Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatic glutathione (GSH) S-transferase (GST) activity and the tissue distribution of a cationic GST were investigated in biopsy liver samples obtained from patients with alcoholic liver diseases. GST activities in alcoholic fatty liver were significantly high, whereas those in cirrhosis were significantly low compared with normal liver. In fatty liver, immunohistochemically, the staining of the enzyme was strongly positive in hepatocytes around intensive fatty metamorphosis. Then, using experimental chronic alcohol-fed rats, the changes in hepatic GST and GSH peroxidase (GPx) activities and lipid peroxide (LPO) and GSH contents in alcoholic fatty liver were evaluated. Hepatic GST isoenzymes were analyzed and tissue distribution of cationic and neutral GSTs was also investigated. Liver GSH content decreased at two weeks and increased at six weeks. Liver LPO content was elevated at four and six weeks and cytosolic GPx activity was enhanced at four weeks. Cytosolic GST activity was enhanced at six weeks. The cationic and neutral GST isoenzyme pattern was unchanged compared with normal liver. Immunohistochemically, the distribution and intensity of the staining of GSTs were essentially unchanged. There was no evidence of an increase in the GST isoenzyme with selen-independent GPx activity. However, GSTs were strongly stained in the hepatocytes with fatty droplets. Thus, in alcoholic fatty liver, hepatic GST and GPx activities are thought to be enhanced by different mechanisms. The elevated GPx activity may relate to the production of LPO. However, the enhancement of GST activity may result from some other causes which include the enzyme induction.
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PMID:Glutathione S-transferase in alcoholic fatty liver. 177 80

Micro-and macronodular experimental liver cirrhosis was induced in female rats by administration of 0.03% thioacetamide (TAA) in drinking water for 3 or 6 months, respectively. The glutathione (GSH) status (content, synthesis, export) and ultrastructural changes of liver were investigated 14 d after withdrawal of TAA. The hepatic level of GSH was increased after 6 months TAA treatment. The levels of oxidized glutathione (GSSG) were not changed after 3 months or 6 months TAA administration. The GSH synthesis was not disturbed in the cirrhotic livers; only the ratio between the 2 synthesizing enzymes was changed in macronodular liver cirrhosis. The plasma GSH content was reduced in both cases, independent of the stage of liver cirrhosis. The electron microscopic studies on cirrhotic rat livers revealed a series of characteristic structural changes, such as disorganization and total lack of the microvilli border, appearance of basement membrane-like deposits within the narrowed space of Disse, disappearance of the highly porous endothelial cell lining and partly an intensively detoriated blood supply within the pseudolobules. It is suggested that all these changes may contribute to a disturbance of the GSH export from the hepatocytes into the blood. It is very likely, however, that the alterations of the sinusoidal cell surface play the most important role. 1. The GSH/GSSG redox potential is shifted in favour of the reduced form in this cirrhosis model. This shift seems to be connected with later stages of cirrhogenesis. 2. A GSH export disturbance is responsible for the decreased plasma GSH level in liver cirrhosis.
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PMID:Glutathione synthesis and export in experimental liver cirrhosis induced by thioacetamide: relations to ultrastructural changes. 276 4

Studies in animals have demonstrated the central role of the liver in regulating the circulating pool of glutathione (GSH). Most of the hepatic GSH production is released into blood and most of the circulating GSH originates in the liver. We have estimated the production of GSH in eight healthy volunteers and eight patients with cirrhosis by an analysis of the kinetics of plasma GSH. The basal plasma concentrations of free GSH were 9.3 +/- 2.4 microM in healthy volunteers and 3.6 +/- 1.1 microM in cirrhotics (P less than 0.001), and the concentrations of total GSH 16.6 +/- 6.2 microM in control subjects and 7.1 +/- 2.6 microM in cirrhotics (P less than 0.002). The concentration of GSH in the circulating pool depends on the input of GSH into this compartment and is inversely proportional to the volume of distribution of GSH (Vd) and to the fractional rate of elimination of GSH from plasma (kel). Assuming that the kinetics of endogenously produced and exogenously administered GSH are identical, Vd and kel can be calculated from the plasma concentration-time curve of a single i.v. injection of GSH. Both Vd (0.100 +/- 0.044 l kg-1 in controls and 0.131 +/- 0.043 l kg-1 in cirrhotics) and kel (0.2718 +/- 0.0555 min-1 in controls and 0.2912 +/- 0.0781 min-1 in cirrhotics) were identical in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Decreased production of glutathione in patients with cirrhosis. 312 44

