Inducible nitric oxide synthase-mediated decrease of intestinal P-glycoprotein expression under streptozotocin-induced diabetic conditions

Abstract

Aims: P-glycoprotein (P-gp), one of the important drug-efflux pumps, is known to be affected by pathological conditions such as inflammation or infection. Recently, it is reported that high glucose or hyperglycemia can alternate P-gp expression levels at the blood-brain barrier or in the kidney, although the details are still unknown. Here, we analyzed the alteration of intestinal P-gp expression and function in the development of diabetes and elucidated the mechanisms.

Main methods: Type 1 diabetes was induced in male ddY mice by an i.p. injection of streptozotocin (STZ) (230 mg/kg). We analyzed ileal P-gp expression and function using Western blot analysis and an in situ closed loop method, respectively.

Key findings: A significant reduction of P-gp expression level in ileum was found 9 days after STZ administration. In contrast, a remarkable decrease in P-gp function was observed on the 3rd and 9th days. Interestingly, nitric oxide synthase (NOS) activity in ilea was significantly increased on the 9th day. The decrease of P-gp expression levels observed on the 9th day was completely suppressed by L-N(G)-nitroarginine methyl ester (L-NAME), a broad range NOS inhibitor, or aminoguanidine, a specific inducible NOS (iNOS) inhibitor.

Significance: These results indicate the possibility that nitric oxide (NO), produced by iNOS in the ileum, is involved in the reduction of ileal P-gp expression under STZ-induced diabetic conditions.