Yonezawa Atsushi
Department of Pharmacy, Kyoto University Hospital, Kyoto, Japan.
Yakugaku Zasshi. 2012;132(11):1281-5. doi: 10.1248/yakushi.12-00211.
Platinum agents are widely used in cancer chemotherapy. Cisplatin, carboplatin, oxaliplatin and nedaplatin have a common chemical structure consisting of platinum, carrier groups and leaving groups, and undergo the similar mechanism of cytotoxicity. Only cisplatin induces nephrotoxicity, although the molecular mechanism involved is unclear. Organic cation transporter (OCT)/SLC22A, and multidrug and toxin extrusion (MATE)/SLC47A play a role in renal handling of cationic drug in the kidney. We focused on a role of transporters in nephrotoxicity of platinum agents. OCT2 mediates the transport of cisplatin and is the determinant of cisplatin-induced nephrotoxicity. In addition, MATE1 protects cisplatin-induced nephrotoxicity. Oxaliplatin, which was a superior substrate of the luminal efflux transporter, MATE2-K as well as OCT2, did not show nephrotoxicity. Moreover, carboplatin and nedaplatin were not transported by these transporters. Substrate specificity could regulate the features of platinum agents. Recent findings indicate that organic cation transporters are key to the nephrotoxicity of platinum agents.
铂类药物广泛应用于癌症化疗。顺铂、卡铂、奥沙利铂和奈达铂具有由铂、载体基团和离去基团组成的共同化学结构，并经历相似的细胞毒性机制。尽管所涉及的分子机制尚不清楚，但只有顺铂会诱发肾毒性。有机阳离子转运体（OCT）/溶质载体家族22成员A（SLC22A）以及多药和毒素外排转运体（MATE）/溶质载体家族47成员A（SLC47A）在肾脏对阳离子药物的处理中发挥作用。我们关注转运体在铂类药物肾毒性中的作用。OCT2介导顺铂的转运，是顺铂诱导肾毒性的决定因素。此外，MATE1可保护顺铂诱导的肾毒性。奥沙利铂是管腔外排转运体MATE2-K以及OCT2的优质底物，未表现出肾毒性。此外，卡铂和奈达铂不被这些转运体转运。底物特异性可调节铂类药物的特性。最近的研究结果表明，有机阳离子转运体是铂类药物肾毒性的关键因素。
