The present results showed that cholangiocarcinomas occurred at a high incidence in relatively young workers of a printing company, who were exposed to chemicals including chlorinated organic solvents.
Glutathione functions to scavenge oxidants or xenobiotics by covalently binding them and transporting the resulting metabolites through an adenosine 5'-triphosphate-dependent transport system. It has been reported that the intracellular concentration of glutathione decreases in diabetes mellitus. In order to elucidate the physiological significance and the regulation of anti-oxidants in diabetic patients, changes in the activity of the glutathione-synthesizing enzyme, gamma-glutamylcysteine synthetase, and transport of thiol [S-(2,4-dinitrophenyl)glutathione] were studied in erythrocytes from patients with non-insulin-dependent diabetes and K562 cells cultured with 27 mmol/l glucose for 7 days. The activity of gamma-glutamylcysteine synthetase, the concentration of glutathione, and the thiol transport were 77%, 77% and 69%, respectively in erythrocytes from diabetic patients compared to normal control subjects. Treatment of patients with an antidiabetic agent for 6 months resulted in the restoration of gamma-glutamylcysteine synthetase activity, the concentration of glutathione, and the thiol transport. A similar impairment of glutathione metabolism was observed in K562 cells with high glucose levels. The cytotoxicity by a xenobiotic (1-chloro-2,4-dinitrobenzene) was higher in K562 cells with high glucose than in control subjects (50% of inhibitory concentration 300 +/- 24 mumol/l vs 840 +/- 29 mumol/l, p < 0.01). Expression of gamma-glutamylcysteine synthetase protein was augmented in K562 cells with high glucose, while enzymatic activity and expression of mRNA were lower than those in the control subjects. These results suggest that inactivation of glutathione synthesis and thiol transport in diabetic patients increases the sensitivity of the cells to oxidative stresses, and these changes may lead to the development of some complications in diabetes mellitus.
To elucidate the pathological metabolism of glutathione synthesis in diabetic endothelial cells, we studied the expression of gamma-glutamylcysteine synthetase (gamma-GCS) using a mouse vascular endothelial cell line. Exposing normoglycemic endothelial cells to tumor necrosis factor-alpha (TNF-alpha) or interleukin-1beta (IL-1beta) increased the activity and the mRNA expression of gamma-GCS. The addition of inhibitors for nuclear factor kappaB (NF-kappaB) to the cells caused a loss of the gamma-GCS mRNA expression in response to TNF-alpha. A shift of the concentration of glucose in the medium from 5.5 to 28 mM glucose and a following incubation for 7 days decreased the expression of gamma-GCS mRNA. These cells showed no apparent responses of gamma-GCS mRNA or the activity of NF-kappaB to TNF-alpha or IL-beta. Increase in the GSH concentration of the cells treated with 28 mM glucose restored the expression of gamma-GCS mRNA and its response to TNF-alpha or IL-beta, suggesting that redox regulation is involved in the expression of gamma-GCS. In summary, the expression of gamma-GCS is regulated by TNF-alpha or IL-1beta in endothelial cells mediated by NF-kappaB stimulation, and impairment of the regulation of gamma-GCS in hyperglycemic cells may be a cause of medical complications that develop in diabetes mellitus.
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