UMLS:C0019158 - FACTA Search

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Query: UMLS:C0019158 (hepatitis)
30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Microsomal antigen autoantibodies are typical of type 2 autoimmune hepatitis, and a strong association with chronic hepatitis C virus (HCV) infection has been reported in certain geographical areas. These autoantibodies have been denominated LKM-1 to differentiate them from those associated with thienylic acid-induced hepatitis (LKM-2) and from those seen in patients with chronic delta hepatitis (LKM-3). To investigate the antigenic specificity of autoantibodies associated with chronic hepatitis C and delta, we analyzed 52 LKM-1 positive serum samples from patients with chronic hepatitis C and 17 LKM-3 positive serum samples from patients with chronic delta hepatitis by indirect immunofluorescence and Western blotting (immunoblotting). Reactivity of subjects with chronic hepatitis C was heterogeneous: only 5 out of 52 LKM-1 positive patients, tested by Western blot, recognized a single protein of 50 kD, previously identified by Manns et al. with an immunogenic epitope of cytochrome P450IID6. Thirteen of the 52 patients also reacted with a 70 kD microsomal protein, and 12 out of 52 reacted only with a 59 kD protein. Twenty-two sera, notwithstanding the high titer in immunofluorescence, did not evidence any reactivity when tested by Western blot. The same sera tested positive in LKM-1 ELISA when solubilized human microsomal proteins were used. Fourteen out of 17 LKM-3 positive sera from patients with chronic hepatitis delta recognized a 55 kD microsomal protein in Western blot; three sera, HCV and HIV positive, did not react with any protein by Western blot. None of these sera was positive in ELISA LKM-1.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Heterogeneity of antimicrosomal autoantibodies in chronic hepatitis C virus infection and delta hepatitis]. 754 66

Drug hepatotoxicity is partially determined by genetic factors involved in drug metabolism, which may involve the debrisoquine oxidation polymorphism mediated by cytochrome (CYP) 2D6. The purpose of this study was to assess the relationship between drug hepatotoxicity and another genetic polymorphism of drug oxidation, namely that of S-mephenytoin metabolism mediated by CYP2CMP. Mephenytoin hydroxylation capacity was assessed by a hydroxylation index in 24 patients with drug-induced hepatitis and in 23 healthy controls. Hydroxylation index was calculated as the ratio of S-mephenytoin dose to the (0-10 h) urinary excretion of 4-hydroxymephenytoin after oral administration of 100 mg racemic mephenytoin. The test was performed following the patient's recovery. In three patients, hepatitis was related to Atrium, a drug containing phenobarbital, febarbamate and difebarbamate. The mean hydroxylation index (+/- SD) value in patients with Atrium hepatitis (12.4 +/- 8.3) was markedly higher than that found in healthy controls (1.8 +/- 0.4) or in patients with other drug-induced hepatitis (2.5 +/- 3.3). Mean hydroxylation index values were similar in the two latter groups. Considered individually, oxidation capacity was low (hydroxylation index > 9) in two of the three patients with Atrium hepatitis and intermediate (hydroxylation index between 4 and 9) in the third patient. In contrast, all 23 healthy subjects exhibited a high oxidation capacity (hydroxylation index < 4). In the 21 patients with other drug-induced hepatitis, oxidation capacity was high in 19 subjects, intermediate in one subject with chlorpromazine hepatitis, and low in one subject with dapsone hepatitis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Possible association between poor metabolism of mephenytoin and hepatotoxicity caused by Atrium, a fixed combination preparation containing phenobarbital, febarbamate and difebarbamate. 769 30

Oxidation of tienilic acid (TA) by microsomes of yeast expressing two closely related human liver cytochrome P-450s (P450), P450 2C9 and 2C10, led to catalysis-dependent loss of activity of these P450s. Under identical conditions, oxidation of a tienilic acid isomer (TAI) failed to give any P450 inactivation. The loss of P450 activity during TA oxidation was concomitant with product (5-hydroxytienilic acid, 5-OHTA) formation, showed pseudo-first-order and saturation kinetics, and was inhibited by an alternative substrate, tolbutamide. Covalent binding of TA metabolites to microsomal proteins occurred in parallel with enzyme inactivation and was partially inhibited by the presence of glutathione in the reaction medium. However, glutathione did not protect P450 enzyme from inactivation. Thus, TA exhibited all of the characteristics of a mechanism-based inactivator for P450 2C9 and 2C10 enzymes. The following kinetic parameters were determined in the case of P450 2C10: t1/2,max = 3.4 min, k(inact) = 3.6 10(-3) s-1, KI = 4.3 microM, k(inact)/KI = 813 L mol-1 s-1, and partition ratio = 11.6. Moreover, a specific covalent binding of 0.9 mol of TA metabolite per mole of P450 2C10 was found to occur before the complete loss of enzyme activity (in incubations performed in the presence of glutathione). A plausible mechanism for P450 2C10 (2C9) inactivation during TA oxidation is proposed. It involves the intermediate formation of an electrophilic thiophene sulfoxide, which may react at position 5 of its thiophene ring either with H2O to give 5-OHTA or with a nucleophilic group of an amino acid residue of the P450 active site, which results in its covalent binding to P450 protein. This alkylation and inactivation of P450 2C9 (2C10) by TA could be a starting point for the appearance of anti-P450 2C antibodies detected in patients treated with TA and suffering from immunoallergic hepatitis.
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PMID:Thiophene derivatives as new mechanism-based inhibitors of cytochromes P-450: inactivation of yeast-expressed human liver cytochrome P-450 2C9 by tienilic acid. 828 35

