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)

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

The main pathway for the hepatic oxidation of ethanol to acetaldehyde proceeds via ADH and is associated with the reduction of NAD to NADH; the latter produces a striking redox change with various associated metabolic disorders. NADH also inhibits xanthine dehydrogenase activity, resulting in a shift of purine oxidation to xanthine oxidase, thereby promoting the generation of oxygen-free radical species. NADH also supports microsomal oxidations, including that of ethanol, in part via transhydrogenation to NADPH. In addition to the classic alcohol dehydrogenase pathway, ethanol can also be reduced by an accessory but inducible microsomal ethanoloxidizing system. This induction is associated with proliferation of the endoplasmic reticulum, both in experimental animals and in humans, and is accompanied by increased oxidation of NADPH with resulting H2O2 generation. There is also a concomitant 4- to 10-fold induction of cytochrome P4502E1 (2E1) both in rats and in humans, with hepatic perivenular preponderance. This 2E1 induction contributes to the well-known lipid peroxidation associated with alcoholic liver injury, as demonstrated by increased rates of superoxide radical production and lipid peroxidation correlating with the amount of 2E1 in liver microsomal preparations and the inhibition of lipid peroxidation in liver microsomes by antibodies against 2E1 in control and ethanol-fed rats. Indeed, 2E1 is rather "leaky" and its operation results in a significant release of free radicals. In addition, induction of this microsomal system results in enhanced acetaldehyde production, which in turn impairs defense systems against oxidative stress. For instance, it decreases GSH by various mechanisms, including binding to cysteine or by provoking its leakage out of the mitochondria and of the cell. Hepatic GSH depletion after chronic alcohol consumption was shown both in experimental animals and in humans. Alcohol-induced increased GSH turnover was demonstrated indirectly by a rise in alpha-amino-n-butyric acid in rats and baboons and in volunteers given alcohol. The ultimate precursor of cysteine (one of the three amino acids of GSH) is methionine. Methionine, however, must be first activated to S-adenosylmethionine by an enzyme which is depressed by alcoholic liver disease. This block can be bypassed by SAMe administration which restores hepatic SAMe levels and attenuates parameters of ethanol-induced liver injury significantly such as the increase in circulating transaminases, mitochondrial lesions, and leakage of mitochondrial enzymes (e.g., glutamic dehydrogenase) into the bloodstream. SAMe also contributes to the methylation of phosphatidylethanolamine to phosphatidylcholine. The methyltransferase involved is strikingly depressed by alcohol consumption, but this can be corrected, and hepatic phosphatidylcholine levels restored, by the administration of a mixture of polyunsaturated phospholipids (polyenylphosphatidylcholine). In addition, PPC provided total protection against alcohol-induced septal fibrosis and cirrhosis in the baboon and it abolished an associated twofold rise in hepatic F2-isoprostanes, a product of lipid peroxidation. A similar effect was observed in rats given CCl4. Thus, PPC prevented CCl4- and alcohol-induced lipid peroxidation in rats and baboons, respectively, while it attenuated the associated liver injury. Similar studies are ongoing in humans.
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PMID:Role of oxidative stress and antioxidant therapy in alcoholic and nonalcoholic liver diseases. 889 26

Erythrocyte membrane Na+,K+: Ca2+ ATP ase activities, cholesterol (CH) phospholipid (PL) composition and erythrocyte glutathione (GSH) contents were determined in controls, in patients with chronic active hepatitis and liver cirrhosis. NA+,K+ ATP ase activities were significantly (P < 0.0001) less in patients with chronic active hepatitis and liver cirrhosis (n = 8, 0.102 +/- 0.02 mumol P/mg protein/hour; n = 8, 0.081 +/- 0.02 mumol P/mg protein/hour) than in controls (n = 10, 0.219 +/- 0.05). Histopathological analysis of liver sections obtained from patients with chronic active hepatitis (n = 3) and liver cirrhosis (n = 2) correlated well with erythrocyte biochemical findings. There was a significant negative correlation between Na+,K+ ATP ase activity and portal fibrosis (P < 0.05, r = -8680). However, further experiments performed on larger study populations are needed to better elucidate this correlation. Therefore, NA+K+ ATP ase activity measurement can be reliable assessment of liver fibrosis.
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PMID:Erythrocyte membrane Na+,K+ ATP ase activity can be a marker of liver histopathology. 895 35

