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, markers of autoimmune diseases, can also be detected in chronic allograft rejection. However, the appearance of these autoantibodies in acute rejection after orthotopic liver transplantation has not yet been reported. Liver-kidney-microsome type-1 (LKM-1) antibodies directed against the autoantigen cytochrome CYP2D6 define a group of patients with autoimmune hepatitis type-2 (AIH-2), distinct from autoimmune hepatitis type-1 (AIH-1) in which anti-nuclear antibodies and anti-smooth muscle antibodies (SMA) with actin specificity are present in patient sera. Autoantibodies were studied by the quantitative CYP2D6 radioligand assay (RLA) that uses a radiolabeled CYP2D6 as antigen, immunoblotting using recombinant CYP2D6 protein and human liver microsomal and cytosolic fractions, and indirect immunofluorescence (IIF) using rat kidney-stomach-liver cryostat sections. In addition, the specificity of anti-SMA was detected by IIF on HEp2 cell line harvested with colchicin. This report describes the time course of CYP2D6 antibodies and the appearance of anti-SMA (without anti-actin, cytokeratin and vimentin reactivity) associated with acute rejection during a 2-year follow-up, in a patient who underwent transplantation at end-stage type 2 autoimmune hepatitis. In addition, we report a new reactivity against an unknown 40-kDa protein using a rat cytosolic fraction. The detection of autoantibodies in sequential samples may be important to better predict rejection or relapse, and to establish adequate therapy.
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PMID:Autoantibodies associated with acute rejection after liver transplantation for type-2 autoimmune hepatitis. 1090 2

Numerous human Cytochrome P450 enzymes (CYPs) associated with 'phase I' drug metabolism have been identified. Among them, CYP2D6 is thought to be the major target autoantigen to anti-liver kidney microsome (LKM)-1 autoantibody, a characteristic feature of autoimmune hepatitis (AIH) type II. In this study, we were able to clone CYP2D6 cDNA from a human liver cDNA library and express the CYP2D6 recombinant protein, and also to prepare four other representative human CYP proteins (CYP1A2, 2C9, 2E1, and 3A4). These preparations were used to assay the immunoreactivity of patients with AIH type I (n=35) and type II (n=9). As comparison groups, sera from patients with chronic hepatitis B (n=15), chronic hepatitis C (n=55; 24 anti-LKM-1-positive, 31 anti-LKM-1-negative), and from normal controls (n=30) were included. The five CYP proteins did not react with sera from normal controls nor from patients with chronic hepatitis B. CYP2D6 reacted with sera from 100% (9/9) of AIH type II patients, 79% (19/24) of patients with anti-LKM-1-positive chronic hepatitis C, and 6.5% (2/31) of patients with anti-LKM-1-negative chronic hepatitis C. In contrast, CYP1A2 reacted with serum from one patient with AIH type I, CYP2E1 reacted with sera from two patients with AIH type I, one patient with anti-LKM-1-positive chronic hepatitis C, and two patients with anti-LKM-1-negative chronic hepatitis C, and CYP3A4 reacted with sera from one patient with AIH type II and one patient with anti-LKM-1-positive chronic hepatitis C. CYP2C9 did not react with any of the sera included in this study. From these results, it is suggested that CYPs other than CYP2D6 can function as immunotargets in certain disease conditions.
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PMID:Immunoreactivity to various human cytochrome P450 proteins of sera from patients with autoimmune hepatitis, chronic hepatitis B, and chronic hepatitis C. 1120 50

