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)

This study reproduces in experimental animals the sequential development of all the liver lesions seen in the human alcoholic: in 15 baboons fed ethanol, all developed fatty liver, five progressed to hepatitis, and five had cirrhosis. Maintenance of a nutritionally adequate regimen despite the intake of inebriating amounts of ethanol (50% of total calories) was achieved by incorporation of the ethanol in a totally liquid diet. Upon ethanol withdrawal, signs of physical dependence, such as seizures and tremors, developed. Ultrastructural changes of the mitochondria and the endoplasmic reticulum were already present at the fatty liver stage and persisted throughout the hepatitis and cirrhosis. The lesions were similar to those observed in alcoholics (including the inflammation and the central sclerosis) and differed from the alterations produced by choline and protein defiencies. At the fatty liver stage, some "adaptive" increases in activity of microsomal enzymes [aniline hydroxylase (EC 1.14.14.1) and the microsomal ethanol oxidizing system] were observed, but these tended to disappear with the development of hepatitis and cirrhosis. Fat accumulation was also much more pronounced in the animals with the hepatitis as compared with those with simple fatty liver (an 18-fold compared with 3- to 4-fold increase in liver triglycerides). The demonstration that these lesions can develop despite an adequate diet indicates that in addition to correction of the nutritional status, control of alcohol intake is mandatory for the management of patients with alcoholic liver injury.
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PMID:Sequential production of fatty liver, hepatitis, and cirrhosis in sub-human primates fed ethanol with adequate diets. 105 27

A model has been developed for the administration to rats and baboons of ethanol as part of a nutritionally adequate liquid diet. With this regimen, ethanol intake was much higher than with conventional procedures. All animals gained or maintained their body weight, and liver morphology was normal in the controls. Isocaloric substitution of carbohydrate by ethanol (36% of total calories in rats and 50% in baboons) resulted in the production of fatty liver in all animals, while the baboons also developed alcoholic hepatitis and cirrhosis with increased activities of serum glutamic oxaloacetic transaminase. Inebriation and manifestation of dependence upon withdrawal of the diet were observed in baboons and quantitated in the rat. Chemical alterations produced by ethanol at the fatty liver stage were characterized by hyperlipemia, striking triglyceride accumulation in the liver and enhanced activities of microsomal drug metabolizing enzymes, including the microsomal ethanol oxidizing system (MEOS). Ultrastructural changes of the mitochondria and the endoplasmic reticulum were already present at the fatty liver stage and persisted throughout the hepatitis and cirrhosis. The lesions were similar to those observed in alcoholics (including the inflammation and the central sclerosis), and differed strikingly from the alterations produced by other models of liver injury. In showing that all aspects of liver injury observed in alcoholics can be reproduced in animals by the feeding of pure ethanol with an adequate diet, this study incriminates ethanol itself as a cause for the hepatic complications. This new experimental model is proposed as a tool for the study of the pathogenesis and treatment of alcoholic liver injury and dependence.
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PMID:Alcoholic liver injury: experimental models in rats and baboons. 123 25

Full clinical and laboratory details of 203 patients with postoperative jaundice were submitted to a panel of hepatologists. All patients whose jaundice may have had an identifiable cause were excluded, which left 76 patients with unexplained hepatitis following halothane anaesthesia (UHFH). Hepatitis in 95% of these cases followed multiple exposure to halothane, with repeated exposure within four weeks in 55% of cases. Twenty-nine patients were obese, 52 were aged 41-70, and 53 were women. Thirteen patients died in acute hepatic failure. Rapid onset of jaundice after anaesthesia, male sex, and obesity in either sex were poor prognostic signs. Of the clinical stigmata of hypersensitivity, only eosinophilia was impressive. The UHFH group had a much greater incidence of liver kidney microsomal (LKM) and thyroid antibodies and autoimmune complement fixation than those patients whose jaundice related to identifiable factors. Thirteen of the 19 patients with LKM antibodies also had thyroid antibodies. In six patients retested two to three years later LKM antibodies had disappeared, although thyroid antibodies persisted. Rapidly repeated exposure to halothane may cause hepatitis, but such a complication is probably rare. Possibly obese women with a tendency to organ-specific autoimmunity may be more at risk. Nevertheless, the comparative risks of rapidly repeated halothane or non-halothane anaesthesia cannot be determined from the present data. If alternative satisfactory agents are available halothane should be avoided in patients with unexplained hepatitis after previous exposure, although in three to five patients with UHFH who were re-exposed to halothane jaundice did not recur.
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PMID:Unexplained hepatitis following halothane. 126 12

