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)

We describe the first use of an emission probe, based on the cuprous thiolate chromophore, for direct microscopical observation of cuprous metallothioneins located in liver of 15-week-old (just before spontaneous hepatitis) Long-Evans Cinnamon rats. The rats show remarkable accumulations of copper and cuprous metallothioneins. In the mildly fixed liver, we visualized the same yellowish-orange luminescence as the specific emission from cuprous metallothioneins, following excitation in 330-385 nm region. In liver from Long-Evans Agouti rat, a counter part of Long-Evans Cinnamon rat, no similar luminescence was found. So, it was thought that cuprous metallothioneins accumulated in the Long-Evans Cinnamon rat liver might emit the yellowish-orange light. To verify this presumption, we tentatively defined three histochemical criteria, quenching tests by oxidation, protonation and mercury treatment, based on the coordination chemical characteristics of metallothioneins. The emission completely satisfied these criteria. Furthermore, the reliability of these criteria was supported by immunocytochemical and biochemical results. Consequently, all results sufficiently indicate that the yellowish-orange luminescence in the Long-Evans Cinnamon rat liver is the emission from cuprous metallothioneins.
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PMID:Visualization of yellowish-orange luminescence from cuprous metallothioneins in liver of Long-Evans Cinnamon rat. 860 26

A food-borne heterocyclic amine, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), induces hepatocellular carcinomas (HCCs) in F344 male rats at an incidence of 95%, when fed in the diet at 400 ppm for 61 weeks. In this study, the effect of a low dose of MeIQx was examined in Long-Evans with cinnamon-like coat color (LEC) rats, which have a mutation in Atp7b and suffer from hereditary hepatitis and HCCs, with high levels of copper accumulation in the liver. Rats of the LEC and Long-Evans with agouti coat color (LEA) sibling lines were given a diet containing 40 ppm MeIQx from the age of 23 weeks to 63 weeks, for a total administration period of 40 weeks. In LEC rats, HCCs were observed in 8/8 animals administered MeIQx, and 2/8 rats receiving a normal diet. The number of HCCs per rat (mean +/- SD) was 2.8 +/- 2.0 and 0.3 +/- 0.5, respectively. In the LEA rats, however, no tumors were induced by administration of MeIQx. These results indicate that damaged liver associated with compensatory cell proliferation is much more susceptible to chemical hepatocarcinogens, including MeIQx, than the normal liver.
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PMID:Hepatocellular carcinoma induction in LEC rats by a low dose of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline. 860 44

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

The Long-Evans Cinnamon (LEC) rat is a mutant strain established from Long-Evans rats that displays spontaneous hepatitis and liver cancer. We previously demonstrated that LEC rats died of acute ethanol intoxication after being fed a liquid diet containing 5% ethanol. Furthermore, we found that both alcohol dehydrogenase (ADH) and aldehyde dehydrogenase activities were remarkably suppressed in the liver of LEC rat, compared with Wistar rats. In the present study, we further investigated ethanol metabolism in the non-ADH pathway and what caused the decrease of liver ADH activity in LEC rats. Blood ethanol concentration 5 hr after intraperitoneal administration of ethanol in LEC rats was higher than in the Wistar rats, indicating that ethanol oxidation was impaired in LEC rats. The expression of liver cytochrome P-450IIE1 in the LEC rat was as much as that in Wistar rats. Regarding decreased ADH activity in the liver of LEC rats, we examined an alternating purine-pyrimidine (CA) repeat-length polymorphism in the first intron of a class I ADH gene that would play a role in altering ADH activity. A polymerase chain reaction method was used to amplify the CA repeat in the first intron of this class I ADH gene, a nine CA repeat insertion and a point mutation were detected in LEC rats. These results suggest that this alternating sequence would modify transcription of the class I ADH gene in LEC rats. Thus, LEC rats have abnormal ethanol metabolism in the ADH pathway.
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PMID:Analysis of CA repeats in first intron of class I ADH gene in Long-Evans Cinnamon rats developing fatal intoxication after ethanol intake. 865 85

