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)

Autoantibodies are important diagnostic markers for autoimmune type chronic active hepatitis (AI-CAH) and primary biliary cirrhosis (PBC). At least three subgroups of AI-CAH can be distinguished serologically. Antinuclear antibodies (ANA), smooth muscle antibodies (SMA), and liver membrane autoantibodies (LMA) characterize classical autoimmune type 'lupoid' hepatitis, while liver kidney microsomal (LKM) antibodies identify a second, and antibodies to a soluble liver antigen (anti-SLA), a third subgroup of AI-CAH. Patients with autoimmune type CAH in contrast to patients with virus-induced liver diseases profit from immunosuppressive therapy. PBC is characterized by disease-specific subtypes of antimitochondrial antibodies (AMA). Technical developments, like immunoblotting and molecular cloning, led to a better definition and characterization of autoantibody-antigen systems. Molecular cloning has been successfully applied to identify the main 70 kDa mitochondrial antigen in PBC. This and other mitochondrial autoantigens have been identified as enzymes: E2 component of pyruvate dehydrogenase (PDH-E2) and its component X, branched chain alpha-keto acid dehydrogenase (BCKD-E2), and 2-oxoglutarate dehydrogenase. LKM-1 antigen has been identified as cytochrome P-450 db1, a drug metabolizing enzyme with a known genetic polymorphism. These cloned hepatic autoantigens share some characteristics with other autoantigens: they are enzymes, autoantibodies react with active sites of these enzymes and the autoepitopes are highly conserved. After the identification of these autoepitopes, specific and sensitive diagnostic reagents will become available. B and T cell epitope mapping will help to elucidate whether these autoantibodies are just clinically valuable diagnostic markers or whether they contribute to the immunopathogenesis or help to identify the aetiological agents.
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PMID:Autoantibodies and antigens in liver diseases--updated. 268 96

Sera from 23 children with autoimmune chronic active hepatitis and positive for anti-liver-kidney-microsome antibody (LKMA), as defined by immunofluorescence, were analysed by Western blot (WB) and two-dimensional gel electrophoresis using rat liver microsomes as antigen, and by WB and dot-blot analysis with rat liver microsomal subfractions. Western blot analysis showed three patterns of reactivity: 13 sera recognized a 50 kD polypeptide, six sera a 66 kD polypeptide and four sera both of them. Two-dimensional gel electrophoresis, WB, and dot-blot analysis showed the 66 kD antigen to have a pI of 5.4 and to be located in the smooth domain of the endoplasmic reticulum. Western blot analysis using monospecific antisera against human IgG subclasses showed the LKMA directed against the 66 kD antigen to be mainly of the IgG1 subclass. These results indicate that LKMA associated with a subgroup of autoimmune hepatitis of children react with at least two different microsomal antigens in rat liver: (1) the 50 kD polypeptide, recently shown to be a cytochrome P-450 of the IID subfamily, and (2) a new antigen of 66 kD, the location of which suggests it may also be part of the mono-oxygenase complex.
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PMID:A new antigen recognized by anti-liver-kidney-microsome antibody (LKMA). 270 79

Isaxonine and several other drugs transformed by cytochrome P-450 into reactive metabolites apparently lead to immunoallergic hepatitis in man. Protein epitopes modified by the covalent binding of the metabolites have been proposed as possible targets for the immune response. The purpose of this work was to determine whether covalently bound metabolites are indeed present on hepatocyte plasma membrane proteins. In a first series of experiments, rats were killed 15 or 60 min after administration of [2-14C]isaxonine (0.2 mmol.kg-1 i.p.), and various fractions were prepared from isolated hepatocytes; microsomal contamination of the plasma membrane fraction was 1.2% or less. At 60 min, the amount of isaxonine metabolite covalently bound per mg of protein was similar in plasma membranes (0.42 nmole metabolite.mg protein-1) and in microsomes (0.38); both values were decreased by about 70% in rats pretreated with piperonyl butoxide, an inhibitor of cytochrome P-450. At 15 min, however, covalent binding to plasma membrane proteins (0.06 nmole metabolite.mg protein-1) was only half of that to microsomal proteins (0.12). In a second series of experiments, [2-14C] isaxonine (0.1 mM) was incubated with NADPH, hepatic microsomes and plasma membranes. The reactive isaxonine metabolite became bound extensively to microsomal proteins, but not to plasma membrane proteins. These results show that administration of isaxonine leads to the presence of isaxonine adducts on the proteins of the hepatocyte plasma membrane.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Presence of covalently bound metabolites on rat hepatocyte plasma membrane proteins after administration of isaxonine, a drug leading to immunoallergic hepatitis in man. 270 34