Liver glutathione-peroxidase (L-GSH-Px) and glutathione-reductase (GSSG-Red) activities were measured in supernatants of liver tissues obtained from a total of 36 subjects. Sixteen of these patients had a functionally normal liver (control group), whereas of the remaining 20 patients, 10 were cirrhotic and 10 had a liver disease other than cirrhosis. The mean value of L-GSH-Px of the control group was 33.12 +/- 12.66 U/g protein, a value similar to that found in patients with liver disease. The L-GSH-Px of the control group was positively correlated with the age of the subjects (r = 0.620; p less than 0.02). In contrast, in patients with liver disease an opposite behaviour of the two parameters was noted (r = -0.497; p less than 0.05). L-GSH-Px activity tended to be higher in males than in females, whereas the erythrocyte glutathione-peroxidase (E-GSH-Px) of the same patients was higher in females, albeit not significantly. L-GSH-Px and E-GSH-Px were not correlated either in normal or in liver disease. The mean GSSG-Red of the control group was 40.63 +/- 11.10 U/g protein, which is not different from that of the group of liver patients. GSSG-Red was not correlated with L-GSH-Px or with the age of patients. In two patients with hepatoma, the GSH-Px activity of the cancer tissue was low and the GSSG-Red activity high.
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PMID:Glutathione-peroxidase and glutathione-reductase activities of normal and pathologic human liver: relationship with age. 625 11

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

Alcoholic liver disease (ALD) is one the most serious consequences of chronic alcohol abuse. Liver cirrhosis, the culmination of the illness, is one of the leading causes of death in Western countries. Mitochondria are a target of ethanol intoxication mainly due to the toxic effects of acetaldehyde, a byproduct of ethanol metabolism. Morphological and functional changes in mitochondria are one of the key hallmarks of chronic ethanol exposure in both chronic alcoholics and experimental models of alcoholism. The functional changes observed in mitochondria from ethanol-treated animals are translated in an overall decrease in ATP levels resulting from a lower rate of ATP synthesis as a consequence of impaired processing at the translational level of some components of oxidative phosphorylation encoded by mitochondrial DNA genome. Mitochondrial glutathione (GSH) plays a critical role in the maintenance of cell functions and viability and in mitochondrial physiology by metabolism of oxygen free radicals generated in the respiratory chain. GSH in mitochondria originates from cytosol by a transport system which translocates GSH into the matrix. This transport system is impaired in chronic ethanol-fed rats, which translates in a selective and significant depletion of the mitochondrial GSH content resulting in the development of an increased susceptibility to oxidant stress. Using the intragastric infusion model of experimental ALD in rats, the profound and selective mitochondrial GSH depletion precedes the onset of alcoholic liver disease, mitochondrial lipid peroxidation, and progression of liver damage.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mitochondrial glutathione depletion in alcoholic liver disease. 812 2

The glutathione (GSH) S-transferases are believed to have dual functions as hepatic detoxifying enzymes and intrahepatic binding proteins. Little is known about their alterations in human liver diseases. Therefore, we have studied the relationship between the enzyme activity and rose bengal (RB) binding in hepatic cytosol and plasma indocyanine green (ICG) kinetics in patients with various liver diseases. The enzyme activity was measured in samples of hepatic cytosol obtained from 52 patients. In addition, the content of cationic and neutral transferases was estimated in 17 biopsy samples by densitometry of Coomassie blue stained sodium dodecyl sulphate polyacrylamide gel electrophoretograms. RB binding studies also were performed on cytosol samples. ICG kinetic parameters were determined using the two-compartment open model in 17 patients who were given the dye (0.5 mg kg-1) intravenously. Correlations between the enzyme activity and liver function tests, content of the enzyme, RB binding and ICG kinetic parameters were evaluated. The following results were obtained. (1) The enzyme activities were high in alcoholic liver disease, fatty liver and Gilbert's syndrome, and low in cirrhosis. (2) The enzyme activities were positively correlated with serum cholinesterase activity, serum albumin level and hepaplastin test, and negatively correlated with ICG retention rate at 15 min. (3) The enzyme activity, its content and RB binding affinity of the cytosol were positively correlated with each other. (4) The enzyme activity was positively correlated with hepatic ICG distribution volume. These results are consistent with the role of the GSH S-transferases as ligandins in intracellular storage of dyes.
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PMID:Relationship between content of hepatic glutathione S-transferases and the kinetics of indocyanine green elimination in various liver diseases. 825 11

