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)

The authors report the case of a patient with ajmaline hepatitis. The clinical presentation suggested angiocholitis; serum bilirubin concentration and the activity of alkaline phosphatase were markedly increased; serum transaminase activity was moderately increased; the prothrombin time remained normal. After interruption of the drug, the outcome was favorable, with complete recovery within 2 months. Histologic examination of a liver specimen obtained early after the onset of jaundice showed inflammatory cells in the portal tracts and mild hepatocytic lesions. Electron microscopy disclosed dilatation of the endoplasmic reticulum. The microfilamentous network of the hepatocytes was reduced and disorganized. Biliary canaliculi were enlarged with absent or blunted microvilli. There was evidence for passage of bile products from the biliary caniculi into the space of Disse. These aspects are reminiscent of those observed in animals after the administration of cytochalasin B. It is suggested that ajmaline may, in some patients, trigger an immune response which then alters the microfilamentous network of the hepatocytes, and may, thereby, produce cholestasis.
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PMID:[Ajmaline-induced hepatitis. A case report with ultrastructural study]. 687 68

A close correlation between the presence of hepatitis B surface antigen and albumin in the cytoplasm of hepatocytes infected with hepatitis B virus was established by immunofluorescence and immunoelectron microscopy in 52 liver biopsy specimens of various forms of hepatitis and liver cirrhosis. Albumin deposits usually accompanied cytoplasmic content of hepatitis B surface antigen, but were less frequently observed together with hepatitis B antigen localized in or on the membranes. Ultrastructural observations demonstrated albumin on the tubular and spherical forms of hepatitis B surface antigen in the endoplasmic reticulum. The hepatocytes with the content of hepatitis B surface antigen and albumin showed the ability of binding with the fluorescein-labeled preparation of polymerized human serum albumin. The affinity of polymerized albumin to hepatitis B surface antigen was considerably increased after preincubuation of liver sections with 2-mercaptoethanol that removed most of the originally present albumin. This may be indicative for the role of disulfide bonds in the formation of hepatitis B surface antigen-albumin complexes. These results justify the hypothesis that albumin may be incorporated into the viral coat protein during its synthesis in the cytoplasm of infected hepatocytes.
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PMID:Hepatitis B surface antigen and albumin in human hepatocytes. An immunofluorescent and immunoelectron microscopic study. 700 3

Hepatitis C virus is a positive single-strand RNA virus distantly related to flaviviruses. Therefore RNA replicase, an RNA-dependent RNA polymerase, may be essential for the replication of hepatitis C virus, as well as other RNA viruses. In this study we synthesized the recombinant polypeptide (HCV-NS5 antigen) with a 576 bp cDNA encoding a part of the NS5 region of the HCV genome that has the Gly-Asp-Asp motif. The antibody against this polypeptide was obtained from rabbit serum. In Western-blot analysis with NS5 IgG HCV antibody, an 84-kD protein was clearly detected as a single band in the microsomal fraction but not in the nuclear and mitochondrial fractions or in the cytosol fraction. Immunohistochemically, HCV-NS5 antigen was clearly stained in the cytoplasm of hepatocytes but not in the nucleus or cell membrane. Moreover, as determined on immunoelectron microscopy, HCV-NS5 antigen was demonstrated with fine granular distribution along the endoplasmic reticulum but not in other organelles, including the nucleus and mitochondria. Immunoreaction in other cell types was negative. These results indicate that replication of HCV may occur only in hepatocytes and that HCV-NS5 may be produced in the endoplasmic reticulum of these cells. HCV-NS5 antigen was stained only in the livers of hepatitis C virus-positive patients but not in sections from patients with chronic type B hepatitis or alcoholic fibrosis. In chronic type C liver disease, the overall detection rate of HCV-NS5 antigen was 56% (33% in chronic persistent hepatitis, 52% in chronic active hepatitis and 86% in cirrhosis).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Detection of antigens related to hepatitis C virus RNA encoding the NS5 region in the livers of patients with chronic type C hepatitis. 750 61