Dimethyl diphenyl bicarboxylate (dimethyl-4,4'-dimethyloxy-5,6,5',6'-dimethylene-dioxy-di phe nyl-2,2'- bicarboxylate, DDB), a synthetic mimic of the natural product schizandrin C, is used in China as a hepatoprotective agent to improve the liver functions of patients with hepatitis or under cancer chemotherapy. In this study, we investigated the effects of DDB on liver microsomal drug-metabolizing enzymes. When male Sprague-Dawley rats were treated with a daily intragastric dose of DDB (200 mg.kg-1) for 3 d, the microsomal pentoxyresorufin dealkylase activity and P-450 2B1 protein levels were markedly increased. The fold increase was lower than that by phenobarbital (75 mg.kg-1, ip once daily x 3 d). The level of P-450 2B1 mRNA was elevated by DDB but the magnitude of the elevation was much less than that caused by phenobarbital. DDB also increased the rates of testosterone hydroxylation at positions 16 beta, 16 alpha, 6 beta, and 2 beta as well as the rate of ethoxyresorufin dealkylation, suggesting moderate increases in the levels of P-450 3A and P-450 1A1 in addition to the huge increase in P-450 2B1. The level of glutathione S-transferase was also slightly increased, but the levels of P-450 2E1 and NAD(P)H: quinone oxidoreductase were not changed. The results indicate that DDB is an inducer of P-450 2B1.
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PMID:Induction of liver microsomal cytochrome P-450 2B1 by dimethyl diphenyl bicarboxylate in rats. 130 34

Recently, we showed that a murine member of the carcinoembryonic antigen family of glycoproteins serves as a cellular receptor (MHVR) for the coronavirus mouse hepatitis virus A59 (MHV-A59) (G. S. Dveksler, M. N. Pensiero, C. B. Cardellichio, R. K. Williams, G.-S. Jiang, K. V. Holmes, and C. W. Dieffenbach, J. Virol. 65:6881-6891, 1991; R. K. Williams, G.-S. Jiang, and K. V. Holmes, Proc. Natl. Acad. Sci. USA 88:5533-5536, 1991). To examine the role of posttranscriptional modification of MHVR on virus-receptor interactions, a vaccinia virus-based expression system was employed. Expression from the vaccinia virus recombinant (Vac-MHVR) in BHK-21 cells resulted in high levels of MHVR glycoprotein on the cell surface and made these cells susceptible to MHV-A59 infection. Nonglycosylated core MHVR proteins were made in Vac-MHVR-infected BHK-21 cells in the presence of tunicamycin by in vitro translation of MHVR mRNA in a rabbit reticulocyte cell-free system in the absence of microsomal membranes and by expression of an N-terminal deletion clone of MHVR lacking its signal peptide. These three nonglycosylated MHVR proteins were recognized by polyclonal antibody against affinity-purified receptor but did not bind antireceptor monoclonal antibody (MAb) CC1 or MHV-A59 virions. Partial glycosylation of MHVR, either expressed in Vac-MHVR-infected cells treated with monensin or synthesized by in vitro translation with microsomal membranes, restored both the MAb CC1- and the virus-binding activities of the MHVR glycoprotein. Deletion of 26 amino acids at the carboxyl terminus of MHVR resulted in a secreted protein which was able to bind MAb CC1 and MHV-A59. These results suggest that either a carbohydrate moiety is an element of the MHVR-binding site(s) for virus and MAb CC1 or a posttranslational membrane-associated process is required for functional conformation of the receptor glycoprotein.
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PMID:Binding of the coronavirus mouse hepatitis virus A59 to its receptor expressed from a recombinant vaccinia virus depends on posttranslational processing of the receptor glycoprotein. 131 94