Anti-liver kidney microsome type 1 autoantibodies (anti-LKM-1) are known to be present in sera of autoimmune hepatitis type II and a subset of chronic hepatitis C patients. The autoantigen to anti-LKM-1 has been identified to be cytochrome P450 IID6 (CYP2D6) and the most frequently cited CYP2D6 antigenic sites of anti-LKM-1 in sera from autoimmune hepatitis type II patients spans the region aa 256-269. Other antigenic sites on CYP2D6 exist and have been identified in the two patient groups. However, most of these sites are concentrated on the carboxyl-terminal side of the protein, and the amino-terminal region has not been thoroughly investigated. Here, we have studied the antigenicity of the CYP2D6 amino region and compared reactivities between hepatitis C virus (HCV)-negative and -positive Japanese patient groups. A total of 34 anti-LKM-1-positive sera (eight with autoimmune hepatitis type II and 26 with chronic hepatitis C) were included. The immunoreactivity of patients' sera was examined against four conformational and one linear CYP2D6 peptide fragments. A defined antigenic site spanning aa 181-245 was found to react with 88% (7/8) of autoimmune hepatitis type II patients, as opposed to only 38% (10/26) of chronic hepatitis C patients. This was a significant difference (P< 0.043). Among these positively reacting samples, five of the seven autoimmune hepatitis type II sera and four of the ten chronic hepatitis C sera also reacted with a synthetic peptide spanning aa 256-269. Anti-LKM-1 thus may be able to recognize simultaneously at least two antigenic sites on the CYP2D6 protein, and reactivities against individual epitopes may differ according to HCV infectivity status.
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PMID:Differences in anti-LKM-1 autoantibody immunoreactivity to CYP2D6 antigenic sites between hepatitis C virus-negative and -positive patients. 1171 62

Eukaryotically expressed CYP2D6 is the universal target of liver kidney microsomal Ab type 1 (LKM1) in both type 2 autoimmune hepatitis (AIH) and chronic hepatitis C virus (HCV) infection. In contrast, reactivity to prokaryotically expressed CYP2D6 protein and synthetic peptides is significantly lower in HCV infection than in AIH. The aim of the present study was to characterize LKM1 reactivity against a panel of eukaryotically expressed CYP2D6 constructs in the two conditions. LKM1-positive sera obtained from 16 patients with AIH and 16 with HCV infection were used as probes to perform a complete epitope mapping of CYP2D6. Reactivity to the full-length protein and 16 constructs thereof was determined by radioligand assay. We found that antigenicity is confined to the portion of the molecule C-terminal of aa 193, no reactivity being detectable against the aa sequence 1-193. Reactivity increases stepwise toward the C-terminal in both AIH and HCV, but the frequency of reactivity in the two conditions differs significantly between aa 267-337. To further characterize this region, we introduced a five and a three amino acid swap mutation selected from the homologous regions of CYP2C9 and HCV. This maneuver resulted in a substantial loss of LKM1 binding in both conditions, suggesting that this region contains a major epitope. Molecular modeling revealed that CYP2D6(316-327) is exposed on the surface of the protein, and may represent a key target for the autoantibody. These findings provide an initial characterization of the antigenic constitution of the target of LKM1 in AIH and HCV infection.
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PMID:Key residues of a major cytochrome P4502D6 epitope are located on the surface of the molecule. 1207 55

Autoimmune diseases, especially autoimmune thyroid disease, frequently develop after delivery due to the immune rebound mechanism. Most cases involve transient dysfunction of affected organs. We examined three patients who developed liver dysfunction after delivery. They were all diagnosed with definite or probable autoimmune hepatitis using the scoring system of the International Autoimmune Hepatitis Group. Moreover, all of them had anti-CYP2D6 antibodies detected by a sensitive radioligand assay. Our findings strongly suggest that liver dysfunction is induced by postpartum autoimmune hepatitis, and clinicians should be aware of this disease.
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PMID:Development of liver dysfunction after delivery is possibly due to postpartum autoimmune hepatitis. A report of three cases. 1236 9

