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)

2-Acetylaminofluorene (AAF) is a complete carcinogen in rat liver. The genotoxic effects of reactive metabolites are considered necessary but not sufficient to explain tumor formation. An overview is given of an AAF-feeding experiment designed to demonstrate early effects, preceding the development of enzyme-altered foci to support the hypothesis that toxic effects lead to a cirrhosis-like transformation as a prerequisite for the expansion of initiated foci and how those effects influence the dose-time-response relationship of tumor formation. Male Wistar rats were fed 0.005, 0.01, 0.02, 0.04 and 0.08% AAF in the diet for 2, 4, 8, and 16 weeks. GST-P-positive foci developed more than proportionately only at 16 weeks. As a first sign of morphological alterations the number of apoptoses increased (2 weeks), the proliferation rate followed with some delay and was maximal at 4 weeks. The most sensitive parameter for adaptive responses was the inhibition of the mitochondrial permeability transition, studied ex vivo. All parameters increased dose-dependently at low doses. A threshold could not be detected, but effects developed much more gradually with the lowest, non-toxic dose. The situation of massive development of foci observed with the higher doses at 16 weeks was not reached. Apoptosis and proliferation rate reach a plateau between 4 and 8 weeks with some of the doses indicating a period in which some balance between adaptation and stress response exists.
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PMID:New insights into carcinogenesis of the classical model arylamine 2-acetylaminofluorene. 1050 8

We evaluated the effects of angiogenesis inhibitor, TNP-470, on hepatocellular carcinoma (HCCs) induced by a choline-deficient L-amino acid defined (CDAA) diet in rats. Male Fisher 344 rats were fed CDAA for 68 weeks. Rats were treated by subcutaneous injection of TNP-470 (15 mg/kg) or saline (control) three times per week from 53 to 68 weeks. At the end of the experiment, we determined the frequency and size of HCCs and glutathione S-transferase placental form (GSTP)-positive lesions, histology of liver cirrhosis, liver function, and liver weight per body weight. We also determined, using histologic and immunohistochemical semiquantification analyses, the degree of vascularity, apoptosis and proliferation in HCC and adjacent tissues. Treatment with TNP-470 resulted in a reduction of the size and frequency of HCC compared to untreated rats. However, TNP-470 did not influence the histology of liver cirrhosis and liver function. The liver weight per body weight of TNP-470-treated rats was slightly heavier in comparison with that of the controls. Treatment with TNP-470 significantly reduced tumor vascularity relative to the controls. There were no significant differences in the Ki-67 labeling index of HCCs between TNP-470 treated and control rats. The frequency of apoptotic hepatoma cells in TNP-470-treated rats was higher than in control rats. Our results indicate that TNP-470 suppresses the progression of CDAA-induced HCCs in rats through inhibition of angiogenesis, and suggest that TNP-470 might be useful clinically for HCCs.
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PMID:Angiogenesis inhibitor TNP-470 suppresses the progression of experimentally-induced hepatocellular carcinoma in rats. 1063 83