Anti-GOR is an autoantibody found in hepatitis C virus (HCV) infection. We have studied the specificity of this antibody for HCV infection in various groups of autoimmune liver diseases. Anti-HCV was detected by a second generation HCV enzyme-linked immunosorbent assay in 14 of 29 patients with liver-kidney-microsomal (LKM-1) -antibody-positive autoimmune hepatitis type 2 and in all 6 control patients with HCV-RNA-positive chronic hepatitis C. Anti-HCV was not found in those with antinuclear-antibody-positive autoimmune hepatitis type 1 (10 patients), with soluble-liver-protein-antibody-positive autoimmune hepatitis type 3 (8), with primary biliary cirrhosis (9), with systemic lupus erythematosus (SLE) (10), or in healthy controls (13). Anti-GOR was detected in 11 of 14 patients with autoimmune hepatitis type 2 who were all positive for anti-HCV but only in 1 of 15 LKM-1 patients who were negative for anti-HCV. We did not find anti-GOR in any other group of autoimmune liver disease, SLE, or control sera, but this antibody was detected in 3 of 6 patients with chronic hepatitis C. Autoimmune hepatitis type 2 patients who were anti-GOR positive and anti-HCV positive were less likely to be female, were older (p less than 0.001), and had lower LKM-1 antibody titres (p less than 0.001), lower disease activity, and responded less effectively to immuno- suppression than did those who were anti-HCV negative/anti-GOR negative. The findings show that anti-GOR reflects HCV-specific autoimmunity. HCV seems to induce autoimmunity to both GOR (an HCV-specific autoepitope) and LKM-1 (an epitope that is also recognised by autoimmune hepatitis sera of a different cause). Anti-GOR and LKM-1 antibodies contribute to a better differentiation of chronic hepatitis, a finding that has therapeutic implications.
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PMID:Anti-GOR and hepatitis C virus in autoimmune liver diseases. 137 81

Isaxonine phosphate or Nerfactor (2-isopropylaminopyrimidine) has been implicated in several cases of hepatitis which is reversible after withdrawal of the drug. In order to understand the cause of such hepatitis, the metabolic activation of isaxonine phosphate with different liver microsomes was investigated. The major metabolites were 5-hydroxyisopropylaminopyrimidine and 2-aminopyrimidine. Covalent binding to microsomal proteins was also detected. In vitro metabolic activation required intact microsomes, NADPH and O2 as cofactors and was cytochrome P-450 dependent. A sensitive fluorimetric assay of 5-hydroxyisaxonine was developed. The metabolism of isaxonine phosphate was compared in liver microsomes from rat, rabbit, dog, monkey and man and found to be qualitatively similar. Treatment of rats with phenobarbital increased the formation of 5-hydroxyisaxonine, while treatment with 3-methylcholanthrene increased the formation of 2-aminopyrimidine but decreased that of 5-hydroxyisaxonine. Inhibition and reconstitution experiments demonstrated that 5-hydroxylation of isaxonine was catalyzed by a cytochrome P-450. Metabolic oxidation of isaxonine phosphate using 5-[3H]isaxonine phosphate led to a total loss of tritium in 5-hydroxyisaxonine and partial loss of tritium in 2-aminopyrimidine and covalent binding to proteins.
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PMID:In vitro metabolism of isaxonine phosphate: formation of two metabolites, 5-hydroxyisaxonine and 2-aminopyrimidine, and covalent binding to microsomal proteins. 139 69

