Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rat microsomal epoxide hydrolase (mEH) is one of the detoxification enzymes and selectively expressed in liver. A 350-bp DNA fragment of the proximal promoter was found to contain information sufficient to express the mEH gene in hepatoma cells, however not in nonhepatoma cells. We identified two cis-acting elements, epoxide hydrolase proximal element 1 (EHP1) and 2 (EHP2), in this promoter region by using transient transfection assays. Each element is a new cell-type-specific transcriptional up-regulator. The cell-type-specific activity of EHP1 correlates to the limited cell distribution of its cognate transacting factor(s). In the case of EHP2, a similar or possibly the same cognate factor(s) binding to EHP2 was detected by DNase I footprinting and gel retardation assays in both hepatoma and nonhepatoma cells. However, EHP2 functions as an up-regulator only in hepatoma cells. Our finding adds repertoire to a battery of cis-regulatory elements that are required for liver-specific transcription.
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PMID:Hepatic transcriptional up-regulator of the rat microsomal epoxide hydrolase gene. 828 38

1. Epoxide hydrolases form an enzyme family involved in the metabolism of a variety of xenobiotics including cytostatic drugs and carcinogens. Whether human microsomal epoxide hydrolase--one of the main members of the epoxide hydrolase family--is expressed in neoplasia of the liver has been the subject of a controversial discussion. 2. We therefore developed a quantitative immunohistochemical assay and monitored epoxide hydrolase expression in hepatocellular carcinomas (HCC, n = 20), cholangio-cellular carcinomas (CCC, n = 2) and liver metastases (n = 57) of tumours of various origins, and compared the expression intensities and patterns to normal liver tissue. 3. In normal liver tissue microsomal epoxide hydrolase displays expression of the constitutive type with non-zonal staining of all hepatocytes. 4. When using a quantitative immunohistochemical approach statistically significant differences in microsomal epoxide hydrolase expression were observed between normal tissue, hepatocellular carcinoma and liver metastases (mean optical density 2.35, 1.63 and 0.21 respectively, p = 2.9, 6.3 and 18.9). These data indicate differential expression in different types of liver neoplasm. 5. As microsomal epoxide hydrolase is involved in metabolism of different xenobiotics our findings may have implications for tumour progression.
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PMID:Immunohistochemical assessment of human microsomal epoxide hydrolase in primary and secondary liver neoplasm: a quantitative approach. 885 25

Microsomal epoxide hydrolase (EPHX) is one of many enzymes involved in the metabolism of endogenous and exogenous toxicants. Polymorphic forms of the human EPHX gene have been described that vary in enzymatic activity, and one, Tyr113His, has been associated with hepatocellular carcinoma susceptibility. We demonstrated that EPHX was highly expressed in the human ovary, and investigated whether specific EPHX genotypes are associated with ovarian cancer susceptibility. Seventy-three Caucasian patients with ovarian cancer and 75 Caucasian-female controls without cancer were genotyped for the Tyr113His polymorphism by a polymerase chain reaction-restriction fragment length polymorphism assay. The frequency of the homozygous high-activity genotype was 41% in the control population and 64% in the ovarian cancer patients. The odds ratio for ovarian cancer with this genotype was 2.6 (95% confidence interval 1.3, 5.0; P < 0.01). The increased ovarian cancer risk associated with the high-activity genotype could reflect differences in metabolic activation of endogenous or exogenous carcinogens.
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PMID:Microsomal epoxide hydrolase polymorphism as a risk factor for ovarian cancer. 894 76

