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)

Carbamazepine therapy is occasionally complicated by hypersensitivity reactions, the mechanism of which is poorly understood. It has been suggested that affected individuals may have a genetically-determined defect of microsomal epoxide hydrolase. The aim of this study was to determine whether a single genetic mutation or pattern of mutations could be used to predict individual susceptibility to carbamazepine-hypersensitivity. DNA was isolated from 10 carbamazepine-hypersensitive patients and 10 healthy volunteers. The patients had developed various forms of toxicity with carbamazepine, including toxic epidermal necrolysis, Stevens-Johnson syndrome, hepatitis and pneumonitis. The technique of polymerase chain reaction single-strand conformation polymorphism analysis (PCR-SSCP) was used to screen for mutations in all nine exons of the microsomal epoxide hydrolase gene. Any new mutations detected by this method were characterised by direct sequencing of the DNA. In addition, in the most severely affected patient, we sequenced all nine exons of the gene. There was a higher frequency of mutations in the hypersensitive group when compared with the controls, but there was no consistent mutation (or pattern of mutations) in the microsomal epoxide hydrolase gene which was common to the hypersensitive group. DNA sequencing of all nine exons of the microsomal epoxide hydrolase gene from the most severely affected patient showed the sequence to be "wild-type," when compared to the previously published sequences. The results of this study suggest that a single mutation within the coding region of the microsomal epoxide hydrolase gene cannot be the sole determinant of the predisposition to carbamazepine hypersensitivity.
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PMID:Genetic analysis of microsomal epoxide hydrolase in patients with carbamazepine hypersensitivity. 750 83

Germander, a plant used in folk medicine, caused an epidemic of cytolytic hepatitis in France. In about half of these patients, a rechallenge caused early recurrence, suggesting an immunoallergic type of hepatitis. Teucrin A (TA) was found responsible for the hepatotoxicity via metabolic activation by CYP3A. In this study, we describe the presence of anti-microsomal epoxide hydrolase (EH) autoantibodies in the sera of patients who drank germander teas for a long period of time. By Western blotting and immunocytochemistry, human microsomal EH was shown to be present in purified plasma membranes of both human hepatocytes and transformed spheroplasts and to be exposed on the cell surface where affinity-purified germander autoantibodies recognized it as their autoantigen. Immunoprecipitation of EH activity by germander-induced autoantibodies confirmed this finding. These autoantibodies were not immunoinhibitory. The plasma membrane-located EH was catalytically competent and may act as target for reactive metabolites from TA. To test this hypothesis CYP3A4 and EH were expressed with human cytochrome P450 reductase and cytochrome b(5) in a "humanized" yeast strain. In the absence of EH only one metabolite was formed. In the presence of EH, two additional metabolites were formed, and a time-dependent inactivation of EH was detected, suggesting that a reactive oxide derived from TA could alkylate the enzyme and trigger an immune response. Antibodies were found to recognize TA-alkylated EH. Recognition of EH present at the surface of human hepatocytes could suggest an (auto)antibody participation in an immune cell destruction.
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PMID:Human microsomal epoxide hydrolase is the target of germander-induced autoantibodies on the surface of human hepatocytes. 1095 47

Hepatocellular carcinoma (HCC) is a multifactorial disease with various host and environmental factors involved in its etiology. Of these, aflatoxin exposure has been established as an important risk factor in the development of HCC; the presence of aflatoxin-albumin (AA) adducts in the blood serves as a valuable biomarker of human exposure. In this study, the relationship between a variety of different HCC host factors and the incidence of AA adduct levels was examined in a Ghanaian population at high risk for HCC. These factors included age, gender, hepatitis virus B (HVB) and hepatitis C virus (HCV) status, and genetic polymorphisms in both microsomal epoxide hydrolase (mEH) and glutathione S-transferases (GSTs). Blood samples were analyzed for AA adducts and HBV and HCV status. GSTM1 and GSTT1 deletion polymorphisms and mEH exon 3 and exon 4 single-nucleotide polymorphisms (SNPs) were determined from urine samples. In univariate analysis, age, HBV and HVC status, and GSTT1 and mEH exon 3 genotypes were not associated with AA adduct levels. However, mean adduct levels were significantly higher in both females and individuals typed heterozygous for mEH exon 4 (vs. wild types). Stratification analysis also showed that gender along with mEH exon 4 genotype and HBV status had a significant effect on adduct levels. Both females typed HBsAg+ and males with mEH exon 4 heterozygote genotypes showed significantly higher adduct levels as compared to the HBsAg- and wild types, respectively. Understanding the relationships between these host factors and the variability in aflatoxin-adduct levels may help in identifying susceptible populations in developing countries and for targeting specific public health interventions for the prevention of aflatoxicoses in populations with HCC and chronic liver diseases.
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PMID:Determinants of the variability of aflatoxin-albumin adduct levels in Ghanaians. 1716 98