The genotoxic effects of 2-acetylaminofluorene (AAF) alone cannot explain the formation of rat liver tumors. It has been proposed that mitochondrial effects are associated with its tumor-promoting properties. These mitochondrial effects are thought to trigger apoptosis and regenerative proliferation, which alters the liver lobule in a cirrhosis-like manner. A situation is generated which favors the growth of initiated cells. To test this sequence of events, the dose dependence of early effects with time was studied. Male Wistar rats received 50, 100, 200, 400, or 800 ppm AAF in the diet and the following endpoints were analyzed at 2, 4, 8, and 16 weeks of feeding: apoptotic cell death, cell proliferation, GST-P-positive foci (placental form of glutathione S-transferase), and morphological alterations. Hydrolyzable hemoglobin adducts were used as a dosimeter for metabolic activation after 2 weeks of feeding. The hemoglobin adduct levels increased linearly with dose. With the conventional carcinogenic concentration of 200-ppm AAF in the diet, the number of apoptoses increased first, predominantly in the periportal area (2 weeks). Cell proliferation followed with some delay (4 weeks). This reflects regenerative tissue response and not the growth of initiated cells, because the number of enzyme-altered foci was still extremely low at that time. Foci developed only later when the morphology had changed. With 50 ppm AAF in the diet, a no-effect level had not been reached for any of the endpoints, but foci developed much more gradually than with higher doses. Unexpectedly, the proliferative response stabilized at 8 weeks with a labeling index of 12-17, with all AAF concentrations. The observed sequence of events supports the hypothesis. It is concluded that (1) The proliferation of initiated cells-defined as promotable cells-is largely determined by the cellular environment, such as morphologically altered liver. (2) The morphological alterations in rat liver result from imperfect regeneration from toxic effects. (3) Imperfect regeneration results from limitations in the possibilities to adapt to chemical stress. (4) If these limits are overwhelmed and morphology has changed to a certain extent, preneoplastic foci develop; this occurs much faster, at least, than without these changes.
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PMID:Dose response of early effects related to tumor promotion of 2-acetylaminofluorene. 1078 58

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

To clarify the sequential changes in pRB and p16 during different stages of hepatocarcinogenesis such as fibrosis, cirrhosis, hepatocellular adenoma (HCA), and hepatocellular carcinoma (HCC), male Fischer 344 rats were singly injected with diethylnitrosamine (DEN), immediately followed with phenobarbital for 1 wk and then thioacetamide (TAA) for 39 wk in drinking water. Rats were killed at 9, 20, 30, and 40 wk after DEN initiation and changes of pRB level, p16 gene hypermethylation, and in vivo gankyrin expression were examined. Histologic examination showed stepwise appearances of fibrosis, cirrhosis, HCA, and HCC at weeks 9, 20, 30, and 40, respectively. Hypermethylation of p16 exon 1 was not found until HCA but appeared in 50% of the rats with HCC accompanied by complete loss of its mRNA expression. The amount of glutathione S-transferase--gankyrin bound to pRB and pRB degradation in the liver depended on the concentration of gankyrin and incubation time. Gankyrin expression preceded pRB degradation in liver cirrhosis. In conclusion, gankyrin expression induced in liver fibrosis accelerated the degradation of pRB during liver cirrhosis, and inactivation of p16 exon 1 by DNA hypermethylation occurred during the progression of tumor cells to poorly differentiated HCC. Inactivation of pRB and/or p16 resulted in complete loss of regulation in the cell-division cycle during early and late stages, respectively, of hepatocarcinogenesis. Mol. Carcinog. 30:138--150, 2001.
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PMID:Sequential changes in hepatocarcinogenesis induced by diethylnitrosamine plus thioacetamide in Fischer 344 rats: induction of gankyrin expression in liver fibrosis, pRB degradation in cirrhosis, and methylation of p16(INK4A) exon 1 in hepatocellular carcinoma. 1130 74

We examined the cellular distribution of glutathione transferase A4 (GSTA4) in various human tissues by indirect immunoperoxidase using a specific polyclonal antibody raised in rabbit. This enzyme was localized in hepatocytes, bile duct cells, and vascular endothelial cells in liver, upper layers of keratinocytes and sebaceous and sweat glands in skin, proximal convoluted tubules in kidney, epithelial cells of mucosa and muscle cells in colon, muscle cells in heart, and neurons in brain. Staining was increased in pathological situations such as cirrhosis, UV-irradiated skin, and myocardial infarction and was strongly decreased in hepatocellular carcinoma. These results strongly support the view of a close correlation between cellular GSTA4 localization and the formation of reactive oxygen species in the tissues investigated.
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PMID:Immunohistological analysis of glutathione transferase A4 distribution in several human tissues using a specific polyclonal antibody. 1172 5