In this study we have investigated the mechanism of the processing of trifluoroacetylated liver microsomal protein antigens associated with halothane hepatitis to learn how the immune system might come in contact with these proteins to form antibodies directed against them. Rats were treated with halothane and parenchymal (PC) and non-parenchymal cells (NPC) were isolated 16 hours later. Immunoblotting of the cell lysates with antisera directed against the trifluoroacetyl hapten showed the presence of high levels of trifluoroacetylated proteins in parenchymal cells, whereas none of these proteins were detected in endothelial or Kupffer cells that were isolated by centrifugal elutriation. The half-lives of 100-, 82-, 80-, 63-, 59-, 58-, and 57-kd trifluoroacetylated and native carrier proteins of the trifluoroacetyl hapten in cultures of rat primary parenchymal cells were approximately 1 day. The turnovers of all of these trifluoroacetylated proteins, except for that of the trifluoroacetylated 100-kd protein, were inhibited by treatment of the cells with ammonium chloride, leupeptin, 4-(2-aminoethyl)-benzenesulfonyl fluoride, or 3-methyl-adenine (3-MA). These results indicate that, in liver, the major source of the formation of trifluoroacetylated antigens associated with halothane hepatitis is the parenchymal cells, It appears that most of the trifluoroacetylated antigens and possibly the native carrier protein of the trifluoroacetyl haptens are transferred from the endoplasmic reticulum (ER) to an acidic compartment of PCs, where they are enzymatically degraded. The processing of the trifluoroacetylated proteins by this pathway may be a protective mechanism that prevents these covalently altered proteins from inducing an antibody response in most patients who are administered halothane.
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PMID:Processing of endoplasmic reticulum luminal antigens associated with halothane hepatitis in rat hepatocytes. 765 2

LKM1 autoantibody, directed against P450IID6, is accepted as a marker of a particular type of autoimmune hepatitis, but its role in the pathogenesis of the disease is controversial. Localization of P450IID6 on the cell surface of rat hepatocytes was previously reported, suggesting that membrane-bound P450IID6 could be the target of LKM1 antibodies, thus allowing immune lysis of hepatocytes. The objective of the present study was to determine, using various methods, the cell localization of P450IID6 in human and rat hepatocytes. Incubation of rat and human hepatocytes with LKM1-positive serum showed slight, if any, cell membrane staining using immunofluorescence, immunoperoxidase and immunoelectron microscopic studies. No staining of the plasma membrane of human hepatocytes was observed when incubations were carried out with immunoaffinity-purified antibody directed against peptide 254-271, the main epitope of P450IID6 recognized by all LKM1 sera tested. Chinese hamster ovary cells, transfected with the complete P450IID6 cDNA and incubated with the supernatant from a B cell lymphoblastoid cell line prepared with the lymphocytes of a LKM1-positive patient, did not show any staining of the cell surface by immunofluorescence. Incubation of rat microsomal fraction vesicles with LKM1-positive serum, followed by protein A-gold immunoelectron microscopy, displayed a staining of almost all vesicles, confirming that P450IID6 is present on the cytoplasmic side of the microsomal membrane, which makes it unable to be expressed on the cell surface even if it were transported from the endoplasmic reticulum (ER). Sulpho NHS Biotin labelling of rat hepatocyte cell membranes did not show the presence of a 50-kD molecule that could have reacted with LKM1 antibody. DNA sequencing of exon 1 of the CYP2D6 gene of a patient positive for LKM1 antibody did not show any difference from that of the normal published sequence of the gene. This does not favour an alteration of the NH2 terminal sequence of the P450IID6 molecule that could explain a translocation of the molecule to the luminal side of the ER, allowing its expression on the cell surface. These results indicate that, in all likelihood, P450IID6 molecule is not present on the cell surface of normal rat and human hepatocytes. Other mechanisms than antibody-mediated cell lysis directed against membrane P450IID6 antigenic determinants must be found to account for the destruction of hepatocytes observed in this disease.
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PMID:Cytochrome P450IID6 recognized by LKM1 antibody is not exposed on the surface of hepatocytes. 839 Mar 32

The mouse hepatitis virus M protein is a triple spanning membrane glycoprotein that, when expressed independently, localizes to trans-Golgi as well as to the trans-Golgi network (TGN). Passage of this protein from the endoplasmic reticulum through the intermediate compartment to the late Golgi and TGN can be conveniently followed by analyzing its O-linked sugars. Using pulse-chase analyses we studied the oligomerization of the M protein in sucrose gradients. The Golgi and TGN forms migrated as large heterogeneous complexes, whereas the endoplasmic reticulum and intermediate compartment forms of the protein appeared to migrate as monomer. Moreover, a mutant of the M protein lacking the 22 COOH-terminal amino acids, that is transported to the plasma membrane, gave rise to similar complexes, albeit smaller in size, that persisted at the plasma membrane. We propose that the trans-Golgi/TGN retention of the MHV-M protein is governed by two mechanisms: oligomerization possibly mediated by the transmembrane domains and binding of its cytoplasmic tail to cellular factors in trans Golgi/TGN.
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PMID:Oligomerization of a trans-Golgi/trans-Golgi network retained protein occurs in the Golgi complex and may be part of its retention. 772 88

