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.
Endotoxin is known to cause a dose-dependent impairment of hepatic bile secretion, organic anion excretion, and activity of Na+,K'-activated ATPase. Since it is possible that this impaired excretory function is a result of direct interaction of endotoxin with hepatocytes, we examined: (a) the excretion of endotoxin into bile, and (b) its association with an hepatocyte-enriched, Kupffer cell-depleted population of liver cells. Escherichia coli 0127:B8 endotoxin (17 to 54 pg per 100 g m body weight) was given i.v. to male Sprague Dawley rats and bile collected up to 48 hr. The expected significant decrease in bile secretion was seen, confirming the biological effectiveness of the endotoxin. Endotoxin was quantitated by a gas chromatography/mass spectroscopy method which detects the P-hydroxymyristic acid in the lipid A moiety of endotoxin. Approximately 7% of the administered dose of endotoxin was recovered as P-hydroxymyristic acid in bile in the 48 hr following injection. Approximately two thirds of the administered dose of endotoxin was recovered as P-hydroxymyristic acid in the whole liver. Further analysis of the /3-hydroxymyristic acid in bile and liver by Folch extraction and thin-layer chromatography was performed. The P-hydroxymyristic acid in bile was associated with polar and nonpolar metabolites of endotoxin. The P-hydroxymyristic acid recovered in the liver distributed similarly in Folch extraction to intact endotoxin added in vitro. Endotoxin quantitated as P-hydroxymyristic acid was measured in whole liver homogenate and hepatocyte-enriched preparations 3 hr following i.v. administration. The mass abundance by gas chromatography/mass spectrometry of P-hydroxymyristic acid per lo6 hepatocytes was similar in crude liver homogenate and the hepatocyte-enriched fractions indicating the presence of substantial amounts of P-hydroxymyristic acid in association with parenchymal liver cells. Thus, our studies indicate that the bulk of the P-hydroxymyristic acid of endotoxin given i.v. to rats is found in hepatocytes in a form suggesting minimal degradation of the endotoxin. A small proportion of the P-hydroxymyristic acid associated with the endotoxin in the liver is then released slowly into bile as a complex mixture of polar and nonpolar metabolites of endotoxin.The liver plays the major role in clearing circulating endotoxin from the blood of all experimental animals studied. Using (51Cr) -labeled endotoxin, within 15 min after injection, the liver contained 65% of the administered radioactivity (1). In vzuo studies have shown subcellular localization of 14C-endotoxin in the nuclear and mitochondrial fractions of hepatocytes as well as Kupffer cells (2). In a recent study, (I2'I) radioactivity was present in the gallbladder bile of rabbits following i.v. injection of '251-lipopolysaccharide (LPS) suggesting the possibility that LPS might be processed by hepatocytes and released into the bile canalicular system (3). However, the same
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