Department of Drug Absorption and Pharmacokinetics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192–0392, Japan.
Biol Pharm Bull. 2011;34(3):408-14. doi: 10.1248/bpb.34.408.
P-glycoprotein is one of the most important transporters in the ATP binding cassette transporter. Moreover, it is well known that the efficacy of immunosuppressants, which are used after organ transplantation, is controlled by P-glycoprotein (P-gp). We investigated how ischemia/reperfusion (I/R), which occurs after transplantation, influences the expression level and function of P-gp. To clarify the influence of intestinal I/R on the localization of P-gp, an intestinal ischemia model was produced using a spring scale and surgical sutures for 1 h, followed by reperfusion for 24 h. The expression levels of mRNA and protein of P-gp were examined. The protein expression levels of P-gp in ileal homogenate and the brush border membrane (BBM) were significantly decreased until 3 h after reperfusion. While the protein expression level of P-gp in homogenate showed a tendency to increase, that in the BBM continued to significantly decrease until 24 h after reperfusion. In contrast, the protein expression level of P-gp in the basolateral membrane (BLM) increased significantly until 24 h after reperfusion. While no significant change in multidrug resistance (mdr)-1a mRNA was found, the levels of mdr-1b and mdr-2 significantly increased during intestinal I/R. In addition, the levels of inflammatory cytokines mRNA and nitric oxide (NO) also significantly increased. It was shown that mdr-1b and mdr-2 mRNA strongly participate in the recovery of P-gp protein level after intestinal I/R. We detected the abnormal localization of P-gp in the ileal membrane during intestinal I/R, suggesting NO and/or inflammatory cytokines participate in the abnormal localization of P-gp.
P-糖蛋白是三磷酸腺苷结合盒转运蛋白中最重要的转运体之一。此外，众所周知，器官移植后使用的免疫抑制剂的功效受 P-糖蛋白（P-gp）控制。我们研究了移植后发生的缺血/再灌注（I/R）如何影响 P-gp 的表达水平和功能。为了阐明肠道 I/R 对 P-gp 定位的影响，使用弹簧秤和手术缝线制作肠道缺血模型 1 小时，然后再灌注 24 小时。检查 P-gp 的 mRNA 和蛋白表达水平。回肠匀浆和刷状缘膜（BBM）中 P-gp 的蛋白表达水平在再灌注后 3 小时显著降低。虽然匀浆中 P-gp 的蛋白表达水平有增加的趋势，但 BBM 中的蛋白表达水平一直持续到再灌注后 24 小时显著降低。相比之下，再灌注后 24 小时，BLM 中 P-gp 的蛋白表达水平显著增加。虽然多药耐药（mdr）-1a mRNA 没有明显变化，但 mdr-1b 和 mdr-2 的水平在肠道 I/R 期间显着增加。此外，炎症细胞因子 mRNA 和一氧化氮（NO）的水平也显着增加。表明 mdr-1b 和 mdr-2 mRNA 强烈参与肠道 I/R 后 P-gp 蛋白水平的恢复。我们在肠道 I/R 期间检测到 P-gp 在回肠膜中的异常定位，表明 NO 和/或炎症细胞因子参与了 P-gp 的异常定位。
