Department of Pharmacy, Hokkaido University Hospital, Kita 14-jo, Nishi 5-chome, Kita-ku, Sapporo 060-8648, Japan.
Laboratory of Clinical Pharmaceutics & Therapeutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12-jo, Nishi 6-chome, Kita-ku, Sapporo 060-0812, Japan.
Eur J Pharmacol. 2017 Sep 15;811:191-198. doi: 10.1016/j.ejphar.2017.05.034. Epub 2017 May 18.
Cisplatin (CDDP)-induced nephrotoxicity (CIN) is one of the most serious toxicities caused by this potent antitumor agent. It has been reported that Mg premedication attenuates CIN in clinical trials; however, the mechanism underlying its nephroprotection is not fully understood. Therefore, the aim of this study was to determine whether Mg administration affects CDDP accumulation by regulating the expression level of renal transporters. Rats were divided into control, Mg (40mg/kg) alone, 2.5mg/kg CDDP with (20 and 40mg/kg) and without Mg, 5mg/kg CDDP groups. These substances were administered on the same day and 7 days later their kidneys were removed. The expression levels of renal transporters and platinum (Pt) accumulation were analyzed. The serum creatinine level was significantly increased by CDDP administration and treatment with Mg significantly ameliorated such elevation. The expressions of the renal organic cation transporter 2 (rOct2) and renal multidrug and toxin extrusion protein 1 (rMate1) were downregulated and upregulated, respectively following co-administration with Mg, which significantly reduced the renal Pt accumulation in the 2.5mg/kg CDDP-treated group. Moreover, Mg dose-dependently downregulated rOct2, not affecting rMate expression, resulting in the attenuation of CIN. Mg co-administration protected the downregulation of the transient receptor potential subfamily Melastatin 6 (rTrpm6), but not the epidermal growth factor (rEgf), as a result, Mg co-injection attenuated CDDP-induced hypomagnesemia. In conclusion, Mg co-administration reduced Pt accumulation by regulating the expression of the renal transporters, rOct2 and rMate1 and, thereby, attenuated CIN.
顺铂（CDDP）诱导的肾毒性（CIN）是该有效抗肿瘤药物引起的最严重毒性之一。据报道，镁预处理可减轻临床试验中的 CIN；然而，其肾保护作用的机制尚不完全清楚。因此，本研究旨在确定镁给药是否通过调节肾脏转运体的表达水平来影响 CDDP 的蓄积。将大鼠分为对照组、单独给予镁（40mg/kg）组、2.5mg/kg CDDP 联合（20 和 40mg/kg）和不给予镁组、5mg/kg CDDP 组。这些物质在同一天给予，7 天后取出肾脏。分析肾脏转运体和铂（Pt）蓄积的表达水平。CDDP 给药后血清肌酐水平显著升高，镁治疗可显著改善这种升高。与镁联合给药后，肾脏有机阳离子转运体 2（rOct2）和肾脏多药和毒素外排蛋白 1（rMate1）的表达分别下调和上调，从而显著减少 2.5mg/kg CDDP 处理组的肾 Pt 蓄积。此外，镁呈剂量依赖性地下调 rOct2，不影响 rMate 的表达，从而减轻 CIN。镁联合给药可保护瞬时受体电位亚家族 Melastatin 6（rTrpm6）的下调，而不影响表皮生长因子（rEgf），从而减轻 CDDP 诱导的低镁血症。总之，镁联合给药通过调节肾脏转运体 rOct2 和 rMate1 的表达减少 Pt 蓄积，从而减轻 CIN。