An autoantibody to liver cytosol was previously described in childhood autoimmune chronic active hepatitis type 2. The antigen, liver cytosol antigen type 1, was for the first time partially purified using gel filtration and ion exchange chromatography, and it was characterized using immunodiffusion, immunoblot and sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of the immunoprecipitate. Immunoblot detected a unique antigenic peptide at 62 kD from human cytosol and at 58 kD from rat cytosol. The same peptides were also detected when immunoprecipitates of liver cytosol antigen type 1 and autoantibodies to liver cytosol antigen were submitted to sodium dodecyl sulfate-polyacrylamide gel electrophoresis. A polymeric structure, probably a tetramer, is suggested for native liver cytosol antigen type 1 because in gel filtration chromatography liver cytosol antigen type 1 was eluted as a protein of a molecular weight between 240 and 290 kD when human liver cytosol was fractionated and between 220 and 270 kD from rat liver cytosol. Liver cytosol antigen type 1 is probably poor in carbohydrates because it was not stained by periodic acid-Schiff stain. The autoantibodies to liver cytosol were frequently found in association with antiliver kidney microsomal autoantibodies type 1, which are directed against the cytochrome P-450 of the IID6 subfamily. Antiliver kidney microsomal autoantibodies type 1 but not antiliver cytosol autoantibodies were found in association with antibodies to hepatitis C virus. Autoantibodies to liver cytosol antigen type 1 seem to be a more specific marker for autoimmune hepatitis type 2 than antiliver kidney microsomal antibodies type 1 autoantibodies.
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PMID:Characterization of the liver cytosol antigen type 1 reacting with autoantibodies in chronic active hepatitis. 139 95

The M protein of mouse hepatitis virus strain A59 is a triple-spanning membrane protein which assembles with an uncleaved internal signal sequence, adopting an NexoCcyt orientation. To study the insertion mechanism of this protein, domains potentially involved in topogenesis were deleted and the effects analyzed in topogenesis were deleted and the effects analyzed in several ways. Mutant proteins were synthesized in a cell-free translation system in the presence of microsomal membranes, and their integration and topology were determined by alkaline extraction and by protease-protection experiments. By expression in COS-1 and Madin-Darby canine kidney-II cells, the topology of the mutant proteins was also analyzed in vivo. Glycosylation was used as a biochemical marker to assess the disposition of the NH2 terminus. An indirect immunofluorescence assay on semi-intact Madin-Darby canine kidney-II cells using domain-specific antibodies served to identify the cytoplasmically exposed domains. The results show that each membrane-spanning domain acts independently as an insertion and anchor signal and adopts an intrinsic preferred orientation in the lipid bilayer which corresponds to the disposition of the transmembrane domain in the wild-type assembled protein. These observations provide further insight into the mechanism of membrane integration of multispanning proteins. A model for the insertion of the coronavirus M protein is proposed.
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PMID:Membrane assembly of the triple-spanning coronavirus M protein. Individual transmembrane domains show preferred orientation. 140 May 1

Considerable clinical and experimental evidence points to the importance of immune responses in the development of alcoholic liver disease. In the present study it was investigated whether circulating antibodies from patients with alcoholic liver disease recognize acetaldehyde-liver protein adducts. Cytosolic and microsomal fractions from livers of Wistar rats or from normal human liver were incubated with acetaldehyde (0.5-2.5 mmol/L) and/or cyanoborohydride (100 mmol/L) then analysed by immunoblotting. Cytosolic fractions that had been incubated with acetaldehyde and cyanoborohydride expressed a 200-kilodalton protein antigen not present in untreated fractions or fractions incubated with acetaldehyde or cyanoborohydride alone. The 200-kilodalton antigen was recognized by immunoglobulin (Ig)A antibodies in a large proportion of sera from patients with alcoholic hepatitis (70%, n = 23), but in significantly smaller proportions of sera from patients with alcoholic cirrhosis without hepatitis (30%, n = 10; P < 0.05), heavy drinkers without overt liver disease (20%, n = 10; P < 0.02), patients with nonalcoholic liver disease (35%, n = 17; P < 0.05), or normal control subjects consuming moderate quantities of alcohol (25%, n = 20%; P < 0.005). These results indicate that IgA antibodies to a 200-kilodalton acetaldehyde-protein adduct are present in a large proportion of patients with alcoholic liver disease and in a significantly smaller proportion of other individuals.
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PMID:Immunoglobulin A antibody to a 200-kilodalton cytosolic acetaldehyde adduct in alcoholic hepatitis. 145 88


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