Dietary exposure to aflatoxins is one of the major risk factors for hepatocellular carcinoma. Individual susceptibility to aflatoxin-induced hepatocarcinogenesis may be modulated by both genetic and environmental factors affecting metabolism. A cross-sectional study was performed to evaluate determinants of the formation of aflatoxin covalently bound to albumin (AFB1-albumin adducts). A total of 474 subjects who were free of liver cancer and cirrhosis and were initially selected as controls for previous case-control studies of aflatoxin-induced hepatocarcinogenesis in Taiwan, were employed in this study. Aflatoxin-albumin adducts were determined by competitive enzyme-linked immunosorbent assay, hepatitis B surface antigen and antibodies to hepatitis C virus by enzyme immunoassay, as well as genotypes of glutathione S-transferase M1-1 and T1-1 by polymerase chain reaction. The detection rate of AFB1-albumin adducts was significantly higher in males (42.5%) than in females (21.6%) (multivariate-adjusted odds ratio=2.6, 95% confidence interval=1.4-5.0). The formation of detectable albumin adducts was moderately higher in hepatitis B surface antigen carriers (42.8%) than in non-carriers (36.6%) (multivariate-adjusted odds ratio=1.4, 95% confidence interval=1.0-2.1). In addition, the detection rate of AFB1-albumin adducts tended to increase with the increasing number of null genotypes of glutathione S-transferase M1-1 and glutathione S-transferase T1-1. In conclusion, this cross-sectional study has assessed the relative contributions of environmental exposure and host susceptibility factors in the formation of AFB1-albumin adducts in a well characterised Chinese adult population. This study further emphasises the necessity to reduce aflatoxin exposure in people living in an area endemic for chronic hepatitis B virus infection.
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PMID:Determinants of formation of aflatoxin-albumin adducts: a seven-township study in Taiwan. 1243 85

The effects exerted on hepatocytes by alcohol metabolites, drugs or other toxins and also hepatotropic viruses lead to chronic liver diseases. Reactive oxygen species (ROS) have been implicated in a number of pathologies, including different types of liver diseases. Organism has developed several mechanisms to counteract or prevent reactive oxygen species effects. These include enzymes such as: glutathione peroxidase (GSH-Px) with selenium (Se) in the active site and glutathione S-transferase (GST). Measurement of GST, compared with alanine aminotransferase (AIAT), has been advocated as a superior marker of hepatocellular damage. The aim of this study was to assess selenium concentration, glutathione peroxidase and glutathione S-transferase activities in plasma of patients with various types of liver diseases. The study population consisted of 54 patients and 25 healthy volunteers. The patients were divided into two groups according to etiology of the disease. Plasma selenium concentration was reduced in patients with cirrhosis, as compared to controls, irrespective of etiology and activity of AIAT. Plasma GSH-Px activity was significantly lower in both groups of patients with normal AIAT activity, whereas it was higher in both groups with activity of AIAT higher than 40 U/l. GST activity was higher only in post-viral group in patients with high AIAT activity. Impaired intestinal absorption and distribution of selenium among plasma proteins have been suggested as possible mechanism of reduced selenium concentration. Changes in the activities of glutatthione-dependent enzymes in plasma may arise from increased formation of reactive oxygen species or from release of these enzymes from injured hepatocytes to plasma.
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PMID:[Plasma selenium concentration, glutathione peroxidase and glutathione S-transferase activities in patients with chronic liver diseases]. 1255 39