Liver cirrhosis, which is associated with decreased plasma and hepatic glutathione (GSH), has been reported to cause the suppression of NK activity in peripheral blood mononuclear cells. Since low GSH levels in lymphocytes are known to alter lymphocyte function, we examined the correlation between intracellular GSH levels and the cytotoxic activity of liver-associated mononuclear cells (liver MNC). We show here that rat liver contains a highly active population of NK cells (CD3- NKR-P1 + cells) that kill Yac-1 in vitro and that the cytotoxic activity of this NK population is directly proportional to liver MNC GSH. This proportionality is independent of the methods used to alter GSH level. Thus, in vitro treatment of liver MNC with buthionine sulfoximine to lower GSH levels lowers the cytotoxic activity. MNC from cirrhotic liver, in which implanted tumor cells grow faster, have both low GSH levels and low cytotoxicity, and supplementation of cirrhotic liver MNC with N-acetylcysteine raises GSH levels and increases cytotoxicity. These findings suggest a physiologic mechanism, i.e. decreased GSH, may be causally associated with the increased incidence of hepatoma in cirrhotic individuals and the increased growth of hepatoma cells in cirrhotic animals. Thus, we suggest that the GSH is important to the optimal functioning of the hepatic immunity that protects against hepatoma development.
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PMID:N-acetylcysteine improves cytotoxic activity of cirrhotic rat liver-associated mononuclear cells. 979 17

We do not know much about the changes that occur in reduced (GSH) and oxidized (GSSG) glutathione in the development of liver cirrhosis. Therefore, we investigated the glutathione redox system during development of liver cirrhosis after bile-duct ligation in rats. We compared the GSH and GSSG content of liver and plasma between bile-duct-ligated rats and sham-operated controls 6 and 24 h and 5, 15, 23, and 38 days after operation. Compared to controls (x +/- SD: 6.07 +/- 0.52 mumol/g wet wt.), liver GSH significantly increased 24 h (+ 37%) and 5 days (+ 53%) after bile-duct ligation. Thereafter, GSH continuously declined to 4.25 +/- 0.64 mumol/g (-31%; P < 0.001) at the end of the observation period after 38 days. The GSH turnover in 5-day bile-duct-ligated rats with high GSH concentrations was not significantly different than in sham-operated controls (16 nmol/min per g after bile-duct ligation and 15 nmol/min per g in controls). GSSG (211 +/- 42 nmol/g wet wt. in controls) was significantly lower 6 and 24 h after bile-duct ligation (-34% and -43%, respectively). Thereafter, GSSG increased and was about 100% higher than in controls after 23 and 38 days. The relation of GSSG to GSH in liver continuously increased from 3.4 to 20.5% after bile-duct ligation. The course of plasma GSH (9.57 +/- 0.79 mumol/l) paralleled hepatic GSH on a lower level: + 14% at day 5, -41% at day 15 and -51% at the end of the observation period. Plasma GSSG (0.99 +/- 0.31 mumol/l) was inversely related to liver GSSG: there were increased concentrations early after bile duct ligation (day 5: + 91%) and reduced concentrations (-44%) at the end of the observation period. Dynamic changes of the glutathione status occur in the development of liver cirrhosis after bile-duct ligation. These changes are consistent with increased oxidative stress in the liver and a deficit of transporting GSSG from the cells into plasma.
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PMID:Glutathione status in liver and plasma during development of biliary cirrhosis after bile duct ligation. 987 95

