specificity of the OCT and MATE families. (c) 2007 Elsevier Inc. All rights reserved.