Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To study effects of dietary Cu and Fe levels on the onset of hepatitis in Long-Evans Cinnamon (LEC) rats, female rats (40 days old) were fed a semipurified diet containing 0.1 or 10 mg Cu/kg and 1.5 or 150 mg Fe/kg in a 2 x 2 factorial arrangement for 35 days. At 75 days after birth, LEC rats (+Cu-Fe) fed a Cu-sufficient but Fe-deficient diet (Cu, 10 mg/kg; Fe, 1.5 mg/kg) showed jaundice, with lethargy, anorexia, and malaise. The biochemical variables relating to liver function were significantly increased compared to three other groups, a Cu- and Fe-deficient (-Cu-Fe) group, a Cu-deficient but Fe-sufficient (-Cu+Fe) group, and a Cu and Fe sufficient (+Cu+Fe) group. Furthermore, the +Cu-Fe rat liver showed massive necrosis with huge nuclei. The other three groups presented no biochemical and histological findings of hepatitis. Hepatic Cu and metallothionein concentrations were 289 +/- 87 (mean +/- SD) microg/g liver and 8.7 +/- 1.8 mg/g liver, respectively, in the +Cu-Fe rats. However, in the +Cu+Fe group the values were 196 +/- 28 microg Cu/g liver and 10.8 +/- 1.0 mg/g liver. Hepatic Fe deposition was not influenced significantly by the dietary Cu level. The +Cu-Fe group with jaundice showed the highest free Cu concentration in the liver among the four groups, but the hepatic free Fe concentration was similar to those in the -Cu+Fe and +Cu+Fe groups. Our results indicate that an Fe-deficient diet enhances the deposition of hepatic Cu due to increased absorption of Cu from the gastrointestinal tract. This deposition stimulated the onset of hepatitis.
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PMID:An iron-deficient diet stimulates the onset of the hepatitis due to hepatic copper deposition in the Long-Evans Cinnamon (LEC) rat. 1055 Apr 76

Serum metal levels and their ratios are frequently reported to be good signals for diagnosing various diseases. These parameters are not always specific to the disease, however, it is necessary to use other serum parameters for an exact diagnosis. We examined whether the monitoring of these serum parameters such as metallothionein, copper, and zinc levels are useful in diagnosing hepatic disorders. Metallothionein levels of patients with liver cirrhosis and hepatocellular carcinoma were found to be significantly lower than those of patients with chronic hepatitis and those of controls. In contrast, copper levels of the patients with liver cirrhosis and hepatocellular carcinoma were significantly higher than those with chronic hepatitis and controls. Zinc levels of the patients with chronic hepatitis and hepatocellular carcinoma were lower than those of controls. Using these three parameters, we are introducing a new parameter, (Cu/Zn)/MT, by which we can discriminate between patients in the [control+miscellaneous diseases+chronic hepatitis] group and those in the [liver cirrhosis+hepatocellular carcinomal group. The new parameter does not, however, allow us to clearly distinguish between the liver cirrhosis and hepatocellular carcinoma groups. Multivariate discriminant analysis was found to be very useful, with combinations of two discriminant functions having been designed to discriminate both between chronic hepatitis and liver cirrhosis and between liver cirrhosis and hepatocellular carcinoma. This method recognizes the differences between hepatic disorder, including chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma groups. On the basis of these results, we propose here that the diagnosis of hepatic disorders should be made based on a combination of three serum levels such as those of metallothionein, copper, and zinc.
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PMID:A new diagnostic method for chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma based on serum metallothionein, copper, and zinc levels. 1199 18

