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Query: UMLS:C0008370 (cholestasis)
 9,378 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The possible relevance of alterations in intracellular Ca2+ and hepatic glutathione levels (GSH) in the pathogenesis of cholestasis induced by lithocholic acid (LCA) was examined by comparing effects of LCA and acetaminophen on these parameters and bile flow (BF) in rats. Intracellular Ca2+ activity was measured via glycogen phosphorylase a determination in rats given an intravenous bolus injection of either LCA (12 mumol/100 g body wt.), acetaminophen (60 mg/100 g body wt.), or a mixed solution of LCA and acetaminophen. BF was reduced immediately after LCA administration, with a maximum decrease occurring at 60 min followed by an increase to normal values at 210 min. On the other hand, glycogen phosphorylase a activity was elevated during all time periods after LCA treatment. Hepatic glutathione followed the BF curves being markedly depleted at the peak of cholestasis (60 min) and normal in the total recovery period (210 min). In contrast, acetaminophen had no effect on BF but significantly increased glycogen phosphorylase a activity and depleted hepatic glutathione levels. These results suggest that cholestatic effect of LCA is not due to changes in intracellular Ca2+ or hepatic glutathione levels.
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PMID:Do intracellular Ca2+ activity and hepatic glutathione play a role in the pathogenesis of lithocholic acid-induced cholestasis? 164 72

alpha-Naphthylisothiocyanate (ANIT) injures bile duct epithelium and hepatic parenchymal cells in rats. It is commonly believed that ANIT must undergo bioactivation by hepatic, cytochrome P450-dependent mixed-function oxidases (MFO), since agents which are inducers or inhibitors of hepatic MFO activity enhance or attenuate, respectively, the liver injury associated with ANIT. Several of these agents also affect hepatic glutathione (GSH) content and/or GSH S-transferase activity in a manner to suggest a causal role for GSH in ANIT-induced hepatotoxicity. To determine whether GSH might be involved in the mechanism of injury, buthionine sulfoximine (BSO), diethyl maleate (DEM), or phorone was used to reduce hepatic non-protein sulfhydryl (NPSH) content, an indicator of GSH content. Twenty-four hours after ANIT treatment, rats exhibited cholestasis and elevations in serum of total bilirubin concentration, total bile acid concentration, aspartate aminotransferase (AST) activity, and gamma-glutamyltransferase activity. Cotreatment of rats with BSO decreased NPSH content by 70% at 24 hr and prevented the cholestasis and elevations in serum markers of liver injury caused by ANIT. Likewise, cotreatment of rats with DEM afforded protection against markers of liver injury. Phorone treatment attenuated ANIT-induced elevations in serum total bilirubin concentration and AST activity. Although BSO treatment afforded protection against ANIT-induced liver injury at 24 hr, the injury was evident at 48 hr, and it appeared to coincide with a return of hepatic NPSH content. These results suggest that GSH plays a causal or permissive role in the liver injury caused by ANIT.
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PMID:Protection against alpha-naphthylisothiocyanate-induced liver injury by decreased hepatic non-protein sulfhydryl content. 167 29