The metabolism of chemical carcinogens was investigated in liver preparations from 28 captive woodchucks (Marmota monax). Of these, 23 were naturally infected with the woodchuck hepatitis virus (WHV), and eight also had primary hepatocellular carcinoma (PHC). Twenty-nine parameters were investigated in liver subcellular fractions, including cross-reactivity with HBsAg, and biochemical parameters, such as gamma-glutamyl transpeptidase, cytochrome P-450 and microsomal monooxygenases (aryl hydrocarbon hydroxylase, ethoxycoumarin and ethoxyresorufin deethylases, aminopyrine and dimethylnitrosamine demethylases, and testosterone 7 alpha-, 16 alpha- and 6 beta-hydroxylases), uridine 5'-diphosphoglucuronosyl transferase, GSH and related enzymes (peroxidase, reductase and S-transferase), as well as other cytosolic enzyme activities (glucose 6-phosphate and 6-phosphogluconate dehydrogenases, NADPH- and NADH-dependent diaphorases, and DT diaphorase). In addition, liver preparations were used in order to quantify the metabolic activation into bacterial mutagens of five procarcinogens (aflatoxin B1, the pyrolysis products Trp-P-2 and MeIQ, 2-aminofluorene and dimethylnitrosamine) and the decrease of potency of three direct-acting mutagens (sodium dichromate, ICR 191 and 4-nitroquinoline 1-oxide). WHV infection produced a significant stimulation of carcinogen metabolism, as shown by the simultaneous change in detoxification parameters (GSH depletion) and activation indices (enhancement of microsomal monooxygenases and of procarcinogen activation into mutagenic metabolites). There were no significant differences between WHV-positive samples from animals without PHC and the noncancerous tissue of PHC-bearing animals, whereas a decrease of both activation and detoxification indices was recorded in the tumorous tissue. There was a considerable interindividual variability among WHV carriers, which was tentatively ascribed to genetic factors. Pregnancy was the only known factor influencing the results in WHV carriers. However, even by excluding pregnant animals, the effects on carcinogen metabolism produced by WHV infection were still statistically significant. These results, together with previous data obtained in humans, revealed that metabolic factors may play a role in the synergism between viral hepatitis and chemical hepatocarcinogens in the etiopathogenesis of PHC.
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PMID:Enhanced metabolic activation of chemical hepatocarcinogens in woodchucks infected with hepatitis B virus. 272 Sep 3

Recombinant human alpha-interferon is now under intensive investigation as therapy for chronic Type B hepatitis. Recent reports have suggested that prolonged alpha-interferon therapy may induce autoimmune reactions. We have evaluated the problem of autoimmunity related to alpha-interferon therapy by testing for 15 different antibodies in the sera of 31 patients treated with alpha-interferon. No patient had autoantibodies before treatment; 27 (87%) of 31 patients developed at least one autoantibody. Eleven patients had antinuclear antibodies and 21 had smooth muscle antibodies, both of which usually developed during alpha-interferon therapy. In contrast, antibodies to endocrine organs such as thyroid microsomal, thyroglobulin and parietal cell antibodies arose in 12 patients, but usually several months after alpha-interferon treatment. The appearance of these autoantibodies did not correlate with disease activity or response to alpha-interferon. No patient developed autoantibodies specifically associated with autoimmune liver diseases such as liver kidney microsomal antibodies, autoantibodies to soluble liver antigen and the primary biliary cirrhosis specific subtypes of antimitochondrial antibodies. These results suggest that prolonged alpha-interferon therapy can induce autoantibody production and, in susceptible patients, may lead to autoimmune disorders.
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PMID:Treatment of chronic type B hepatitis with recombinant alpha-interferon induces autoantibodies not specific for autoimmune chronic hepatitis. 273

Amineptine-induced immunoallergic hepatitis is unpredictable. It may be related to its oxidation into a reactive metabolite acting as hapten. We have looked for a possible genetic predisposition involving drug oxidation capacity and/or cell defense mechanisms in nine patients with previous amineptine hepatitis. Drug oxidation capacity was assessed using dextromethorphan, a test compound recently proposed as a substitute for debrisoquine. The eight patients tested had the extensive metabolizer phenotype. The susceptibility to amineptine metabolites was studied by an in vitro test assessing the destruction of the patients' lymphocytes by reactive metabolites generated from amineptine by a standardized oxidation microsomal system. Lymphocyte death increased with the dose of amineptine (1 to 2.5 mM); it was increased by preincubation with trichloropropene oxide, but was absent when amineptine was omitted or when the oxidation system was not operating. Mean lymphocyte death was twice higher in the nine patients with amineptine hepatitis than in 17 healthy controls. In contrast, when the test was performed with acetaminophen (3 to 10 mM), lymphocyte death was similar in controls and in patients. Basal epoxide hydrolase activity toward benzo[a]pyrene-4,5-oxide and glutathione concentration was similar in lymphocytes from controls and patients. Family studies showed an increased susceptibility to amineptine metabolites in lymphocytes from several first-degree relatives of two patients. These results show that amineptine hepatitis occurs in patients with extensive dextromethorphan oxidation capacity but with an increased susceptibility to amineptine reactive metabolites, probably related to a genetic deficiency in a cell defense mechanism.
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PMID:Genetic predisposition to drug hepatotoxicity: role in hepatitis caused by amineptine, a tricyclic antidepressant. 274 28

