Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The LEC (Long-Evans with a cinnamon-like color) rat is a mutant of the Long-Evans strain which develops hereditary hepatitis and hepatoma with age. Activities and mRNA levels of N-acetylglucosaminyltransferase III and V (GnT-III and GnT-V, respectively) were determined during hepatocarcinogenesis in this rat using a LEA (Long-Evans with an agouti color) rat as a control. GnT-III activity in LEC rat liver increased after 30 weeks of age, at the stage of chronic hepatitis, to about 2.5-11.5 times the level in LEC rats aged 1-9 weeks. GnT-V activity in the LEC rat liver increased after 20 weeks of age, at the stage of acute hepatitis, to about 1.5-2.5 times the level in LEC rats of 1-9 weeks of age and then remained elevated. Both enzymes showed more dramatic increases in males than in females. The mRNA levels of the enzymes increased in proportion with the enzyme activities. Furthermore, GnT-III and GnT-V mRNAs were highly expressed in both cancer lesion and adjacent tissues. In one case of hepatoma with lymph node metastasis, GnT-III and GnT-V mRNA expression was much higher in the metastatic lesion than in the original cancer. GnT-III and GnT-V levels in the original cancer lesions were similar to those in the cancer lesions of the other LEC rats. These results indicated that expression of GnT-III and GnT-V was induced by chronic liver damage and hepatocarcinogenic changes in the LEC rats.
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PMID:N-acetylglucosaminyltransferase III and V messenger RNA levels in LEC rats during hepatocarcinogenesis. 824 May 32

Long-Evans Cinnamon (LEC) rats, a mutant strain originating from Long-Evans rats, spontaneously develop hereditary hepatitis followed by hepatocellular carcinoma. The hepatic disorder in LEC rats is associated with their abnormal copper metabolism; metal-catalyzed reactions often give rise to oxygen radicals, which may be related to the carcinogenesis. By means of high-pressure liquid chromatography with electrochemical detection, cellular DNA damage caused by oxygen radicals can be assessed in terms of the amount of 8-hydroxydeoxyguanosine (oh8dG). We assayed the amount of oh8dG in DNA of liver, kidneys, and brain of LEC and Long-Evans Agouti (LEA) control rats in seven groups (n = 3 to 6) aged from 5 weeks to 24 months. Control rats, a healthy sibling line, were age-matched. The amount of oh8dG was correlated with the severity of the age-related clinical symptoms in LEC rats. The amount was higher in LEC rats than in the controls, especially in the liver at the acute stage of hepatitis. These findings suggest that oxygen radicals may be important in the carcinogenesis that occurs in LEC rats.
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PMID:Elevated level of 8-hydroxydeoxyguanosine in DNA of liver, kidneys, and brain of Long-Evans Cinnamon rats. 832 Jan 67

The LEC (Long-Evans cinnamon) rat is a mutant strain displaying hereditary hepatitis and spontaneous hepatocellular carcinoma, and shows abnormal hepatic copper accumulation similar to that occurring in Wilson's disease. We evaluated the iron metabolism of LEC rats compared to LEA (Long-Evans agouti) rats. Hepatic iron and ferritin concentrations were remarkably increased depending on age in LEC rats but not in LEA rats. Increased hepatic iron is normally associated with decreased serum transferrin and total iron binding capacity in hepatic iron overload. In LEC rats, however, both serum transferrin and total iron binding capacity increased with increasing hepatic iron. This increase of serum transferrin and hepatic iron may be an additional important factor contributing to liver injury in LEC rats.
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PMID:Abnormal hepatic iron accumulation in LEC rats. 838 76

Acute hepatitis spontaneously develops in the Long-Evans Cinnamon rat at the age of 4 mo, and eventually hepatocellular carcinoma develops after the chronic hepatitis that persists for over a year. Previously, abnormal copper accumulation was found in the livers of Long-Evans Cinnamon rats from birth, and it was reported that short-term administration of D-penicillamine, a copper-chelating agent, prevented acute hepatitis in Long-Evans Cinnamon rats. In this study we investigated whether long-term administration of D-penicillamine could also prevent chronic hepatitis and subsequent hepatocellular carcinoma in Long-Evans Cinnamon rats. During long-term observation, which was continued from 11 to 70 wk after birth, no elevation of serum transaminase levels was observed in the Long-Evans Cinnamon rats treated with D-penicillamine. Moreover, no histological changes characteristic of the chronic hepatitis were observed in D-penicillamine-treated Long-Evans Cinnamon rats, which were killed at 70 wk of age. Furthermore, placental glutathione S-transferase-positive foci, described as a marker for preneoplastic lesions in the liver, were not detected, and thus hepatocarcinogenesis was completely prevented in D-penicillamine-treated Long-Evans Cinnamon rats. We also found that the amount of 8-hydroxy-deoxyguanosine, one of oxidative DNA damage products in the liver, was decreased in the Long-Evans Cinnamon rats treated with D-penicillamine. These findings suggest that a process of the prolonged liver-cell injury and regeneration was essential for spontaneous development of hepatocellular carcinoma in Long-Evans Cinnamon rats with abnormal copper metabolism.
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PMID:Prevention of spontaneous hepatocellular carcinoma in Long-Evans cinnamon rats with hereditary hepatitis by the administration of D-penicillamine. 839 59