Acute administration of alpha-naphthylisothiocyanate (ANIT) to rats has been used as a model of intrahepatic cholestasis. The mechanism of toxicity of ANIT is unknown, although recent evidence suggests a causal or permissive role for glutathione (GSH) (Dahm LJ and Roth RA, Biochem Pharmacol 42: 1181-1188, 1991). In these studies, ANIT treatment elevated hepatic non-protein sulfhydryl (NPSH) content, an indicator of GSH content, when liver injury was evident. The purpose of the present study was to characterize the effects of ANIT on hepatic NPSH content and to relate these changes to the development of liver injury. In rats fasted for 24 hr, administration of ANIT (100 mg/kg, per os [p.o.]) did not change hepatic NPSH content, bile flow, or serum measurements of total bilirubin concentration, alanine aminotransferase (ALT) activity, or gamma-glutamyltransferase (GGT) activity by 12 hr post-treatment relative to corn oil vehicle controls. However, by 24 hr after ANIT treatment, rats exhibited cholestasis and elevations in serum markers of liver injury. These markers were associated temporally with an increase in hepatic NPSH content, which consisted entirely of GSH. To determine whether the cholestasis caused by ANIT treatment might have caused the elevation of hepatic NPSH content, an extrahepatic cholestasis in rats was produced by ligation of the common bile duct. Bile duct ligation elevated hepatic NPSH content between 6 and 12 hr after ligation. Administration to rats of a non-hepatotoxic analog of ANIT, beta-naphthylisothiocyanate, also elevated hepatic NPSH content 24 hr after treatment. Taken together, these results indicate that the elevation in hepatic NPSH content after ANIT treatment is associated temporally with the onset of liver injury, but this elevation does not appear to participate causally in the mechanism of injury.
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PMID:Relationship between alpha-naphthylisothiocyanate-induced liver injury and elevations in hepatic non-protein sulfhydryl content. 167 30

1-Naphthylisothiocyanate (ANIT) is a model compound which causes cholestasis in laboratory animals. Various biochemical and morphological changes including biliary epithelial and parenchymal cell necrosis occur in the liver of animals treated with ANIT. Although the mechanism(s) for these effects is not understood, a role for glutathione (GSH) in toxicity has been implicated. The possible role of GSH in hepatocellular toxicity caused by ANIT was investigated in this study. Treatment of freshly isolated rat hepatocytes with ANIT caused a concentration- and time-dependent depletion of cellular GSH that preceded lactate dehydrogenase (LDH) leakage. Analysis of the incubation medium indicated that the majority of the cellular GSH which was lost was present extracellularly as GSH or as a GSH-releasing compound. Mixing ANIT with GSH at pH 7.5 yielded a compound that was characterized by HPLC and fast atom bombardment-mass spectrometry (FAB-MS) S-(N-naphthyl-thiocarbamoyl)-L-glutathione (GS-ANIT). When dissolved in aqueous solutions at neutral pH, 95% of GS-ANIT dissociated to yield free ANIT and GSH. Under conditions designed to maximize formation and stability of GS-ANIT, GS-ANIT was found in the extracellular medium of hepatocytes treated with ANIT. Treatment of hepatocytes with the GS-ANIT caused GSH depletion and LDH leakage similar to that observed with equimolar amounts of ANIT. These data suggest that ANIT depletes hepatocytes of GSH through a reversible conjugation process. Such a process may play a role in the toxicity of ANIT.
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PMID:Involvement of glutathione in 1-naphthylisothiocyanate (ANIT) metabolism and toxicity to isolated hepatocytes. 195 35

In the present paper we provide a basic enzymatic characterization of biliary epithelial cells (BEC) that have been isolated from normal rat liver. When compared with liver parenchymal cells, BEC display the following major features: (a) a very high specific activity of gamma-glutamyltranspeptidase (approx. 200-times higher than the value usually found in hepatocytes); (b) a lack of enzymes that are usually associated with the endoplasmic reticulum in hepatocytes such as cytochrome P-450, aminopyrine demethylase, glucose 6-phosphatase and NADPH cytochrome-c reductase; (c) the presence of enzymes related to the glutathione redox cycle (e.g., GSH-peroxidase, GSSG-reductase and different isozymes of GSH-transferase), but accompanied by a very low content in reduced glutathione. The enzyme pattern of BEC correlates well with histochemical and immunohistochemical studies, as well as with biochemical studies on bile ductular cells isolated from rat liver during cholestasis.
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PMID:Biochemical studies on bile duct epithelial cells isolated from rat liver. 197 79

