Abstract：
Multidrug and toxin extrusion protein 1 (MATE1), an efflux transporter mainly expressed in renal proximal tubules, mediates the renal secretion of organic cationic drugs. The inhibition of MATE1 will impair the excretion of drugs into the tubular lumen, leading to the accumulation of nephrotoxic drugs in the kidney and consequently potentiating nephrotoxicity. Screening and identifying potent MATE1 inhibitors can predict or minimize the risk of drug-induced kidney injury. Flavonoids, a group of polyphenols commonly found in foodstuffs and herbal products, have been reported to cause transporter-mediated food/herb-drug interactions. Our objective was to investigate the inhibitory effects of flavonoids on MATE1 in vitro and in vivo and to assess the effects of flavonoids on cisplatin-induced kidney injury. Thirteen flavonoids exhibited significant transport activity inhibition (>50%) on MATE1 in MATE1-MDCK cells. Among them, the six strongest flavonoid inhibitors, including irisflorentin, silymarin, isosilybin, sinensetin, tangeretin, and nobiletin, markedly increased cisplatin cytotoxicity in these cells. In cisplatin-induced in vivo renal injury models, irisflorentin, isosilybin, and sinensetin also increased serum creatinine and blood urea nitrogen levels to different degrees, especially irisflorentin, which exhibited the most potent nephrotoxicity with cisplatin. The pharmacophore model indicated that the hydrogen bond acceptors at the 3, 5, and 7 positions may play a critical role in the inhibitory effect of flavonoids on MATE1. Our findings provide helpful information for predicting the potential risks of flavonoid-containing food/herb-drug interactions and avoiding the exacerbation of drug-induced kidney injury via MATE1 mediation.
摘要：
多药和毒素挤出蛋白1（MATE1），外排转运体主要在肾近端小管中表达，介导有机阳离子药物的肾脏分泌。抑制MATE1会损害药物向肾小管的排泄，导致肾毒性药物在肾脏中积累，从而增强肾毒性。筛选和鉴定有效的MATE1抑制剂可以预测或最小化药物诱导的肾损伤的风险。黄酮类化合物,在食品和草药产品中常见的一组多酚，已报道引起转运蛋白介导的食物/草药-药物相互作用。我们的目的是研究黄酮类化合物对MATE1的体外和体内抑制作用，并评估黄酮类化合物对顺铂诱导的肾损伤的影响。13种黄酮类化合物在MATE1-MDCK细胞中对MATE1表现出显著的转运活性抑制(>50%)。其中,六种最强的类黄酮抑制剂，包括irisflorentin,水飞蓟素,异飞蓟宾,sinensetin,橘皮素,和诺比林,在这些细胞中显著增加顺铂的细胞毒性。在顺铂诱导的体内肾损伤模型中，irisflorentin,异飞蓟宾,和西能西汀也不同程度地增加了血清肌酐和血尿素氮水平，尤其是irisflorentin,表现出最有效的顺铂肾毒性。药效团模型表明，3、5和7位的氢键受体可能在类黄酮对MATE1的抑制作用中起关键作用。我们的发现为预测含类黄酮的食物/草药-药物相互作用的潜在风险以及避免通过MATE1介导药物引起的肾损伤的恶化提供了有用的信息。
