顺铂是目前临床上最有效的广谱抗肿瘤药物之一，但严重的肾毒性限制了其在临床上的使用。肾小管上皮细胞基底膜侧高表达的OCT2将顺铂摄取入细胞，使其毒性增强；而顶膜侧MATE1和MATE2-K介导顺铂泵出细胞，降低其毒性。目前，尚未发现安全有效的临床药物，通过影响OCT2/MATEs介导顺铂肾脏转运，达到抑制或降低顺铂肾毒性的效果。申请者研究发现，左旋延胡索乙素 ((-)-THP) 对hOCT2具有显著抑制作用，能抑制顺铂在MDCK-hOCT2与MDCK-hOCT2/hMATE1细胞上的毒性。提出(-)-THP可能通过对OCT2/ MATEs介导顺铂跨膜转运的影响，减少顺铂肾脏蓄积，从而达到减弱或抑制顺铂肾毒性的预期结果。为此，本项目拟运用细胞、组织、基因敲除小鼠等模型，阐明基于OCT2/MATEs 介导的(-)-THP降低顺铂肾毒性机制，为临床(-)-THP用于降低顺铂肾毒性提供科学依据。

Cisplatin is one of the most widely used and most potent chemotherapy drugs, however severe nephrotoxicity limits its clinical application. Recent research has shed significant new lights on the mechanism of cisplatin nephrotoxicity, especially on renal organic transporters, such as OCT2, MATE1 and MATE2-K, which have been linked to cisplatin-induced nephrotoxicity. Previously, the renal toxicity of cisplatin was suggested to be a result of OCT2-mediated extensive renal accumulation from the circulation, and weak tubular secretion into the urine by multidrug and toxin extrusion protein 1 and 2 (MATE1 and MATE2-K), primarily located at the apical membrane of proximal tubular cells. Currently, it has not yet been found an effective drug in clinic, which has the potential to prevent cisplatin-induced nephrotoxicity in patients, mainly based on the effect of OCT2- or MATEs-mediated renal transport of cisplatin. Our previous work demonstrated that (-)-THP ((-)-tetrahydropalmatine) had significant inhibitory effect on OCT2, and protected against severe cisplatin-induced cytoxicity on MDCK-hOCT2 and MDCK-hOCT2/hMATE1 cells in a concentration-dependent manner. Therefore, we proposed that (-)-THP co-administrated with cisplatin, might have an effect on cisplatin accumulation via OCT2 and/or MATEs, then reduces cisplatin-induced nephrotoxicity. To confirm the hypothesis, the models of the transgenic cells, renal primary cells, renal cortical slices and Oct1/2 (-/-) mouse would be used to investigate the molecular mechanism in the protective effect of (-)-THP on the cisplatin-induced nephrotoxicity based on the renal transport of cisplatin mediated by OCT2, MATE1 and MATE2-K. If the results as our expect，the concomitant administration of (-)-THP was revealed to be a useful strategy preventing cisplatin-induced nephrotoxicity，meanwhile (-)-THP could ameliorate cancer pain in patients. The results offer the scientific basis for the future clinical (-)-THP as a specific modifier of cisplatin-induced nephrotoxicity.