We carried out the following three experiments to clarify the mechanism of hepatocarcinogenesis in Long-Evans Cinnamon (LEC) rats. (1) Sensitivity to diethylnitrosamine (DEN): LEC rats (8 and 25 weeks old) without and with hepatitis and age-matched F344 rats were administered an intraperitoneal injection of a low dose of DEN. Eight weeks after the injection, the numbers of glutathione-S-transferase placental-form (GST-P)-positive foci in the 33-week-old LEC rat liver were significantly higher than those in the livers of the other three groups of rats. (2) Potential for unscheduled DNA synthesis (UDS): Isolated hepatocytes of 25-week-old LEC rats with chronic hepatitis showed about one-third the level of UDS induced by UV irradiation, as compared to that of age-matched F344 rats, while no significant difference was found between the UDS of isolated hepatocytes of 8-week-old LEC rats and age-matched F344 rats. (3) Potential for proliferation: Isolated hepatocytes from 8-week-old LEC rats responded well to epidermal growth factor (EGF) in culture, to almost the same degree as F344 rat hepatocytes, while a remarkable decrease in the responsiveness of hepatocytes isolated from 25-week-old LEC rats to EGF was found. These results suggested that LEC rat hepatocellular carcinoma could be naturally initiated after the onset of hepatitis by carcinogens contaminating food and the environment, probably due to the reduction of DNA repair activity, after which initiated hepatocytes selectively proliferate in response to growth stimuli endogenously produced as a result of continuous loss of hepatocytes (chronic hepatitis), because of a decrease in growth activity of non-initiated hepatocytes.
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PMID:High sensitivity of LEC rats with chronic hepatitis to hepatocarcinogenesis: decreases in unscheduled and replicative DNA synthesis of the hepatocytes. 840 64

Long-Evans Cinnamon (LEC) rats are autosomal recessive mutants that develop hepatitis and hepatocellular carcinoma. Because copper accumulates in the livers of these rats, and some of their clinical and pathological features are similar to those of patients with Wilson's disease, LEC rats are proposed as an animal model of Wilson's disease. It has been thought that unbound copper generates free radicals, which act as hemolytic and hepatocytotoxic agents. To examine the effects of vitamin E as an antioxidant on hereditary hepatitis in LEC rats, we fed 3-week-old rats for 25 weeks either vitamin E-deficient, control, or vitamin E-supplemented diets which contained < 0.01 mg of total tocopherols, 2 mg of d,l-alpha-tocopheryl acetate (2 I.U.), and 58.5 mg of d,l-alpha-tocopheryl nicotinate (50 I.U.), respectively, per 100 mg of feed. In males, body weight loss was first observed in the vitamin E-deficient group, and mean ages at which jaundice occurred were in the order: deficient younger than control younger than supplemented groups. The ages when plasma glutamic oxaloacetic transaminase and glutamic pyruvic transaminase activities began to increase sharply and peaked followed the same order. Thus, it is likely that free radicals are involved in jaundice and hepatitis in LEC male rats, and they are a model for studying the relationship of copper, free radicals, and hepatitis. Conversely, in females, no apparent differences in clinical and biochemical changes were observed among the three groups. Causes for the discrepancy between the sexes remain to be clarified.
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PMID:Effects of dietary vitamin E on clinical course and plasma glutamic oxaloacetic transaminase and glutamic pyruvic transaminase activities in hereditary hepatitis of LEC rats. 845 79

