Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University, Kobe 650–8586, Japan.
Biol Pharm Bull. 2011;34(3):436-8. doi: 10.1248/bpb.34.436.
P-glycoprotein (P-gp), a drug efflux transporter, affects the pharmacokinetics of a wide range of substrate drugs. Our previous study clearly revealed that intestinal P-gp expression levels were decreased via an inducible nitric oxide synthase (iNOS)-mediated mechanism in the early phases of diabetes. Here, we focused on changes in ileal P-gp expression and the influences of NOS on the P-gp expression levels in the later phase of diabetic condition using streptozotocin (STZ)-induced diabetic mice. The ileal P-gp expression and activity was analyzed by Western blot analysis and by in situ closed loop method, respectively. In STZ-treated mice, ileal P-gp expression levels and activity significantly decreased on the 9th day after STZ administration. Interestingly, the decrease of P-gp function was recovered to the control level on 15th day in same conditioned mice. In addition, the recovery of P-gp expression levels was completely suppressed by a non-selective NOS inhibitor. These results indicate that the diabetic condition-induced decline of P-gp expression levels was temporary, and both decline- and recovery-process of intestinal P-gp expression levels are mediated by NOS. Furthermore, this study shows the bidirectional effect of NOS on regulation of intestinal P-gp expression.
P-糖蛋白（P-gp）是一种药物外排转运蛋白，影响广泛的底物药物的药代动力学。我们之前的研究清楚地表明，在糖尿病的早期阶段，通过诱导型一氧化氮合酶（iNOS）介导的机制，肠道 P-gp 表达水平降低。在这里，我们使用链脲佐菌素（STZ）诱导的糖尿病小鼠，重点研究了糖尿病后期回肠 P-gp 表达的变化以及 NOS 对 P-gp 表达水平的影响。通过 Western blot 分析和原位闭环法分别分析回肠 P-gp 的表达和活性。在 STZ 处理的小鼠中，在 STZ 给药后第 9 天，回肠 P-gp 表达水平和活性显著降低。有趣的是，在相同条件的小鼠中，P-gp 功能的降低在第 15 天恢复到对照水平。此外，非选择性 NOS 抑制剂完全抑制了 P-gp 表达水平的恢复。这些结果表明，糖尿病引起的 P-gp 表达水平下降是暂时的，回肠 P-gp 表达水平的下降和恢复过程均由 NOS 介导。此外，本研究表明 NOS 对调节肠道 P-gp 表达具有双向作用。
