Ayaka Nawa1, Wakako Fujita Hamabe, Shogo Tokuyama. 1. Department of Clinical Pharmacy, Kobe Gakuin University Faculty of Pharmaceutical Sciences, 1-1-3 Minatojima, Chuo-ku, Kobe 650-8586, Japan.
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. Copyright (c) 2010 Elsevier Inc. All rights reserved.
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. Copyright (c) 2010 Elsevier Inc. All rights reserved.
Authors: Zhao Wei; Li Liang; Liu Junsong; Chen Rui; Chang Shuai; Qiu Guanglin; He Shicai; Wang Zexing; Wang Jin; Che Xiangming; Wang Shufeng Journal: J Exp Clin Cancer Res Date: 2015-06-18