The mechanism for the vasopressin- and epinephrine-induced decrease in bile formation and increase in sinusoidal efflux of glutathione was investigated in rat livers perfused with recirculating fluorocarbon emulsion. Vasopressin and epinephrine transiently decreased bile flow and excretion of endogenous bile acids and glutathione and increased the bile/perfusate ratio of [14C]sucrose, suggesting an increase in junctional permeability, but had no effect on the bile/perfusate ratio of [3H]polyethylene glycol-900. The decreased biliary glutathione was balanced by an increase in sinusoidal efflux, such that total hepatic release remained unchanged. The adrenergic antagonist dihydroergotamine blocked the effects of epinephrine. To examine whether an increase in junctional permeability per se could account for the changes in glutathione efflux, biliary permeability was increased by either bile duct ligation, lowering of perfusate Ca2+ concentration with ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), or addition of taurolithocholate, a cholestatic bile acid. All three maneuvers produced a decrease in biliary glutathione excretion and a concomitant increase in sinusoidal glutathione efflux, whereas total glutathione release was largely unaffected. The effects of EGTA were partially reversed if CaCl2 was reintroduced into the perfusate. Because the GSH/GSSG ratio in perfusate could not be measured in this experimental system due to the spontaneous oxidation of GSH to GSSG, additional experiments in the nonrecirculating mode examined the effects of vasopressin and bile duct ligation on sinusoidal release of GSH and GSSG. In control livers there was no detectable GSSG in perfusate (less than 0.5 nmol.min-1.g-1). After vasopressin administration, the additional sinusoidal glutathione was mainly as GSH, although there was also a significant amount of GSSG (1-2 nmol.min-1.g-1). The additional glutathione released into perfusate after bile duct ligation was 47% as GSSG. When vasopressin was administered to livers whose bile duct had been ligated, its ability to enhance sinusoidal glutathione release was diminished, suggesting that the effects of vasopressin and bile duct ligation are not additive. These observations support previous findings that vasopressin and epinephrine can modulate hepatocyte tight junctional permeability and demonstrate that these hormones produce cholestasis and inverse changes in sinusoidal and biliary glutathione efflux. Other maneuvers that increased biliary permeability to [14C]sucrose also produced cholestasis and a redistribution of glutathione efflux from bile to perfusate, suggesting that an increase in junctional permeability may allow biliary glutathione to reflux from bile to plasma.
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PMID:Cholestasis, altered junctional permeability, and inverse changes in sinusoidal and biliary glutathione release by vasopressin and epinephrine. 211 13

The aim of the present study was to investigate the possible role of reactive oxygen species in the pathogenesis of hypoxic damage in isolated perfused rat liver. One hour of hypoxia caused severe cell damage (lactate dehydrogenase release of greater than 12,000 mU/min/g liver wt) and total irreversible cholestasis which was accompanied by a loss of cellular ATP and a marked decrease in lactate efflux. Tissue glutathione disulfide (GSSG) content and GSSG efflux as a measure of hepatic reactive oxygen formation was less than 1% of total glutathione before and during hypoxia. Upon reoxygenation, however, hepatic GSSG content increased sharply to about twice the control values and GSSG efflux increased several-fold to around 3-4 nmol GSH-equivalents/min/g. The release of lactate dehydrogenase decreased upon reoxygenation and tissue ATP content recovered partially. When livers were reoxygenated at an earlier time interval than 1 hr of hypoxia, i.e., before the onset of damage, no enhanced GSSG formation was observed. The results demonstrate that hypoxic damage is a prerequisite to reactive oxygen formation during the subsequent reoxygenation period. Thus, reactive oxygen species appear unlikely to play a crucial role in the pathogenesis of hypoxic liver damage in the hemoglobin-free, isolated perfused liver model.
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PMID:Hypoxic damage generates reactive oxygen species in isolated perfused rat liver. 334 37