In an animal model of Wilson disease, Long-Evans rats with cinnamon-colored coat (LEC rats), copper (Cu) accumulates in the liver with age up to the onset of acute hepatitis owing to a hereditary defective transporter for the efflux of Cu, ATP7B. The plasma Cu concentration is low in LEC rats because of the excretion of apo-ceruloplasmin (apo-Cp). However, toward and after the onset of chronic hepatitis, plasma Cu concentration increases in the form of holo-Cp, while the liver Cu concentration is maintained at a constant level without the occurrence of fulminant hepatitis. In the present study, the material balance of Cu was studied in LEC rats with chronic hepatitis in order to elucidate the mechanisms underlying the increase of holo-Cp in plasma and the maintenance of Cu at a constant level in the liver. The relationship between the Cu concentration and ferroxidase activity of Cp was analyzed in the plasma of LEC rats of different ages and of Wistar rats fed a Cu-deficient diet for different durations. Cu was suggested to be delivered to Cp in an all-or-nothing manner, resulting in the excretion of fully Cu-occupied holo-Cp (Cu(6)-Cp) or totally Cu-unoccupied Cu(0)-Cp (apo-Cp), but not partially Cu-occupied Cu(n)-Cp (where n = 1-5). The increase of holo-Cp in acute and chronic hepatitis in LEC rats was explained by the delivery of Cu, accumulating in the non-metallothionein-bound form, to Cp outside the Golgi apparatus of the liver. The plasma Cu concentration and ferroxidase activity were proposed to be specific indicators of the appearance of non-metallothionein-bound Cu in the liver of LEC rats.
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PMID:Copper balance and ceruloplasmin in chronic hepatitis in a Wilson disease animal model, LEC rats. 1224 7

Cadmium is known to be a potent carcinogenic and mutagenic metal. However, we demonstrated that dietary supplementation with 50 ppm cadmium inhibits spontaneous carcinogenesis in C3H/HeN and spontaneous hepatitis in A/J mice. We found that the frequencies of spontaneous hepatocarcinogenesis in C3H/HeN mice and of spontaneous hepatitis in A/J mice fed low-dose cadmium for 54 weeks were significantly lower than those in the respective control groups. A cadmium-induced increase in metallothionein production itself and/or metallothionein-associated increases in hepatic zinc concentrations may be involved in the observed preventive effects of cadmium. Our results suggest that low doses of cadmium in the diet or environment may play a beneficial role in the prevention of hepatic disease in humans and animals.
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PMID:Dietary cadmium inhibits spontaneous hepatocarcinogenesis in C3H/HeN mice and hepatitis in A/J mice, but not in C57BL/6 mice. 1258 87

BACKGROUND: The role of copper accumulation in the onset of hepatitis is still unclear. Therefore, we investigated a spontaneous disease model of primary copper-toxicosis in Doberman pinschers so to gain insights into the pathophysiology of copper toxicosis, namely on genes involved in copper metabolism and reactive oxygen species (ROS) defences. RESULTS: We used quantitative real-time PCR to determine differentially expressed genes within a target panel, investigating different groups ranging from copper-associated subclinical hepatitis (CASH) to a clinical chronic hepatitis with high hepatic copper concentrations (Doberman hepatitis, DH). Furthermore, a non-copper associated subclinical hepatitis group (N-CASH) with normal hepatic copper concentrations was added as a control. Most mRNA levels of proteins involved in copper binding, transport, and excretion were around control values in the N-CASH and CASH group. In contrast, many of these (including ATP7A, ATP7B, ceruloplasmin, and metallothionein) were significantly reduced in the DH group. Measurements on defences against oxidative stress showed a decrease in gene-expression of superoxide dismutase 1 and catalase in both groups with high copper. Moreover, the anti-oxidative glutathione molecule was clearly reduced in the DH group. CONCLUSION: In the DH group the expression of gene products involved in copper efflux was significantly reduced, which might explain the high hepatic copper levels in this disease. ROS defences were most likely impaired in the CASH and DH group. Overall, this study describes a new variant of primary copper toxicosis and could provide a molecular basis for equating future treatments in dog and in man.
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PMID:Differential expression of copper-associated and oxidative stress related proteins in a new variant of copper toxicosis in Doberman pinschers. 1579 Apr 12