Cancer risk can be influenced by the exposure to endogenous or environmental toxins. Polymorphic enzymes involved in the metabolic activation/detoxification of carcinogens may account for individual variations of risk. We studied the polymorphisms of five enzymes of the P450 superfamily, CYP1A1, CYP1A2, CYP2D6, CYP2E1 and CY3A4, as risk factors for liver disease progression and cancer in hepatitis C virus-infected patients. CYP genotyping was performed by polymerase chain reaction (PCR) restriction fragment length polymorphism or allele-specific PCR. Different stages of disease were considered, as follows: 90 asymptomatic carriers and 87 chronic hepatitis, 92 cirrhosis and 91 hepatocellular carcinoma (HCC) cases. Reference allele frequencies were obtained from 99 blood donors. Allele distributions among categories were compared using the chi(2) test. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to express relative risks. Independent associations were modeled by correspondence analysis and logistic regression. Frequencies of the CYP1A1 highly inducible alleles, MspI m2 and Val, were increased in liver disease patients compared with carriers; no specific association with HCC was found. The high-activity CYP2E1 c2 allele was underrepresented among HCC patients with respect to other HCV categories, including cirrhosis. CYP2D6 poor metabolizer (PM) genotypes were significantly more frequent in healthy subjects (7.1%) and carriers (11.1%) than in hepatitis/cirrhosis (4.6%) and HCC (1.2%) patients. This was confirmed by multivariable analysis. PM genotypes protected against progressive disease as ORs reduced proportionally to stage. The age at diagnosis for HCC was anticipated in non-PM individuals. No differences were seen for CYP1A2 and CYP3A4 genes. Polymorphic variants of CYP genes may contribute to the progression of liver disease and HCC risk in HCV-infected subjects.
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PMID:CYP enzyme polymorphisms and susceptibility to HCV-related chronic liver disease and liver cancer. 1256 54

Autoimmune hepatitis (AIH) is an inflammatory disease of unknown cause characterized by periportal hepatitis, increased serum globulins and the presence of certain antibodies. The disorder can be classified in three types. Type 1 AIH is characterized by the presence of antinuclear antibodies (ANA) and smooth muscle autoantibodies (SMA) in up to 70-80% of patients. ANA and SMA can be the only antibodies present in 13 and 33% of cases respectively. Type 2 AIH is defined by the presence of liver and kidney antimicrosomal antibodies (LKM1). Type 2 AIH is the only form of the disease in which the autoantigen has been identified: cytochrome mono-oxygenase (P-450 IID6) CYP2D6. In type 3 AIH the presence of anti-SLA/LP (soluble liver antigen/liver pancreas) targets a cytosolic protein involved in the incorporation of selenocysteine into peptidic chains. The pathophysiology of AIH is complex and involves genetic predisposition, previous exposure to antigens (autoantigens), presence of triggering factors and defects in immunoregulation. In spite of the advances in the understanding of AIH, the role of autoantibodies in the pathophysiology of this disease has not been fully established and their presence does not clearly distinguish any prognostic groups. Further investigations will help in the diagnosis of this disorder, the comprehension of its origins and the establishment of new forms of treatment.
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PMID:[Antibodies and physiopathogeny of autoimmune hepatitis]. 1496 79

Liver dysfunction has been found in 8.1% of postpartum women in the general population. This dysfunction was speculated to be developed by postpartum aggravation of subclinical autoimmune hepatitis. Therefore, we developed two methods for detection of autoantibodies to liver-specific antigens: an ELISA for anti-liver-specific arginase antibodies, and a highly sensitive radioligand assay for anti-CYP2D6 antibodies. Basic examinations of dilution curve, inhibition study and reproducibility were satisfactory for clinical application in both assays. Anti-arginase antibodies and anti-CYP2D6 antibodies were found in 28.6% and 42.6% of patients with autoimmune hepatitis, respectively. There was no correlation between the two autoantibodies and thus, combined use of these antibodies detects 55.3% of autoimmune hepatitis. Autoimmune hepatitis exists frequently when we include mild cases.
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PMID:[Differential diagnosis of hepatitis: development of new laboratory tests for autoimmune hepatitis and progress in pathophysiology]. 1496 59