Bile duct ligation in male rats for two weeks led to a marked increase in both serum sorbitol dehydrogenase activity and serum bile acid concentration indicating cholestatic liver injury. Furthermore, a rise in the hepatic hydroxyproline level indicating collagen accumulation was observed. As a consequence of these alterations, the hepatic microsomal mixed-function oxidase system was impaired as evidenced by a decrease in cytochrome P-450 content and in the activities of NADPH-cytochrome c reductase and aminopyrine-demethylase. While the hepatic glutathione content remained unaffected, the cytosolic GSH S-transferase activity was clearly suppressed due to subchronic cholestasis.
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PMID:Effect of subchronic cholestasis on microsomal mixed-function oxidases and the glutathione-conjugating enzyme system in rat liver. 405 19

Renal function may be compromised by extrahepatic cholestasis. In this context, the nephrotoxic role of bile salts is well known. Recently, however, it has been claimed that other factors, such as lipid peroxides, are involved. We therefore created bile duct ligation in 40 Sprague-Dawley rats. During the follow-up (from 1 to 28 days), significant variations were found in liver histological parameters, but not in renal morphology. Fourteen days after ligation, significant increases were found in serum and urinary thiobarbituric-acid-reactive species and phospholipase A2 (indirect indices of lipid peroxidation), whereas 8-10 days after ligation, a significant decrease was observed in erythrocytic and hepatic GSH levels. The variations in urinary thiobarbituric-acid-reactive species and in phospholipase A2 were not correlated with concomitant variations in the sera. Urinary lipid peroxides were directly correlated with the degree of liver morphological alterations and inversely with circulating GSH. Urinary outputs of lipid peroxides, phospholipase A2 and N-acetyl-glucosaminidase were correlated with each other. These results suggest that there is an imbalance in the oxidative-antioxidant hepatic system in experimental extrahepatic cholestasis. The reduced bioavailability of blood GSH may alter the oxidative equilibrium in other organs, such as the kidney, triggering and favoring the lipoperoxidative cascade.
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PMID:Renal functional alterations in extrahepatic cholestasis: can oxidative stress be involved? 758 5

Hyperplastic nodular cirrhosis was induced in rats by long-term (6 month) i.p. administration of thioacetamide at doses of 2.66 mmol/kg body wt, three times per week. The survival rate of animals at the end of the treatment was 90%. To follow the temporal changes samples at 0, 7, 15, 30, 45, 60, 90, 150 and 180 days from rats during thioacetamide intoxication and from chronological controls were obtained. The cirrhogenic ability of this treatment was assessed on the basis of morphological changes: the development of macronodular cirrhosis and the appearance of fibrous septa of collagen through portal spaces. Parameters of liver injury and cholestasis were obtained by assaying the serum activities of isocitrate dehydrogenase and gamma-glutamyltransferase. Enzymes and metabolites related to glutathione redox systems, as well as other antioxidant enzymes, were tested. Catalase and glutathione peroxidase, the two enzymes involved in the elimination of peroxides, and glutathione reductase decreased significantly at the end of the 6 months of intoxication, while Cu-Zn and Mn superoxide dismutases increased progressively during the long-term thioacetamide treatment. Protein thiol levels profile showed a biphasic change increasing from the 7th day and were insensitive to the 30% depletion of intracellular glutathione (GSH). To study the relationship of the intracellular thiols on the mechanisms of cell proliferation and differentiation during the cirrhogenic process, DNA content was assayed by flow cytometry in isolated hepatocytes, and DNA ploidy and distribution between G0-G1, S and G2 + M phases were determined. Remarkable changes in relation to a sharp increase in diploid population from 7 to 180 days (24.5%-->85.5%), a pronounced decrease in polyploid populations (tetraploid+octoploid) in the same period (73.7%-->12.3%), and elevations in the populations in S phase (S1 + S2) were observed in thioacetamide-treated rats. The results obtained indicate that hepatocytes isolated from thioacetamide-treated rats showed a marked tendency to diploidy, an enhancement in DNA replication parallel to the hepatic content of protein sulphydryl groups and a significant decline in antioxidant enzyme activities. The increase in protein thiols was independent of GSH level and of the thiol redox state.
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PMID:Relationship between antioxidant systems, intracellular thiols and DNA ploidy in liver of rats during experimental cirrhogenesis. 761 93


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