Trientine dihydrochloride (trientine) is an alternative medicinal copper chelating agent for patients with Wilson's disease of penicillamine intolerance. We examined the effects of trientine on the spontaneous development of hepatitis and hepatic tumors, by its short-term and long-term administration to Long-Evans cinnamon (LEC) rats with an accumulation of copper in the liver, as animal models of Wilson's disease. Male rats were given trientine in their drinking water at 1500 ppm for 18 weeks, from 6 weeks to 24 weeks of age in short-term experiment, and 1500 ppm for 27 weeks then 750 ppm for 52 weeks, from 8 to 87 weeks of age in the long-term experiment. Development of hepatitis was observed in the control LEC rats at 18 weeks of age. They had high levels of plasma transaminases (glutamic oxaloacetic transaminase [GOT], glutamic pyruvic transaminase [GPT]), and on pathological examination, hepatocyte destruction was observed. Histological findings revealed that short-term administration of trientine inhibited the development of hepatitis remarkably. The plasma GOT and GPT levels of treated animals were only slightly higher than those of normal LEA (Long-Evans with agouti coat color) rats, a sibling line of LEC rats. Copper levels in the liver were decreased by a maximum of 50 percent. In the long-term administration of trientine, the incidence of hepatic cell carcinoma (HCC) in the treated rats was 67 percent that of the untreated LEC rats, and the number of HCCs per rat in the treated group was 0.7 +/- 0.5, being significantly lower as compared with 4.7 +/- 3.5 in the untreated rats. Additionally, the development of cholangiofibrosis in LEC rats was completely prevented by long-term administration of the agent. The copper level in the liver of treated rats was reduced by 33 percent at 87 weeks of age. Development of HCC in LEC rats might be partly, but not totally, because of copper accumulation. No effects on the levels of copper, iron, or zinc in the liver of LEA rats was detected, and no adverse effects were detected in either LEC or LEA rats after both short- and long-term administration of trientine in drinking water.
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PMID:Inhibition of hereditary hepatitis and liver tumor development in Long-Evans cinnamon rats by the copper-chelating agent trientine dihydrochloride. 866 30

Oval cell proliferation occurs during spontaneous hepatitis in Long-Evans cinnamon (LEC) rats. It has been reported that oval cells undergo differentiation into mature hepatocytes via small hepatocytes during carcinogenesis. This study was designed to demonstrate in vivo differentiation of oval cells into typical bile ductular cells in the liver lobule and the characteristic feature of intralobular bile ductule formation in LEC rats. We have examined kinetics, intralobular distribution, and morphology of oval cells, small hepatocytes, and bile ductular cells in LEC rat livers at prehepatitic, acute hepatitic, chronic hepatitic, and precancerous stages by conventional light and electron microscopy, immunostaining for cytokeratin, and 3-dimensional reconstruction analysis. Our results indicate that oval cells proliferated and extended into the periportal zone of the liver lobule during acute hepatitis at 20 to 23 weeks after birth. They exhibited tubular structures with a poorly defined lumen and incomplete basement membrane. After remission of the jaundice, small hepatocytes proliferated in association with oval cells and predominated in the periportal zone at 26 weeks. In a chronic hepatitic stage at 28 to 30 weeks, tubular structures were transformed into typical bile ductules, which had a well defined lumen and complete basement membrane, and small hepatocytes became a normal size. Intralobular bile ductules originated from the interlobular bile ducts, ran in the space of Disse, giving rise to several branches in the course, and were terminated at the hepatocytes. The present results indicate that oval cells that proliferate in the liver lobule of LEC rats after spontaneous hepatitis not only differentiate into small hepatocytes but also into typical bile ductular cells. This study suggests that intralobular bile ductules may play roles in maintaining the bile excretion during and after the disorganized proliferation of oval cells and small hepatocytes.
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PMID:Development of intralobular bile ductules after spontaneous hepatitis in Long-Evans mutant rats. 868 39

Several clinical studies have suggested that excess hepatic iron accumulation is a progressive factor in some liver diseases including chronic viral hepatitis and hemochromatosis. However, it is not known whether iron-induced hepatotoxicity may be directly involved in hepatitis, cirrhosis, and liver cancer. The Long-Evans Cinnamon (LEC) rat, which accumulates excess copper in the liver as in patients with Wilson's disease, is of a mutant strain displaying spontaneous hemolysis, hepatitis, and liver cancer. We found previously that LEC rats harbored an additional abnormality: accumulation of as much iron as copper in the liver. In the present study, we compared the occurrence of hepatitis and liver cancer in LEC rats fed an iron-deficient diet (ID) with those in rats fed a regular diet (RD). The RD group showed rapid increments of hepatic iron concentrations as the result of hemolysis, characteristics of fulminant hepatitis showing apoptosis, and a 53% mortality rate. However, no rats in the ID group died of fulminant hepatitis. Hepatic iron, especially "free" iron concentration and the extent of hepatic fibrosis in the ID group were far less than those of the RD group. At week 65, all rats in the RD group developed liver cancer, whereas none did in the ID group. These results suggest that the accumulation of iron, possibly by virtue of synergistic radical formation with copper, plays an essential role in the development of fulminant hepatitis, hepatic fibrosis, and subsequent hepatocarcinogenesis in LEC rats.
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PMID:Hepatic iron deprivation prevents spontaneous development of fulminant hepatitis and liver cancer in Long-Evans Cinnamon rats. 877 Aug 63

