PROGRESSIVE DEFECT IN BILIARY GSH SECRETION IN STREPTOZOTOCIN-INDUCEDDIABETIC RATS

This study examined the effect of streptozotocin-induced diabetes on b iliary reduced glutathione (GSH) efflux. Biliary GSH efflux was measur ed before and after acivicin, an irreversible inhibitor of gamma-gluta myl transpeptidase (GGT). One week after streptozotocin treatment, liv er GGT activity doubled in diabetic rats but was inhibited by similar to 90% after acivicin to levels comparable to controls. Despite maxima l GGT inhibition, biliary GSH efflux in untreated diabetic rats decrea sed progressively to similar to 10% of control levels by week 4 and wa s partially restored by insulin. The mechanism for the decrease in bil iary GSH efflux was not increased paracellular permeability. GSH trans port kinetics, ATP-stimulated taurocholate, and oxidized glutathione ( GSSG) transport in canalicular liver plasma membrane prepared from dia betic and control rats were similar. Inhibition of protein kinase C (P KC) with high-dose H-7 increased biliary GSH efflux in diabetic animal s to near control basal levels. In conclusion, streptozotocin-induced diabetic rats exhibit a progressive impairment in biliary GSH transpor t. One of the responsible mechanisms is heightened PKC tone in diabeti c animals.