The Long-Evans with a cinnamon-like color (LEC) rat is a mutant of the Long-Evans strain that develops hereditary hepatitis and hepatoma with ageing. Age-related changes in the mRNA expression of DNA methyltransferase (DNA MTase) were examined in livers of LEC rats using Long Evans with an agouti color (LEA) rats as controls. A dramatic increase in the expression of this mRNA was observed in LEC rats at 20 weeks when acute hepatitis appeared. Their high mRNA levels were maintained until 52 weeks of age. The mRNA expression as well as DNA MTase activities were found to be higher in cancer lesions than in adjacent normal tissue. These increases may be related to liver regeneration and to early events in cellular transformation of LEC rats.
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PMID:Expression of DNA methyltransferase in LEC rats during hepatocarcinogenesis. 847 22

We report changes in free radical-metabolizing enzymes and the increased generation of lipid peroxides associated with extreme metal accumulation in the liver of the Long-Evans with cinnamon-like coat color (LEC) rat, a new mutant strain displaying hereditary hepatitis and subsequent hepatocellular carcinoma. The activity of free radical-metabolizing enzymes and lipid peroxides, and the concentration of metal in the liver were determined sequentially after birth. Mn-superoxide dismutase activity significantly increased immediately after the onset of hepatitis in LEC rats, whereas no remarkable change was observed in control rats. Cu, Zn-superoxide dismutase activity in LEC rats was similar to that in control rats. Glutathione reductase activity increased, while glutathione peroxidase activity was lower in LEC rats than in control rats throughout the observation periods. Lipid peroxides, estimated by thiobarbituric acid reaction, also increased 4- to 5-fold immediately after the onset of hepatitis in LEC rats. Copper concentration was 30- to 50-fold higher in the liver of LEC rats than in control rats, and the iron content also increased significantly before and after the onset of hepatitis. These findings suggested that an oxidant injury generated by toxic metals could be one of the factors responsible for hepatocellular damage in this unique hereditary hepatitis.
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PMID:Changes in free radical-metabolizing enzymes and lipid peroxides in the liver of Long-Evans with cinnamon-like coat color rats. 857 34

Formation of etheno-DNA adducts in the liver was investigated in Long Evans cinnamon (LEC) rats, a Long Evans strain with hereditary abnormal copper metabolism, which develop spontaneous hepatitis and later hepatocellular carcinoma. Using an ultrasensitive immunoaffinity/32P-postlabeling assay (J. Nair et al., Carcinogenesis, 16: 613-617, 1995), the etheno adducts 1,N6-ethenodeoxyadenosine (epsilon dA) and 3,N4-ethenodeoxycytidine (epsilon dC) were measured in the liver of 7-, 18-, 30-, and 87-week-old LEC rats. Levels were highest in the liver of 18-week old rats 85 +/- 17 (epsilon dA) and 85 +/- 30 (epsilon dC) adducts per 10(9) parent nucleotides, and the increase in the levels of etheno adducts was age dependent. Age-matched Long Evans agouti rats, a tumor-free sibling line of LEC rats, had much lower levels of both etheno adducts. Etheno adduct levels in LEC rats were well correlated with the hepatic copper levels, and peak adduct levels coincided with the age of commencement of fulminant hepatitis. Our results demonstrate for the first time a copper- and age-dependent formation of highly miscoding etheno-DNA adducts in the liver of LEC rats. These adducts are formed from lipid peroxidation products (F. El-Ghissassi et al., Chem. Res. Toxicol., 8: 273-283, 1995) and thus could arise in the liver of LEC rats from oxygen radicals generated by copper-catalyzed Fenton-type reactions. Etheno-DNA adducts along with other oxidative DNA base damages may thus be involved in liver carcinogenesis in LEC rats.
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PMID:Copper-dependent formation of miscoding etheno-DNA adducts in the liver of Long Evans cinnamon (LEC) rats developing hereditary hepatitis and hepatocellular carcinoma. 864 Aug 12

We examined age-related changes in the protein and the mRNA expression of aldose reductase in livers of Long-Evans with a cinnamon-like color (LEC) rats, which develop hereditary hepatitis and hepatoma with aging, using Long-Evans with an agouti color rats as controls. The levels of the protein and mRNA of aldose reductase increased after 20 weeks, at the stage of acute hepatitis, and were maintained at 60 weeks of age, while those of aldehyde reductase seemed to be constant at all ages. The expression of aldose reductase was marked in cancerous lesions in hepatoma-bearing LEC rat liver compared to uninvolved surrounding tissues. These results indicated that elevation of aldose reductase accompanied hepatocarcinogenesis and may be related to the acquisition of immortality of the cancer cells through detoxifying cytotoxic aldehyde compounds.
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PMID:Induction of aldose reductase gene expression in LEC rats during the development of the hereditary hepatitis and hepatoma. 864 63


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