Plasma glutathione is markedly decreased in human cirrhosis of the liver. This decrease is said to be caused by reduced concentrations of liver glutathione. However, several studies on hepatic glutathione have revealed its concentrations to be unchanged, decreased, or even elevated. To test these inconsistencies we investigated the glutathione status of plasma, liver, and kidney in rats chronically exposed to carbon tetrachloride (CCl4). After 14 weeks of CCl4 treatment, histological examination revealed progressive cirrhotic transformation. After 20 weeks, complete micro-nodular cirrhosis was present and distinct ascites had developed. Plasma reduced glutathione (GSH) decreased by 34% in the early and by 44% in the late group, paralleled by a 65% and 76% decrease of plasma oxidized glutathione (GSSG). Liver GSH in early stages of cirrhosis was reduced by 49%, but in late cirrhosis it did not differ from controls. In contrast, liver GSSG increased by 35% in the early and by 191% in the late group. Kidney GSH increased by 14% in early and 44% in late stage cirrhosis. Kidney GSSG was unchanged in the early group, but increased by 18% in the late group. The decrease of plasma GSH and GSSG is closely related to the severity of experimental cirrhosis and inversely related to an increase of hepatic oxidized glutathione. The hepatic content of reduced glutathione, however, is decreased in early cirrhosis only. According to these results the inconsistent findings in man could be due to differences in the stages of cirrhosis in the patients. The increase in kidney glutathione is a new finding that needs further investigation, but it may probably be related to kidney dysfunction in liver disease.
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PMID:Glutathione in plasma, liver, and kidney in the development of CCl4-induced cirrhosis of the rat. 852 69

GSH and its related enzymes are one of the protective mechanisms vs. the oxidative damage, both in the circulation and in various tissues, including gastric mucosa. Patients with liver cirrhosis frequently suffer from a gastropathy caused by portal hypertension and they present low circulating levels of GSH. Aging processes cause an increase of gastric damage, of lipoperoxidative phenomenons, and a decrease of GSH in animals. The aim of this study was the evaluation, in humans, of the effect of both these factors, age and liver cirrhosis, on the global pool of GSH and on the antioxidant capability of the cells of gastric mucosa. Therefore, we evaluated the effect of liver cirrhosis and age on the circulating levels of GSH, both in the plasma and in the erythrocytes, and the GSH concentration and the activity of the total GSH-transferase (GSH-T) in gastric mucosa of healthy subjects and in patients affected by liver cirrhosis. Age, but not liver cirrhosis, induced a significant decrease of GSH and GSH-T activity in gastric mucosa; on the contrary, the plasma levels of GSH decreased in cirrhotics but not in elderly healthy subjects. In the erythrocytes, GSH was affected by both these factors (age and liver cirrhosis). These findings indicate that both in patients with liver disease and in elderly healthy subjects the GSH-related cellular defensive mechanisms are depressed and therefore susceptibility to oxidative damage may increase.
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PMID:Effect of liver cirrhosis and age on the glutathione concentration in the plasma, erythrocytes, and gastric mucosa of man. 872 Sep 22

Recent investigations have begun to define more clearly the cellular and molecular roles of oxidant stress in mediating the liver injury and fibrosis of metal storage diseases. Because of a variety of perturbations in antioxidant homeostasis in iron and copper overload, restoring the antioxidant balance to normal, or even exceeding normal levels of selected antioxidants, may provide additional protection against liver injury and prevent the progression to fibrosis and cirrhosis. Inasmuch as GSH levels appear to be elevated in livers of experimentally iron-overloaded animals, attempts to increase this antioxidant should perhaps be limited to copper overload conditions in which hepatic GSH is low. Vitamin C (ascorbate) supplementation should probably be avoided in all metal overload states because of its potentiation of radical generation by transition metals. The safety of beta-carotene in alcoholic liver disease has been questioned. Therefore, until more is known about its toxicity in metal overload, beta-carotene may not be an ideal antioxidant for clinical trials. Vitamin E and related compounds, therefore, appear to be the most reasonable antioxidants to test in metal overload states at this time. In the near future, the results of controlled clinical trials of the use of antioxidants in these and other liver disorders will hopefully provide clearer guidelines for their safety and possible use.
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PMID:Antioxidant defenses in metal-induced liver damage. 872 22


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