Regulatory action of nitric oxide synthase on ileal P-glycoprotein expression under streptozotocin-induced diabetic condition.

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.