The Long-Evans Cinnamon (LEC) rat is characterized by the spontaneous onset of acute and chronic hepatitis, followed by occurrence of liver cancer, and is thus able to provide a unique experimental model for human genetical liver disease, Wilson's disease. Hepatocyte growth factor (HGF) is a potent hepatotrophic factor in liver regeneration, and its expression is up-regulated in response to liver injuries. We found that the plasma HGF level in LEC rats rose markedly during the fulminant hepatitis phase, fell during the phase of chronic/cholangiofibrosis, and fluctuated during the hepatoma phase. Immunohistological staining of the liver revealed that the number of HGF-positive cells increased remarkably during the fulminant hepatitis phase, and that many of these cells were localized at the portal triads. Fewer HGF-positive cells were observed during the phase of chronic hepatitis. The surface of the hepatocellular carcinoma (HCC) cells and the cytoplasm of the nonepithelial cells in cancerous liver tissues were HGF-positive. The HGF-messenger RNA (mRNA) level in the liver rose in the fulminant hepatitis phase, fell in the chronic hepatitis phase, and was intermediate or high during the hepatoma phase. The expression of c-met mRNA was strong in the tissues of LEC rats with fulminant hepatitis and, especially, in the cholangiofibrosis tissues. c-met mRNA was also detected in HCCs. These results suggest that the HGF-c-met system may play an important role in the regeneration of hepatocytes as well as in the development of HCC in paracrine or autocrine mechanisms.
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PMID:Hepatocyte growth factor and c-met expression in Long-Evans Cinnamon rats with spontaneous hepatitis and hepatoma. 878 31

The woodchuck (Marmota monax) has proven to be a suitable animal model for studying hepatitis B virus (HBV) infection owing to similarities in the course of infection between woodchuck hepatitis virus (WHV) in woodchucks and HBV in humans. (-)-beta-L-2',3'-Dideoxy-3'-thiacytidine (3TC; lamivudine) is a nucleoside analog which has demonstrated antiviral activity against HBV as well as human immunodeficiency virus (HIV). The purpose of the present investigation was to characterize the pharmacokinetics of 3TC following intravenous and oral administration of 20 mg of 3TC per kg of body weight to woodchucks. Following intravenous administration, the concentrations of 3TC in plasma declined, with a terminal half-life of 2.84 +/- 0.85 h (mean +/- standard deviation). The systemic clearance and steady-state volume of distribution of 3TC were 0.22 +/- 0.078 liters/h/kg and 0.75 +/- 0.13 liters/kg, respectively. The renal clearance of the nucleoside analog was 0.063 +/- 0.016 liters/h/kg. The oral bioavailability of 3TC ranged from 18 to 54%. Allometric relationships between pharmacokinetic parameters and body weight developed by Hussey et al. (E.K. Hussey, K.H. Donn, M.J. Daniel, S.T. Hall, A.J. Harker, and G.L. Evans, J. Clin. Pharmacol. 34:975-977, 1994) were augmented by including data from woodchucks, monkeys (S.M. Blaney, M.J. Daniel, A.J. Harker, K. Godwin, and F.M. Balis, Antimicrob. Agents Chemother. 39:2779-2782, 1995), and additional data from rats (P. Rajagopalan, L. Moore, C.K. Chu, R.F. Schinazi, and F.D. Boudinot, submitted for publication). Interspecies scaling of the pharmacokinetic parameters of 3TC demonstrated a good correlation between clearance (0.74 . W0.76 [where W is body weight]; r = 0.93; P < 0.025), apparent volume of distribution (1.62 . W0.81; r = 0.98; P < 0.005), and steady-state volume of distribution (1.09 . W0.94; r = 0.99; P < 0.05) and species body weight. The allometric relationships for clearance and volume of distribution at steady state predicted the observed pharmacokinetic parameters in humans quite well; however, the apparent volume of distribution was underestimated in humans. Thus, the pharmacokinetic data obtained with the woodchuck HBV animal model should be useful for designing clinical trials.
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PMID:Pharmacokinetics of (-)-2'-3'-dideoxy-3'-thiacytidine in woodchucks. 885 86


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