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.

Impact of Acute Streptozotocin‐Induced Diabetes on ABC Transporter Expression in Rats

“…7% of control values), while a trend toward increased expression of Abcc3 and significantly increased expression of Abcc4 was observed. Consistent with our findings, an 80% reduction in hepatic Abcc2 protein and decreased elimination of GSH conjugates in STZ-treated rats has been previously reported [61] [62]. The impact of STZ-induced T1DM on the expression of Abcc1, Abcc3, and Abcc4 has not been previously reported.…”

Changes in glutathione homeostasis during liver regeneration in the rat

“…23 The protocol for liver perfusions was the same as above. Perfusate samples were collected at the end of 5-minute intervals; bile samples were collected continuously over the same period.…”

Streptozotocin-induced diabetes increases?-glutamyltranspeptidase activity but not expression in rat liver

“…Chemically induced diabetes mellitus produces changes in hepatobiliary function (1), alters superoxide dismutase activity (25), glutathione synthesis (14,26,27), glutathione peroxidase activity, and catalase activity (27). STZ-induced diabetes increases GGT activity in rat liver (12,13,28,29), resulting in decreased biliary excretion of glutathione (13) and the acetaminophen-glutathione conjugate (2). A reduction in glutathione excretion into bile in diabetics may have important consequences such as impairing the capacity of the intestine to detoxify dietary lipid peroxides or carcinogens.…”

“…GGT activity can be induced in liver as an adaptive response (8,10,12,13). For example, after four days of fasting, GGT activity is increased by twofold in rat liver, while a high protein diet can decrease GGT activity levels (11).…”

“…High activity is found in livers of alcoholics (10); of fasting rats (11); and in prenatal, premalignant, and malignant liver states in rodents (8). Other studies have noted increases in GGT activity in liver and plasma of STZ-induced diabetic rats (12)(13)(14). Enzyme expression was once thought to be under control of thyroid hormone; however, administration of thyroid hormone did not restore GGT activity to normal in diabetic rat liver (15).…”