Elevation of the serum angiotensin-converting enzyme (sACE) level and hepatic granulomas were found during a clinical relapse in a 22 year old patient with acute viral hepatitis type A (AVH-A). The serum transaminase level and sACE level remained high for more than 6 months. In the biopsied specimen of the liver, fibrous rings of granulomas composed of collagen types I, III, and V were observed. Furthermore, the localization of ACE was visible in the rough endoplasmic reticulum of epithelioid cells of granulomas in the liver under electron microscopy using the indirect immunoperoxidase method. These results suggest that granuloma cells in the liver caused by hepatitis A may be involved in ACE production. In addition, other diseases associated with the presence of granulomas in the liver, such as lymphoma, cytomegalovirus infection, visceral leishmaniasis, and lupoid hepatitis, were ruled out. However, the hepatic granulomas disappeared with the healing of AVH-A. In this regard, the present case is considered to be one of the very few cases of hepatic sarcoidosis.
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PMID:A patient with hepatic granuloma formation and angiotensin-converting enzyme production by granuloma cells during clinical relapse of hepatitis A. 804 9

Biotransformation of anaesthetic halothane by cytochrome P450-dependent monooxygenases resulted in the production of reactive intermediate trifluoroacetyl (TFA) halide, capable of covalently binding to hepatocyte proteins. TFA-modified liver proteins can act as antigens and are implicated in the pathogenesis of halothane hepatitis in humans. The aim of this study was to investigate the formation of TFA-neoantigens in halothane-treated primary cultures of adult human hepatocytes and to evaluate the usefulness of this in vitro model for studying immune-mediated halothane hepatotoxicity. Cultured human hepatocytes were incubated with halothane under constant temperature, atmosphere and anaesthetic concentration conditions. The results obtained show that halothane-treated hepatocytes isolated from seven different donors produced TFA-antigens as detected by immunocytochemical and western immunoblot analysis using rabbit anti-TFA antiserum. TFA-adducts were localized mainly in the endoplasmic reticulum and in small amounts on the plasma membrane of parenchymal cells. By immunoblotting, several neoantigens, with molecular masses from 42 to 100 kDa, were detected in halothane-exposed hepatocytes. These observations are consistent with the formation of TFA-adducts through metabolism of the anaesthetic and suggest that primary cultures of human hepatocytes represent a suitable in vitro model to study the pathogenesis of immune-mediated halothane hepatotoxicity.
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PMID:Human hepatocytes express trifluoroacetylated neoantigens after in vitro exposure to halothane. 806 43

The biosynthesis of the secretory core gene product of the woodchuck hepatitis virus (WHV) was studied in human cells. We have shown that the WHV e antigen was a N-glycosylated (most likely a diglycosylated) protein, with an apparent M(r) of 24K. To demonstrate that the WHV precore protein was correctly processed in human cells, we engineered chimeric proteins in which signal peptides or arginine-rich domains of WHV and hepatitis B virus (HBV) precore proteins were exchanged. Our results showed that both the signal peptide and the arginine-rich region of WHV precore protein were cleaved off during the secretion pathway, as previously reported for precore protein of human HBV and duck HBV. These observations demonstrate that the maturation process of the e antigen is conserved in hepadnaviruses. In addition, on the basis of inhibition experiments, we suggest that the cleavage of the carboxy terminus of the WHV precore protein occurred in a post-endoplasmic reticulum compartment, most likely beyond the medial Golgi, and that this cleavage was catalysed by an aspartyl protease.
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PMID:Characterization and biosynthesis of the woodchuck hepatitis virus e antigen. 811 24

We recently showed that when rats were administered the inhalation anesthetic halothane, a 58 kDa liver endoplasmic reticulum protein became covalently trifluoroacetylated by the trifluoroacetyl chloride metabolite of halothane. Although the 58 kDa protein showed 99% identity to that of the deduced amino acid sequence of a cDNA reported to correspond to phosphatidylinositol-specific phospholipase C-alpha, it did not have phosphatidylinositol-specific phospholipase C activity. It was concluded that the reported cDNA of phosphatidylinositol-specific phospholipase C-alpha actually encoded for the 58 kDa endoplasmic reticulum protein of unknown function. Other researchers have come to the same conclusion and have shown that the 58 kDa protein has protein disulfide-isomerase and protease activities. We now report that patients with halothane hepatitis have serum antibodies that react with both purified trifluoroacetylated and native rat liver 58 kDa proteins. These results suggest that when patients are exposed to halothane a human liver orthologue of the rat liver trifluoroacetylated-58 kDa protein is formed. In certain patients, this protein may become immunogenic and lead to the formation of specific antibodies and or specific T-cells, which may react with both trifluoroacetylated and native 58 kDa proteins, and ultimately be responsible, at least in part, for the hepatitis caused by halothane.
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PMID:Association of anti-58 kDa endoplasmic reticulum antibodies with halothane hepatitis. 821 76


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