Department of Pharmaceutics, School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Japan.
Department of Health and Environmental Sciences, School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Japan.
Toxicol Appl Pharmacol. 2021 Jul 15;423:115570. doi: 10.1016/j.taap.2021.115570. Epub 2021 May 7.
The expression of transporters on the apical and basal membranes of renal proximal tubular cells are down- or upregulated to various extents under cisplatin (CDDP)-induced acute kidney injury (AKI). However, little is known about the changes in transporters in tissues other than the kidney under CDDP-induced AKI. This study aimed to investigate the modulation of the expression/function of intestinal efflux transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp), in CDDP-induced AKI rats. On day 3 after the intraperitoneal administration of CDDP (5 mg/kg) to rats, the expression levels of P-gp and Bcrp were compared with those of normal rats. Further, the absorption of three P-gp substrates (6α-methylprednisolone, rhodamine 123, and gatifloxacin) was evaluated in both groups using conventional loop techniques. In the CDDP-induced AKI rats, P-gp expression in the ileum was markedly decreased to approximately 38% of that in the normal rats. However, no significant changes in Bcrp expression were observed in the AKI rats. In contrast with the reduction in P-gp expression in the AKI rats, the absorption of the three P-gp substrates remained almost the same or decreased in the AKI group. The addition of verapamil (a potent P-gp inhibitor) increased the absorption of the three P-gp substrates to the values obtained from the normal rats. In conclusion, our results suggested that P-gp expression is downregulated in rats with CDDP-induced AKI but that P-gp maintains its potency as a "gatekeeper" against the absorption of xenobiotics by amplifying its individual transport capacity under these conditions.
顺铂（CDDP）诱导的急性肾损伤（AKI）可使近曲小管细胞顶膜和基底膜上的转运体表达水平不同程度地下调或上调。然而，人们对 CDDP 诱导的 AKI 除肾脏以外的组织中的转运体变化知之甚少。本研究旨在探讨 CDDP 诱导的 AKI 大鼠肠外排转运体 P-糖蛋白（P-gp）和乳腺癌耐药蛋白（Bcrp）的表达/功能变化。在腹腔注射 CDDP（5mg/kg）后第 3 天，比较 AKI 大鼠和正常大鼠 P-gp 和 Bcrp 的表达水平。进一步，采用传统的环技术在两组大鼠中评估三种 P-gp 底物（6α-甲基泼尼松龙、罗丹明 123 和加替沙星）的吸收情况。在 CDDP 诱导的 AKI 大鼠中，回肠 P-gp 的表达明显降低至正常大鼠的约 38%。然而，AKI 大鼠中 Bcrp 的表达无明显变化。与 AKI 大鼠中 P-gp 表达的减少相反，三种 P-gp 底物的吸收在 AKI 组几乎保持不变或减少。维拉帕米（一种有效的 P-gp 抑制剂）的加入增加了三种 P-gp 底物的吸收，达到正常大鼠的吸收值。总之，我们的结果表明，CDDP 诱导的 AKI 大鼠中 P-gp 表达下调，但在这些条件下，P-gp 通过放大其个体转运能力作为“守门员”来维持其对抗外源性物质吸收的效力。