The effect of carbon tetrachloride (CCl4) on aflatoxin B1 (AFB1)-induced enzyme altered hepatic foci has been examined in young male Fischer rats given AIN-76A diet. A single i.p. dose of AFB1 (0.2 mg/kg body wt) was given to rats 24 h after partial hepatectomy. Two weeks later, CCl4 (0.8 ml/kg body wt) was injected i.p. once a week for 9 weeks. Animals were sacrificed 24 h after the last dose of CCl4 and glutathione S-transferase placental form (GST-P) and gamma-glutamyl transpeptidase (GGT) positive hepatic foci were analyzed by immunohistochemical and histochemical methods, respectively. Ten weeks after AFB1 dosing, treatment with CCl4 increased the number of AFB1-induced enzyme altered foci several fold and produced a ten to twenty-fold increase in area and volume. GST-P was more sensitive than GGT in detecting AFB1-induced enzyme altered foci. Treatment with AFB1 or CCl4 produced mild hepatic fibrosis in zones 1 and 3 respectively, whereas both treatments produced severe fibrosis in zones 1 to 3 areas. Treatment with CCl4 after AFB1 dosing lowered hepatic GSH levels by 20% and increased lipid peroxidation by 40%. It appears that CCl4, by being an effective enhancer of AFB1-induced enzyme altered hepatic foci in the rat, may mimic cirrhosis observed in human hepatocellular carcinoma.
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PMID:Enhancement of aflatoxin B1-induced enzyme altered hepatic foci in rats by treatment with carbon tetrachloride. 989 47

The aim of this study was to evaluate the effects of hepatitis B and C virus infections on liver glutathione status. Reduced and oxidized glutathione levels were determined in liver biopsy specimens obtained from patients with chronic liver disease including chronic active hepatitis and cirrhosis. In patients with hepatitis B virus infections, GSH and GSH/GSSG levels were significantly low compared with those in controls (P<0.01). There was a significant negative correlation between histological activity indices (HAI) and hepatic GSSG levels only in patients with chronic HCV infection (P<0.01; r=-0.895). In addition to this, we also found a positive correlation between indices (HAI) and GSH/GSSG of the same group (r=0.915; P<0.05). These observations suggest that HBV and HCV infections have different effects on liver glutathione status based on diverse mechanisms.
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PMID:The effects of chronic hepatitis C and B virus infections on liver reduced and oxidized glutathione concentrations. 1093 61

1. The aims of the present study were to assess: (i) the temporal relationships between hepatic lipid peroxidation, changes in the glutathione detoxification system and the onset/development of cirrhosis in CCl4-treated rats; and (ii) the effects of oral zinc administration on these parameters. 2. Cirrhosis was induced in 120 rats by intraperitoneal injections of CCl4 twice a week over 9 weeks. One hundred and twenty additional animals were used as controls. Both groups were further subdivided to receive either a standard diet or one supplemented with zinc. Subsets of 10 animals each were killed at weeks 1, 2, 3, 5, 7 and 9 from the start of the study. 3. Induction of cirrhosis produced a decrease in the components of the hepatic glutathione anti-oxidant system: glutathione transferase activity decreased from week 1, the concentration of reduced glutathione (GSH) decreased from week 5 and glutathione peroxidase (GPx) activity decreased from week 7. This impairment was chronologically related to an increase in free radical generation. Hepatic lipid peroxidation was significantly correlated with GPx activity (r = -0.47; P < 0.001) in CCl4-treated rats. Zinc administration did not produce any significant improvement of the hepatic glutathione system. 4. In conclusion, cirrhosis induction in rats by CCl4 administration produced a decrease in the hepatic glutathione antioxidant system that was related to an increase in free radical production. Furthermore, zinc supplementation produced a reduction in the degree of hepatic injury and a normalization of lipid peroxidation, but not an improvement of the hepatic GSH anti-oxidant system.
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PMID:Time-course of changes in hepatic lipid peroxidation and glutathione metabolism in rats with carbon tetrachloride-induced cirrhosis. 1097 35


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