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

The objective of this work is to examine the possible modulation of carcinogen metabolism (activation by cytochrome P450s and detoxification by conjugation via glutathione S-transferases [GST]) in relation to hepatitis B virus (HBV)-associated liver injury. In HBV transgenic mouse lineage 107.5, the hepatitis B surface antigen (HBsAg) is expressed at noncytopathic concentrations but after injection of an HBsAg-specific, major histocompatibility complex (MHC) class I restricted cytotoxic T-lymphocyte (CTL) clone, the mice develop a severe acute necroinflammatory liver disease that reaches maximum severity within 3 days and gradually subsides during the next 2 to 3 weeks. In this model, using immunohistochemical analysis, we observed an increase of P450s (CYP1A and 2A5), both involved in aflatoxin B1, metabolism, but minor changes or no changes for others (2B, 2C, 2E, 3A). There was a fivefold decrease in the total liver P450 microsomal content 3 days' post-CTL injection with the result that the relative proportion of CYP2A5 and 1A compared with other P450s is increased. Individual microsomal P450 enzyme contents estimated by Western blotting; Northern blot analysis of liver CYP messenger RNA (mRNA) levels as well as in vitro metabolism of specific substrates for different P450 isoenzymes were consistent with the immunohistochemical data. Immunohistochemical staining with antibodies to cytosolic pi class GST was increased 1 and 3 days postinjection followed by a progressive decrease at later time points (the same phenomenon was observed to a lesser extent for GST alpha). The activity of hepatic cytosols toward substrates specific for different subclasses of GST (mu, pi, alpha) showed that while GST mu was not changed in the CTL-injected HBV transgenic mice, GST pi and, to a lesser extent, alpha were increased as compared with controls. These results suggest that liver cell injury induced by a process of acute fulminant-like hepatitis can lead to the induction of some carcinogen metabolizing enzymes notably, Cyp 1A, 2A5 and GST pi in the mouse.
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PMID:Differential induction of carcinogen metabolizing enzymes in a transgenic mouse model of fulminant hepatitis. 878 38

The biotransformation of the aerosol propellant 1,1,1,2,3,3,3-heptafluoropropane (HFA-227) was investigated in rats in vivo and in rat and human liver microsomes. In the urine of rats exposed to 5000 ppm HFA-227 for 6 hr, very small amounts of hexafluoroacetone trihydrate were identified as an HFA-227 metabolite by 19F-NMR. Fluoride concentrations in the urine samples (0-48 hr after the end of the exposure) from exposed animals were not significantly different from those found in samples from nonexposed rats. In rat and human liver microsomes, fluoride and hexafluoroacetone trihydrate formation from HFA-227 was detected in very low levels only in liver microsomes from pyridine-treated rats and in two of eight human liver microsome samples, which exhibited the highest cytochrome P4502E1 activities. Because some aldehydes may covalently bind to proteins and the formation of fluorinated protein adducts has been implicated in immune-mediated hepatitis induced by halothane, the binding of hexafluoroacetone trihydrate to proteins was also investigated. Hexafluoroacetone trihydrate also gave only a very small resonance in fluorine NMR experiments when binding to human serum albumin was studied in comparison with the acylating agent S-ethyltrifluoroacetate. Moreover, no fluorine-containing products were formed by the reaction of hexafluoroacetone trihydrate with N alpha-acetyl-L-lysine, and hexafluoroacetone trihydrate was not metabolized to fluorine-containing metabolites or inorganic fluoride in rats. Comparative studies in human liver microsomes demonstrated that a halothane metabolite may covalently bind to proteins; in contrast, metabolism and covalent binding of HFA-227 could not be demonstrated. In summary, these data indicate that HFA-227 is biotransformed at very low rates to hexafluoroacetone trihydrate but irreversible binding of hexafluoroacetone trihydrate cannot be demonstrated, even with the application of very sensitive methods, and is considered unlikely, based on the combination of the results obtained.
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PMID:Biotransformation of the aerosol propellant 1,1,1,2,3,3,3-heptafluoropropane (HFA-227): lack of protein binding of the metabolite hexafluoroacetone. 886 27