Fumonisin B1 (FB1) is a naturally occurring mycotoxin produced by Fusarium verticillioides. Dietary exposure to FB1 has been linked to human cancer in certain parts of the world, and treatment with FB1 causes oval cell proliferation and liver tumors in rats. To study the potential role of oval (liver progenitor) cells in the cellular pathogenesis of FB1-induced liver tumors, we gave male F344 rats prolonged treatment with FB1 for 25 weeks, followed by return to control diet until 50 weeks ('stop study'). The time course of FB1-induced liver lesions was followed by examination of serial liver biopsies at set time intervals and post-mortem liver tissue at the end of the study. The effects of different FB1 treatment regimens (5 versus 25 weeks), as well as the modulating effect of 2-acetylaminofluorene (2-AAF), on the kinetics of oval cell proliferation and development of liver tumors were compared. Prolonged treatment with FB1 in normal diet caused persistent oval cell proliferation and generation of both hepatic adenomas and cholangiofibromas (CFs). These liver lesions occurred in the setting of chronic toxic hepatitis and liver fibrosis/cirrhosis, similar to that seen in human hepatocarcinogenesis. Some adenomas and CFs were dysplastic, and one post-mortem liver contained a hepatocellular carcinoma. OV-6+ oval cells were noted in close relation to proliferative neoplastic liver lesions, and some of these lesions expressed OV-6, suggesting that all these cell types were derived from a common progenitor cell. 2-AAF enhanced the size of FB1-induced glutathione S-transferase pi+ hepatocellular lesions and the incidence of CFs in post-mortem liver specimens, but this was not statistically significant. In conclusion, this study supports the involvement of dietary FB1 in liver carcinogenesis in male F344 rats. Oval cells may be the source of both the hepatocellular and cholangiocellular tumors induced by prolonged treatment with FB1. 2-AAF appears to have an enhancing effect on FB1-induced liver tumors, presumably due to its potent inhibitory effects on hepatocyte regeneration.
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PMID:Fumonisin B1-induced hepatocellular and cholangiocellular tumors in male Fischer 344 rats: potentiating effects of 2-acetylaminofluorene on oval cell proliferation and neoplastic development in a discontinued feeding study. 1498 22

Several phase I and phase II multi-drug metabolizing enzymes, such as CYP2D6, 3A4, and UGTA1, were reported to act as immunotargets in a subset of autoimmune hepatitis and hepatic autoimmunity. However, it is uncertain whether glutathione S-transferase (GST) A1-1, one of the phase II multi-drug metabolizing enzymes, is also an immunotarget in autoimmune hepatitis. So, in the present study, we investigated the frequency and significance of anti-GST A1-1 in sera from patients with autoimmune hepatitis. A total of 74 serum samples from patients with autoimmune hepatitis were examined in the present study. As controls, 20 serum samples from patients with primary biliary cirrhosis, 10 serum samples from patients with primary sclerosing cholangitis, 40 serum samples from patients with liver cirrhosis type B and C, 32 serum samples from patients with systemic lupus erythematosus, and 20 serum samples from normal controls were used. Anti-GST A1-1 antibody was determined by immunoblotting using the recombinant full-length GST A1-1 protein as the antigen. The immunofluorescent staining pattern of anti-GST A1-1 was investigated using rat liver and kidney sections. We compared clinicopathologic findings between anti-GST A1-1-positive and -negative autoimmune hepatitis patients. Anti-GST A1-1 was detected in 12 (16%) of 74 patients with autoimmune hepatitis, however, it was not detected in any control serum samples except for two patients with primary biliary cirrhosis. The immunofluorescence staining pattern of anti-GST A1-1 was found to be unique and different from those of anti-mitochondrial antibody or anti-liver-kidney microsome type 1 antibody. Anti-GST A1-1 coexisted with other autoantibodies such as anti-nuclear or anti-smooth muscle antibodies, but did not coexist with anti-soluble liver antigen/liver pancreas. Anti-GST A1-1-positive autoimmune hepatitis patients had severe clinical features and a poor prognosis compared with anti-GST A1-1-negative patients. These findings suggested that despite the low frequency, anti-GST A1-1 might be the marker of an early progression in autoimmune hepatitis.
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PMID:Frequency and significance of anti-glutathione S-transferase autoantibody (anti-GST A1-1) in autoimmune hepatitis. 1504 Oct 41


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