Progressive defect in biliary GSH secretion in streptozotocin-induced diabetic rats.
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.
Lu
S C
SC
Department of Medicine, University of Southern California School of Medicine, and the Department of Veteran Affairs Outpatient Clinic, Los Angeles 90033, USA.
Kuhlenkamp
J
J
Wu
H
H
Sun
W M
WM
Stone
L
L
Kaplowitz
N
N
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
D004791:Enzyme Inhibitors; D007555:Isoxazoles; D005723:gamma-Glutamyltransferase; D011493:Protein Kinase C; D005978:Glutathione; C006303:acivicin