title: Involvement of ubiquitination in the decrease of intestinal P-glycoprotein in a streptozotocin-induced diabetic mouse model.
abstract: P-Glycoprotein (P-gp), one of the drug efflux pumps, is expressed in some tissues and may affect the pharmacokinetics of its substrates. We have previously reported that a decrease of intestinal P-gp expression affects the pharmacokinetics of orally-administered P-gp substrate drugs in a streptozotocin (STZ)-induced type 1 diabetic mice model. Although we have found the participation of nitric oxide synthase (NOS) activation as a mechanism of the decrease in intestinal P-gp expression under diabetic conditions, more detailed mechanisms other than NOS remain unknown. Here, we studied the involvement of the ubiquitin-proteasome system in the mechanism of the decrease in intestinal P-gp expression under diabetic conditions. Nine days after STZ administration (diabetic condition), ubiquitination levels of ileal P-gp were significantly increased, accompanied by an decrease of intestinal P-gp protein expression levels. Furthermore, treatment with an NO donor could increase the intestinal ubiquitinated P-gp levels. On the other hand, activity of 26S proteasome, an important enzyme in ubiquitin-proteasome system, did not change, suggesting the first step of the system (i.e., ubiquitination) but not the second step (i.e., degradation)-specific up-regulation under diabetic conditions. Our results reveal the participation of the acceleration of the ubiquitin-preotasome system by NO in the decrease of intestinal P-gp expression levels under diabetic conditions.
authors.affiliation: Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Japan.
authors.forename: Ayaka
authors.initials: A
authors.lastname: Nawa
authors.forename: Wakako
authors.initials: W
authors.lastname: Fujita-Hamabe
authors.forename: Shogo
authors.initials: S
authors.lastname: Tokuyama
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D007082:Ileum / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D025801:Ubiquitin; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease