dinoprost and diethyl-maleate

Selenium and glutathione have interrelated oxidant defense roles in vivo. Experiments were carried out to determine the effect of glutathione depletion in selenium-deficient rats.. Selenium-deficient and control rats were injected with phorone to deplete glutathione. Histologic assessment of liver and kidney injury was performed at 24 hours. In another experiment, glutathione depletion, lipid peroxidation, and liver injury were measured for 12 hours after phorone administration to determine their relationships with one another. In a final experiment, selenoproteins were correlated with protection against lipid peroxidation and liver necrosis. Selenium-deficient rats were injected with vehicle alone and with 5, 10, or 25 micrograms of selenium/kg. Twelve hours later, selenoproteins were measured in some of the rats, and phorone was injected into others. Liver injury and lipid peroxidation were assessed 6 hours after the phorone injection.. Twenty-four hours after phorone administration (125 mg/kg), centrilobular hepatic necrosis and renal tubular necrosis were evident in selenium-deficient rats but not in controls. The time-course experiment revealed that phorone (250 mg/kg) caused sharp decreases in liver and kidney glutathione levels in both groups within 2 to 4 hours. Lipid peroxidation, as assessed by F2 isoprostane concentrations, in selenium-deficient animals. Liver necrosis, indicated by a rise in plasma ALT, took place in selenium-deficient rats but not in controls. Selenium injections into selenium-deficient rats increased selenoprotein P concentrations from 4% of control to as high as 39% but had little effect on glutathione peroxidase activities. Six hours after phorone administration, rats that had received selenium had no rise in ALT, and the rises in F2 isoprostanes were abolished or attenuated.. We conclude that depletion of glutathione in selenium-deficient liver and kidney leads to necrosis in those organs associated with evidence of lipid peroxidation. Protection against this injury by selenium correlates with selenoprotein P concentration in plasma but not with glutathione peroxidase activity in tissues or in plasma. These findings raise the possibility that selenoprotein P protects cell membranes against oxidant injury and that glutathione is involved in that protection.

Topics: Animals; Buthionine Sulfoximine; Dinoprost; Glutathione; Ketones; Kidney; Lipid Peroxides; Liver; Male; Maleates; Methionine Sulfoximine; Necrosis; Osmolar Concentration; Proteins; Rats; Rats, Sprague-Dawley; Selenium; Selenoprotein P; Selenoproteins

Exogenous thiol compounds have been reported to protect the stomach from ethanol-induced necrotic lesions. The gastric mucosa contains high levels of an endogenous thiol, glutathion (GSH). Because of the known role of glutathione in protecting against hepatic injury, its role in gastric mucosal cytoprotection was of interest. By use of an animal model for acute gastric injury from ethanol, a close parallel relation between depletion of endogenous mucosal GSH and induction of mucosal protection was demonstrated. Surprisingly, mucosal protection varied inversely with the level of mucosal GSH obtained after treatment with specific GSH-depleting agents (diethyl maleate and cyclohexene-1-one). Depletion of gastric mucosal GSH was associated with an increase in the mucosal content of prostaglandins 6-keto F1 alpha and F2 alpha but not E2. The protective effect induced by GSH-depleting agents was partially reversed by indomethacin in some but not all studies. Although GSH depletors increased gastric juice volume, protection with these agents persisted after the volume and mucosal GSH had returned to control levels and also was not reversed by increasing the dose of ethanol threefold to overcome a possible dilutional effect. We conclude that, contrary to apparent predictions, depletion of endogenous gastric GSH protects the stomach from acute ethanol-induced injury. Although the mechanism of this protection is unknown, a mediation by endogenous release of prostaglandins seems to play a minor role since diethyl maleate was protective even in indomethacin-treated animals.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cyclohexanones; Dinoprost; Dinoprostone; Ethanol; Gastric Mucosa; Glutathione; Indomethacin; Male; Maleates; Necrosis; Prostaglandins E; Prostaglandins F; Rats; Rats, Inbred Strains