Autoimmune responses were observed in a large proportion of hepatitis C cases and are suspected to be part of viral pathogenesis. The AN6520 antigen (AN-Ag) is a normal cellular protein mainly expressed in liver that was found associated with non-A, non-B hepatitis. To elucidate its pathogenic role in hepatitis C, we developed an IgM capture assay using purified AN-Ag and confirmed that the antibody response to AN-Ag is associated almost exclusively with hepatitis C cases (29%). Screening of a human liver expression library revealed that AN-Ag is mainly the microsomal epoxide hydrolase (mEH), a drug-metabolizing enzyme that plays an important role in the metabolism of some mutagenic and carcinogenic epoxides. Using the purified recombinant human mEH as an antigen, we now found that antibodies against this protein are associated with nearly 82% of hepatitis C virus infections and surprisingly with 46% of patients with hepatitis A. The appearance of AN-Ag/mEH in the incubation period of hepatitis C as previously reported and the antibody responses shown here indicate that this enzyme may be a marker for or even a cause of some of the pathology associated with hepatitis C and A.
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PMID:Autoantibody response to microsomal epoxide hydrolase in hepatitis C and A. 1729 85

Hepatocellular carcinoma (HCC) is the fourth most common cancer worldwide, the main etiological factors being chronic infections with hepatitis B and C viruses. Genetic polymorphic forms of glutathione-S-transferase (GST) and microsomal epoxide hydrolase (mEPHX) have been associated with risk for various malignancies. The present study was undertaken to evaluate the association of GSTT1 and GSTM1 null genotypes and mEPHX polymorphisms with hepatitis virus-related HCC risk in an Indian population. Three groups of subjects were considered, control (n = 169), chronic viral hepatitis (n = 174), and HCC (n = 63). Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used for this polymorphic study. Genotype distributions between categories were compared using the chi2 test; odds ratios (ORs) and 95% confidence interval were calculated to express the relative risk. GSTT1 null genotype was associated with 2.23-fold (p < 0.05) increased risk for HCC development as compared to the control group. However, GSTM1 null genotype was found to have a protective effect when hepatitis patients were considered. In case of mEPHX, R139R imposed a risk factor for HCC with both control (OR = 1.81) and chronic hepatitis-infected (OR = 2.06) subjects. Combination of heterozygous mutant genotypes at mEPHX exons 3 and 4 revealed a twofold risk (nonsignificant) for HCC. Further, combination of GSTM1 and T1 genotypes with either of exon 3 or 4 polymorphism of mEPHX displayed synergistic associations (risk or protective) for HCC development. GST and mEPHX variants share a positive association with viral-related HCC risk in Indian population, although a larger sample size is still required to confirm the results.
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PMID:Glutathione-S-transferase and microsomal epoxide hydrolase polymorphism and viral-related hepatocellular carcinoma risk in India. 1881 71

Hepatocellular carcinoma (HCC) is a life-threatening disease that is often associated with chronic infection by hepatitis B and C viruses. Genetic polymorphisms have been reported to alter the risk for HCC development. Genetic studies based on the haplotype have an increased power for detecting disease associations compared with single-nucleotide polymorphism-based analysis. There is sufficient epidemiological evidence suggesting a link between genetic polymorphism and haplotypes of microsomal epoxide hydrolase (mEPHX) and X-ray cross-complementing group 1 (XRCC1) with altered cancer risk. However, no report correlates the risk of HCC development with mEPHX and XRCC1 haplotypes. Genetic polymorphism of these genes was studied for haplotype construction in 169 control subjects, 174 hepatitis patients, and 63 HCC patients. 113Tyr-139Arg and 113His-139His haplotypes of mEPHX significantly elevated the risk for HCC by 1.4- and 1.5-folds, respectively. Arg-His-Arg haplotype of XRCC1 significantly enhanced the risk for hepatitis by 2.8-folds (p = 0.001), but not for HCC (odds ratio = 1.5; p = 0.28). mEPHX haplotypes shared a positive association with HCC risk in India.
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PMID:Haplotypes of microsomal epoxide hydrolase and x-ray cross-complementing group 1 genes in Indian hepatocellular carcinoma patients. 1975 50