Exposure to aflatoxins is a risk factor for hepatocellular carcinoma (HCC). Aflatoxins occur in peanut butter and are metabolized by genetically polymorphic enzymes such as glutathione-S-transferases encoded by glutathione-S-transferase mu 1 gene (GSTM1) and glutathione-S-transferase theta 1 gene (GSTT1) and microsomal epoxide hydrolase encoded by epoxide hydrolase gene (EPHX). The rate at which aflatoxins become activated or detoxified may depend on polymorphisms in the encoding genes. GSTM1 homozygous deletion was indeed found to modify the association between peanut butter consumption and HCC. In this study, we investigate possible roles of GSTT1 and EPHX polymorphisms in this relationship. From a Sudanese case-control study on HCC, we analyzed data of 112 incident cases and 194 controls. All participants were interviewed using a standardized questionnaire inquiring about social and demographic factors, peanut butter consumption, and other known HCC risk factors. Univariate analysis showed that GSTT1 polymorphism was not associated with HCC, whereas EPHX 113HH and 139HH genotypes increased the risk of HCC (Odds ratio, 3.10; 95% Confidence interval, 1.18-8.12). Adjustment for age and region of origin slightly attenuated this association (Odds ratio, 2.56; 95% Confidence interval, 0.83-7.95). Interestingly, unlike GSTM1, both GSTT1 and EPHX polymorphism did not modify the association between peanut butter consumption and HCC. In conclusion, these epidemiological findings do not suggest significant roles of GSTT1 and EPHX in aflatoxin metabolism, although EPHX polymorphism is possibly related to the increased risk of HCC. Further studies are needed to investigate mechanisms by which the EPHX polymorphism potentially modifies cancer risk.
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PMID:Role of genetic polymorphism of glutathione-S-transferase T1 and microsomal epoxide hydrolase in aflatoxin-associated hepatocellular carcinoma. 1144 Sep 64

Microsomal epoxide hydrolase is a biotransformation enzyme which is involved in the hydrolysis of various epoxides and epoxide intermediates. In the present study, its distribution was investigated in both normal human tissues and human tumours of different histogenetic origin using immunohistochemical techniques. In normal tissue, epithelial cells were more often and more intensely immunostained than mesenchymal cells. The main epithelial cell types expressing microsomal epoxide hydrolase were hepatocytes, acinus cells of the pancreas, and cells of salivary and adrenal glands. Immunostained cells of mesenchymal origin included monocytes, fibrocytes, fibroblasts, vessel endothelium, muscle cells, and cells of the reproductive system. Three patterns of expression were observed in tumour tissues: (1) moderate or strong in hepatocellular carcinomas, tumours of the adrenal gland, and theca-fibromas of the ovary; (2) inhomogeneous staining pattern of variable intensity in breast cancer, lung cancer, colorectal carcinomas, carcinoid tumours, and some tumours of mesenchymal origin; and (3) no expression in malignant melanomas, malignant lymphomas, and renal carcinomas. These data indicate that microsomal epoxide hydrolase expression is not restricted to tissue of any particular histogenetic origin. Nonetheless, immunohistochemical identification of microsomal epoxide hydrolase may be helpful in some well-defined histological settings, for example, confirmation of hepatocellular carcinoma.
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PMID:Distribution of microsomal epoxide hydrolase in humans: an immunohistochemical study in normal tissues, and benign and malignant tumours. 1175 9

Factors influencing the progression of liver disease and the development of hepatocellular carcinoma (HCC) in chronic hepatitis C virus (HCV) infection are poorly understood. Inherited variations of drug-metabolizing enzyme (DME) activities may affect liver damage and cancer risk by modifying individual susceptibility to endogenous or exogenous toxic compounds. We investigated the association of liver disease severity with common alleles of microsomal epoxide hydrolase (mEH), an enzyme involved in the metabolism of highly reactive epoxide intermediates. Three polymorphisms (Tyr113His, His139Arg, and -613C/T) were analyzed by polymerase chain reaction (PCR) restriction fragment length polymorphisms (RFLPs) in 394 patients at different stages of disease, including 92 asymptomatic carriers, 109 patients with chronic hepatitis, 100 patients with cirrhosis, and 93 patients with HCC. Reference allele frequencies were obtained from 99 healthy blood donors. Allele distributions between categories were compared using the chi(2) test; odds ratios (ORs) and 95% CI were calculated to express relative risks. Allele frequencies among 99 healthy controls were as follows: 15.1% for 113His/His, 4.0% for 139Arg/Arg, and 46.5% for -613C/T. mEH 113His/His homozygotes were overrepresented in advanced stages of disease, in particular among HCC patients (27.9%; P =.03; OR, 2.2; 95% CI, 1.0-4.6). Differences were more pronounced among men and between extreme patient categories. When mEH genotypes were combined to express a metabolic phenotype, very slow metabolizers were highly prevalent among cirrhotic and HCC patients (18% vs. 3.3% in carriers; P <.001). In conclusion, mEH gene polymorphisms were significantly associated with HCV-related liver disease severity and HCC risk. Men were at higher risk than women; this might be explained by hormonal regulation of gene expression or by differential exposure to environmental toxins.
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PMID:Polymorphisms of microsomal epoxide hydrolase gene and severity of HCV-related liver disease. 1208 65