The Long-Evans rat with a cinnamon-like coat color (LEC rat) is a mutant strain displaying hereditary hepatitis with severe jaundice. The age related difference in microsomal dealkylation of pentoxyresorufin and ethoxyresorufin was examined. The enzyme activity levels of pentoxyresorufin O-depentylase in LEC rats were decreased to 25% of the levels in control [Long-Evans rats with an agouti coat color (LEA rats)]. In contrast, ethoxyresorufin O-deethylase exhibited a much less marked difference between the strains. In parallel with these strain differences in enzyme activities, a decrease in phenobarbital (PB) inducible P450 isozymes, mainly P450b and P450e, was observed by Western blot analysis. The level of P450PB in LEC rats was more markedly depressed than in the LEA strain. On the other hand, microsomes from uninduced LEC rat liver had more 3-methylcholanthrene (MC) inducible P450MC, mainly P450c and P450d, than microsomes from LEA rat liver and these isozymes in the LEC were markedly induced by 3-methylcholanthrene treatment. The great difference in cytochrome P450PB content of the liver microsomes between LEC and LEA rats and the maintained constitutive levels of hepatic cytochrome P450MC in the LEC rats suggest a possible role of these cytochrome isozymes in the onset of spontaneous hepatitis and hepatoma.
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PMID:Selective expression and induction of cytochrome P450PB and P450MC during the development of hereditary hepatitis and hepatoma of LEC rats. 280 35

Previous studies have demonstrated that patients with halothane-induced hepatitis have serum antibodies that are directed against novel liver microsomal neoantigens and have suggested that these neoantigens may play an immunopathological role in development of the patients' liver damage. These investigations have further revealed that the antibodies are directed against distinct polypeptide fractions (100 kDa, 76 kDa, 59 kDa, 57 kDa, 54 kDa) that have been covalently modified by the reactive trifluoroacetyl halide metabolite of halothane. In this paper, the trifluoroacetylated (TFA) 59-kDa neoantigen (59-kDa-TFA) recognized by the patients' antibodies was isolated from liver microsomes of halothane-treated rats by chromatography on an immunoaffinity column of anti-TFA IgG. Antibodies were raised against the 59-kDa-TFA protein and were used to purify the native protein from liver microsomes of untreated rats. Based upon its apparent monomeric molecular mass, NH2-terminal amino acid sequence, catalytic activity, and other physical properties, the protein has been identified as a previously characterized microsomal carboxylesterase (EC 3.1.1.1). A similar strategy may be used to purify and characterized neoantigens associated with other drug toxicities that are believed to have an immunopathological basis.
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PMID:Human anti-endoplasmic reticulum antibodies in sera of patients with halothane-induced hepatitis are directed against a trifluoroacetylated carboxylesterase. 291 77

The structure of the envelope protein E1 of two coronaviruses, mouse hepatitis virus strain A59 and infectious bronchitis virus, was analyzed by applying several theoretical methods to their amino acid sequence. The results of these analyses combined with earlier data on the orientation and protease sensitivity of E1 assembled in microsomal membranes lead to a topological model. According to this model, the protein is anchored in the lipid bilayer by three successive membrane-spanning helices present in its N-terminal half whereas the C-terminal part is thought to be associated with the membrane surface; these interactions with the membrane protect almost the complete polypeptide against protease digestion. In addition, it is predicted that the insertion of E1 into the membrane occurs by the recognition of the internal transmembrane region(s) as a signal sequence.
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PMID:Predicted membrane topology of the coronavirus protein E1. 300 26

The activities of three enzymes catalyzing the production or degradation of phosphatidylcholine, a major structural phospholipid of cell membranes, were assessed in hepatocyte membrane microsomal preparation from patients with various types of liver disease. Choline phosphotransferase activity of preparation from patients with chronic aggressive, chronic active, chronic persistent, alcoholic hepatitis and cirrhosis accompanied by marked necrosis and relatively slight fibrosis was markedly decreased, compared with normal liver; the activity from patients with fatty liver and chronic inactive hepatitis was slightly decreased. Specimens from patients with acute transient hepatitis were not significantly different from normal. Methyltransferase and phospholipase A2 activities tended to parallel that of choline phosphotransferase, although the degree of changes was generally less marked. Our studies indicate that enzyme activities that are critical for hepatic cell membrane integrity and activity are attenuated in liver specimens from patients with disease in which there is marked hepatic cell necrosis.
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PMID:Phospholipid transmethylation and choline phosphotransferase in microsomal fraction of human diseased liver. 301 86


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