title: Progressive defect in biliary GSH secretion in streptozotocin-induced diabetic rats.
abstract: This study examined the effect of streptozotocin-induced diabetes on biliary reduced glutathione (GSH) efflux. Biliary GSH efflux was measured before and after acivicin, an irreversible inhibitor of gamma-glutamyl transpeptidase (GGT). One week after streptozotocin treatment, liver GGT activity doubled in diabetic rats but was inhibited by approximately 90% after acivicin to levels comparable to controls. Despite maximal GGT inhibition, biliary GSH efflux in untreated diabetic rats decreased progressively to approximately 10% of control levels by week 4 and was partially restored by insulin. The mechanism for the decrease in biliary GSH efflux was not increased paracellular permeability. GSH transport kinetics, ATP-stimulated taurocholate, and oxidized glutathione (GSSG) transport in canalicular liver plasma membrane prepared from diabetic and control rats were similar. Inhibition of protein kinase C (PKC) with high-dose H-7 increased biliary GSH efflux in diabetic animals to near control basal levels. In conclusion, streptozotocin-induced diabetic rats exhibit a progressive impairment in biliary GSH transport. One of the responsible mechanisms is heightened PKC tone in diabetic animals.
authors.affiliation: Department of Medicine, University of Southern California School of Medicine, and the Department of Veteran Affairs Outpatient Clinic, Los Angeles 90033, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Lu
authors.forename: J
authors.initials: J
authors.lastname: Kuhlenkamp
authors.forename: H
authors.initials: H
authors.lastname: Wu
authors.forename: W M
authors.initials: WM
authors.lastname: Sun
authors.forename: L
authors.initials: L
authors.lastname: Stone
authors.forename: N
authors.initials: N
authors.lastname: Kaplowitz
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism*; D007555:Isoxazoles / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D008297:Male; D010477:Perfusion; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D007555:Isoxazoles; D005723:gamma-Glutamyltransferase; D011493:Protein Kinase C; D005978:Glutathione; C006303:acivicin