Dihydrodiol dehydrogenase (DDH) is one of the major enzymes catabolizing polycyclic aromatic hydrocarbons in the liver. Although four DDH isoforms have been detected in the normal liver, only DDH1 and DDH2 have been detected in cancer cells of lung and esophagus. Moreover, the available information about hepatic pathophysiological regulation of DDH expression is limited. Therefore we addressed the question of DDH expression in patients with liver disorders, in particular, patients with hepatocellular carcinoma (HCC). Expression of DDH1/2 was determined by immunohistochemistry, immunoblotting and reverse transcription-polymerase chain reaction (RT-PCR) in 52 patients with resected HCC. DDH1/2 expression was detected in 31 (59.6%) of 52 pathological sections. Frequency of DDH1/2 expression was significantly higher in patients with tumor size >2 cm, and in those who had early local recurrence. In addition to the tumor size and frequency of local recurrence, our results further indicated that expression of DDH1/2 was correlated with those of cyclooxygenase 2 (COX-2), interleukin-6 (IL-6), microsomal epoxide hydrolase (mEpH) and soluble epoxide hydrolase (sEpH) in HCC patients. Interestingly, the expression of DDH1/2 was found inversely correlated with that of glutathione S-transferase (GST) and NADPH p450 reductase (NPR). In conclusion, these results indicate that DDH expression was significantly decreased in about 40% of HCC patients. However, in the bordering non-neoplastic region of liver DDH1/2 expression increased, and the increased DDH1/2 expression correlated with tumor size and the disease progression.
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PMID:Reduction of dihydrodiol dehydrogenase expression in resected hepatocellular carcinoma. 1257 57

The bifunctional hepatic protein, microsomal epoxide hydrolase (mEH), plays a central role in the metabolism of many xenobiotics as well as mediating the Na(+)-dependent uptake of bile acids in parallel with the Na(+)-taurocholate co-transporting protein (ntcp). Previous studies have established that mEH is expressed in the endoplasmic reticulum with two topological orientations, where the type II form is targeted to the plasma membrane. In this report the topology and transport properties of mEH as a function of plasma membrane expression in cultured hepatocytes, transfected Madin-Darby canine kidney cells expressing mEH (MDCK[mEH]), and the human hepatoma cell line, HepG2, were studied using confocal fluorescence microscopy and substrate uptake measurements. Analysis of mEH localization with an anti-mEH monoclonal antibody demonstrated the expression of one topological form on the plasma membrane of hepatocytes and MDCK[mEH] cells where both systems exhibited Na(+)-dependent bile acid uptake. In contrast, Na(+)-dependent bile acid transport in HepG2 cells and hepatocytes in culture (72 h) was substantially reduced as was the expression of ntcp. Although the total mEH level was undiminished, the decrease of bile acid transport was associated with the loss of mEH surface expression possibly resulting from an alteration in mEH endoplasmic reticulum topology and/or the plasma membrane protein targeting system in these de-differentiated cells.
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PMID:Cell surface expression and bile acid transport function of one topological form of m-epoxide hydrolase. 1367 44

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

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


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