Hepatocyte apoptosis has been documented in both clinical and experimental alcoholic liver disease. This study was undertaken to examine the effect of dietary zinc supplementation on hepatic apoptosis in mice subjected to a long-term ethanol exposure. Male adult 129S6 mice fed an ethanol-containing liquid diet for 6 months developed hepatitis, as indicated by neutrophil infiltration and elevation of hepatic keratinocyte chemoattractant (KC) and monocyte chemoattractant protein-1 (MCP-1) levels. Apoptotic cell death was detected in ethanol-exposed mice by a terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and was confirmed by the increased activities of caspase-3 and -8. Zinc supplementation attenuated alcoholic hepatitis and reduced the number of TUNEL-positive cells in association with inhibition of caspase activities. Ethanol exposure caused oxidative stress, as indicated by reactive oxygen species accumulation, mitochondrial glutathione depletion, and decreased metallothionein levels in the liver, which were suppressed by zinc supplementation. The mRNA levels of tumor necrosis factor (TNF)-alpha, TNF-R1, FasL, Fas, Fas-associated factor-1, and caspase-3 in the liver were upregulated by ethanol exposure, which were attenuated by zinc supplementation. Zinc supplementation also prevented ethanol-elevated serum and hepatic TNF-alpha levels and TNF-R1 and Fas proteins in the liver. In conclusion, zinc supplementation prevented hepatocyte apoptosis in mice subjected to long-term ethanol exposure, and the action of zinc is likely through suppression of oxidative stress and death receptor-mediated pathways.
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PMID:Zinc supplementation inhibits hepatic apoptosis in mice subjected to a long-term ethanol exposure. 1837 24

Copper is an essential redox-active metal ion which in excess becomes toxic due to the formation of reactive oxygen species. In Wilson disease the elevated copper level in liver leads to chronic oxidative stress and subsequent hepatitis. This study was designed to evaluate the copper chelating efficiency of the bacterial methanobactin (MB) in a rat model for Wilson disease. Methanobactin is a small peptide produced by the methanotrophic bacterium Methylosinus trichosporium OB3b and has an extremely high affinity for copper. Methanobactin treatment of the rats was started at high liver copper and serum aspartate aminotransferase (AST) levels. Two dosing schedules with either 6 or 13 intraperitoneal doses of 200mg methanobactin per kg body weight were applied. Methanobactin treatment led to a return of serum AST values to basal levels and a normalization of liver histopathology. Concomitantly, copper levels declined to 45% and 24% of untreated animals after 6 and 13 doses, respectively. Intravenous application of methanobactin led to a prompt release of copper from liver into bile and the copper was shown to be associated with methanobactin. In vitro experiments with liver cytosol high in copper metallothionein demonstrated that methanobactin removes copper from metallothionein confirming the potent copper chelating activity of methanobactin.
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PMID:The biogenic methanobactin is an effective chelator for copper in a rat model for Wilson disease. 2124 75

Hepatic metallothionein (MT) expression, with various isoforms, and varying cellular localizations is a useful marker for clinico-pathogenesis of liver diseases. In acute liver toxicity caused by cadmium, carbon tetrachloride, or acetaminophen, MT plays a protective role, via the scavenging of radical species. In chronic hepatitis C patients, hepatic MT levels appear to be a biological factor associated with the severity of HCV infection, and are associated with a better response to IFN therapy. Transgenic mice that express HBsAg in the liver show hepatocellular damage, inflammation, regeneration, hyperplasia, and, eventually, neoplasia. The MT isoform, MT-1 help mitigate HBV-induced hepatitis. Analysis of MT gene expression in the livers of chronic hepatitis B patients is useful for understanding the features of distinct liver diseases and for judging disease progression. A profound down-regulation of isoform MT-1G in hepatocellular carcinoma was observed in 63% of tumors relative to the adjacent nonmalignant liver. MT has been implicated in the control of p53 folding with zinc exchange. Therefore, it appears MT may play a role in the pathogenesis of hepatocellular carcinoma. Overall MT is linked to a variety of liver diseases.
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PMID:Significance of metallothionein expression in liver disease. 2359 Jan 40


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