Several phase I and phase II multi-drug metabolizing enzymes, such as CYP2D6, 3A4, and UGTA1, were reported to act as immunotargets in a subset of autoimmune hepatitis and hepatic autoimmunity. However, it is uncertain whether glutathione S-transferase (GST) A1-1, one of the phase II multi-drug metabolizing enzymes, is also an immunotarget in autoimmune hepatitis. So, in the present study, we investigated the frequency and significance of anti-GST A1-1 in sera from patients with autoimmune hepatitis. A total of 74 serum samples from patients with autoimmune hepatitis were examined in the present study. As controls, 20 serum samples from patients with primary biliary cirrhosis, 10 serum samples from patients with primary sclerosing cholangitis, 40 serum samples from patients with liver cirrhosis type B and C, 32 serum samples from patients with systemic lupus erythematosus, and 20 serum samples from normal controls were used. Anti-GST A1-1 antibody was determined by immunoblotting using the recombinant full-length GST A1-1 protein as the antigen. The immunofluorescent staining pattern of anti-GST A1-1 was investigated using rat liver and kidney sections. We compared clinicopathologic findings between anti-GST A1-1-positive and -negative autoimmune hepatitis patients. Anti-GST A1-1 was detected in 12 (16%) of 74 patients with autoimmune hepatitis, however, it was not detected in any control serum samples except for two patients with primary biliary cirrhosis. The immunofluorescence staining pattern of anti-GST A1-1 was found to be unique and different from those of anti-mitochondrial antibody or anti-liver-kidney microsome type 1 antibody. Anti-GST A1-1 coexisted with other autoantibodies such as anti-nuclear or anti-smooth muscle antibodies, but did not coexist with anti-soluble liver antigen/liver pancreas. Anti-GST A1-1-positive autoimmune hepatitis patients had severe clinical features and a poor prognosis compared with anti-GST A1-1-negative patients. These findings suggested that despite the low frequency, anti-GST A1-1 might be the marker of an early progression in autoimmune hepatitis.
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PMID:Frequency and significance of anti-glutathione S-transferase autoantibody (anti-GST A1-1) in autoimmune hepatitis. 1504 Oct 41

Cytochrome P-450 (CYPs) are involved in the metabolism of drugs, chemicals and endogenous substrates. The hepatic CYPs are also involved in the pathogenesis of several liver diseases. CYP-mediated activation of drugs to toxic metabolites induces hepatotoxicity. Well-known examples include acetaminophen and halothane. In some instances, covalent binding of the toxic metabolite to CYP leads to the formation of anti-CYP antibodies and immune-mediated hepatotoxicity (hydralazine, tienilic acid). Anti-CYP2D6 antibodies are also present in the serum of patients with type II autoimmune hepatitis, but the mechanism leading to their presence and their pathogenic significance remains unclear. Several studies support a role for CYP2E1 in the pathogenesis of alcoholic liver disease and non-alcoholic steatohepatitis. In these conditions, enhanced CYP2E1 activity is associated with lipid peroxidation and the production of reactive oxygen species with secondary damage to cellular membranes and mitochondria. Because of its ability to activate carcinogens, a role for CYP2E1 as a cofactor for hepatocellular carcinoma has also been postulated. On the other hand, drug metabolism is impaired in patients with liver disease, particularly that mediated by CYPs. The content and activity of CYP1A, 2C19 and 3A appear to be particularly vulnerable to the effect of liver disease while CYP2D6, 2C9 and 2E1 are less affected. The pattern of CYPs isoenzymes alterations also differs according to the etiology of liver disease. A strong relationship between the activity of CYPs and the severity of cirrhosis has been demonstrated, but the usefulness of measuring CYP activity to assess hepatic functional reserve remains uncertain.
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PMID:Cytochrome P450 and liver diseases. 1518 Apr 96


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