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1. Drug Metab Pharmacokinet. 2012 Apr 10. [Epub ahead of print]

Involvement of ubiquitination in decrease of intestinal P-glycoprotein in
streptozotocin-induced diabetic mouse model.

Nawa A, Fujita-Hamabe W, Tokuyama S.

Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin
University.

P-glycoprotein (P-gp), one of the drug efflux pumps, expressed in some tissues
and may affect pharmacokinetics of its substrates. We have previously reported
that decrease of intestinal P-gp expression affects pharmacokinetics of
orally-administered P-gp substrate drugs under streptozotocin (STZ)-induced type
1 diabetic mice model. Although we have found the participation of nitric oxide
synthase (NOS) activation as mechanism of the decrease in intestinal P-gp
expression under diabetic condition, more detailed mechanism other than NOS is
remained unknown. Here, we studied the involvement of ubiquitin-proteasome system
in the mechanism of decrease in intestinal P-gp expression under diabetic
condition. Nine days after STZ administration (diabetic condition),
ubiquitination levels of ileal P-gp was significantly increased, accompanying
with decrease of intestinal P-gp protein expression levels. Furthermore,
treatment of 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 condition. Our results reveal the
participation of acceleration of ubiquitin-preotasome system by NO in the
decrease of intestinal P-gp expression levels under diabetic condition.

PMID: 22498644 [PubMed - as supplied by publisher]