Autoantibodies against specific human cytochrome P450s have been found in the sera of patients suffering from a variety of diseases, including those caused by drugs. In the cases of tienilic acid- and dihydralazine-induced hepatitis, patients have serum autoantibodies directed against cytochromes P450 2C9 and P450 1A2, respectively. In the present study, we have found that 25 of 56 (45%) patients diagnosed with halothane hepatitis have autoantibodies that react with human cytochrome P450 2E1 that was purified from a baculovirus expression system. The autoantibodies inhibited the activity of cytochrome P450 2E1 and appeared to be directed against mainly conformational epitopes. In addition, because cytochrome P450 2E1 became trifluoroacetylated when it oxidatively metabolized halothane, it is possible that the covalently altered form of cytochrome P450 2E1 may be able to bypass the immunologic tolerance that normally exists against cytochrome P450 2E1. A similar mechanism may explain the formation of autoantibodies that have been found against other cellular targets of the reactive trifluoroacetyl chloride metabolite of halothane.
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PMID:Human cytochrome P450 2E1 is a major autoantigen associated with halothane hepatitis. 890 72

Some patients with chronic hepatitis C develop liver/kidney microsome type 1 antibodies. Some of these autoantibodies are directed against the cytochrome P450IID6. The aim of this study was to characterize the immunogenic sites on the P450IID6 molecule recognized by autoantibodies from individuals infected with the hepatitis C virus. Serum from 24 patients with markers of hepatitis C infection and liver/kidney microsome type 1 antibodies were tested by immunoblotting with human liver microsomal proteins. Eight of them with anti-P450IID6 antibodies were tested with synthetic peptides representing P450IID6 putative immunogenic sites and for their capacity to inhibit in vitro P450IID6 enzymatic activity. Anti-P450IID6 antibodies in the sera of chronic hepatitis C patients were of IgG subclass 1 and in one patient also of IgM type. These sera recognized different P450IID6 peptide sequences consisting of amino acids (aa) 200-214 and aa 271-339. The synthetic peptide between aa 321 and 339 appears to represent the main antigenic site. Five out of eight anti-P450IID6 positive sera were also able to inhibit P450IID6 enzymatic activity in vitro at a dilution of 1:100. The anti-P450IID6 autoimmune response in chronic hepatitis C patients is polyclonal, probably inducible, and maintained by the liberation of P450IID6 by hepatocyte lysis. The characterization of the P450IID6 immunogenic site recognized by patients with hepatitis C infection may enable a specific test to be designed to identify those patients with autoimmune hepatitis type 2.
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PMID:Study of the B cell response to cytochrome P450IID6 in sera from chronic hepatitis C patients. 891 82

Peripheral blood mononuclear cells (PBMC) of patients with autoimmune hepatitis (AIH) and controls were studied for their proliferative response to six overlapping synthetic peptides covering the 33-amino acid immunodominant region of cytochrome P450IID6, the main target antigen of LKM-1 antibody-positive type II AIH. PBMC from 8 of 8 type II AIH patients (100%), 6 of 12 LKM-1 antibody-negative type I AIH patients (50%), but only 4 of 31 patients with chronic hepatitis C (12.9%) reacted with a 23-amino acid LKM peptide and mainly with a shorter 18-amino acid LKM peptide. Follow-up showed that LKM-specific T-cell responses decreased after immunosuppression had started. Fine specificity, HLA restriction, and cytokine release of LKM-specific T cells were analyzed with 16 CD4+ peptide-specific T-cell lines and 21 CD4+ T-cell clones isolated and expanded from blood and liver tissue of six AIH patients. Activated LKM-specific T cells released interferon gamma (IFN-gamma) but no or little interleukin-4. In three AIH patients, PBMC showed specific recognition of autologous LKM-specific T cells, suggesting the presence of a regulatory T-cell network. These T cells also showed the CD4+ phenotype and secreted large amounts of IFN-gamma. Furthermore, it was assessed that the regulatory T-cell response is clonotypic. To conclude, we describe a major T-cell epitope in AIH that was recognized by Th1 helper cells isolated from blood and liver tissue. This autoreactive T-cell response correlated widely with disease activity and LKM-1 antibody status and seemed to be regulated by anticlonotypic T cells.
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PMID:Autoreactive CD4+ LKM-specific and anticlonotypic T-cell responses in LKM-1 antibody-positive autoimmune hepatitis. 893 73

It is now known that human exposure to certain chemicals e.g. benzene, halocarbons, ketones, nitrosamines, etc. can result in adverse health effects that are often not easily recognised as manifestations of chemical toxicity. These are inflammatory states, such as hepatitis, nephritis, scleroderma, and lupus, due to production of reactive oxygen species (ROS) through activation of cytochrome P4502E1 by the chemical, or by metabolism of the chemical to reactive intermediates and neoantigens which initiate immunotoxic effects. Intracellular glutathione (GSH), vitamins C, E and A protect against this ROS toxicity and inflammation; fasting and consumption of alcohol exacerbate it. Chronic inflammatory states may subsequently develop, including rheumatoid disease, atherosclerosis, diabetes, infertility and birth defects, multiple system organ failure (MSOF), Alzheimer's disease, and cancer.
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PMID:Chemical-induced inflammation and inflammatory diseases. 897 63

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