Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019163 (hepatitis B)
 38,309 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Ah receptor regulates induction of cytochrome P450IA1 and mediates certain toxicities of polyhalogenated aromatics such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). It has been characterized previously in continuous cell lines, notably the mouse hepatoma line Hepa 1, the human squamous cell carcinoma line A431, and the human liver cell line Hep G2. The present work extends our knowledge of the Ah receptor in continuous human liver cell lines. Ah receptor can be detected in Mz-Hep-1, a hepatitis B virus-negative cell line derived from a Thorotrast-induced hepatocellular carcinoma. The mean concentration of Ah receptor in Mz-Hep-1 cells was 341 +/- 22 fmol/mg cytosol protein (mean +/- SEM, nine separate determinations). This is equivalent to approximately 30,000 sites per cell. The concentration of Ah receptor in Mz-Hep-1 cells is similar to that in Hepa 1 cells and approximately three times higher than that in Hep G2 cells. The Mz-Hep-1 Ah receptor sedimented in continuous sucrose gradients at approximately 9 S. Specificity of binding by [3H]TCDD was demonstrated by competitive binding of non-radiolabeled 2,3,7,8-tetrachlorodibenzofuran, 3-methylcholanthrene (MC), and dibenz[a,h]anthracene in 50-fold molar excess. Phenobarbital, which is not a substrate for P450IA1, did not compete with [3H]TCDD for binding to Mz-Hep-1 Ah receptor. Dexamethasone and estradiol also did not compete with [3H]TCDD for binding, suggesting non-identity of Ah receptor with glucocorticoid or estrogen receptor. In separate experiments, glucocorticoid receptor was identified in Mz-Hep-1 cells. By Scatchard plot analysis, the apparent equilibrium dissociation constant (Kd) for binding of [3H]TCDD to Mz-Hep-1 Ah receptor was estimated to be 4.4 nM, compared to 0.8 nM in Hepa 1 cells. By Woolf plot analysis the Kd was 5.4 nM, compared to 1.2 nM in Hepa 1 cells. The [3H]TCDD.Ah receptor complex extracted from nuclei of Mz-Hep-1 cells incubated with [3H]TCDD in culture at 37 degrees sedimented at approximately 6 S under conditions of high ionic strength. Aryl hydrocarbon hydroxylase (AHH) activity was detectable in Mz-Hep-1 cells after pretreatment with inducing chemicals. Mz-Hep-1 cells have the highest concentrations of Ah receptor in any continuous human liver cell line thus far investigated. The Mz-Hep-1 Ah receptor is similar physicochemically to that described in murine systems. AHH activity is inducible in Mz-Hep-1 cells.
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PMID:Ah receptor mediating induction of cytochrome P450IA1 in a novel continuous human liver cell line (Mz-Hep-1). Detection by binding with [3H]2,3,7,8-tetrachlorodibenzo-p-dioxin and relationship to the activity of aryl hydrocarbon hydroxylase. 165 Feb 14

The relative roles of hepatitis B virus (HBV) and aflatoxin and their possible mechanism of interaction in the etiopathogenesis of hepatocellular carcinoma (HCC) are not understood. One hypothesis is that viral infection and associated liver injury alter expression of carcinogen-metabolizing enzymes. We tested this hypothesis in an HBV-transgenic mouse model in which a synergistic interaction occurs between aflatoxin B1 (AFB1) and HBV in the induction of HCC (Sell et al., Cancer Res 51:1278-1285, 1991). In this transgenic mouse lineage, overproduction of the HBV large envelope protein results in progressive liver cell injury, inflammation, and regenerative hyperplasia. Initially, two cytochrome P450s of importance in AFB1 metabolism in the mice were identified, namely Cyp2a-5 and Cyp3a, using specific antibodies and chemical inhibitors. The expression of these P450 isoenzymes and an alpha-class glutathione S-transferase (GST) isoenzyme, YaYa, were examined. Increased expression and altered distribution of Cyp2a-5 were demonstrated, by immunohistochemical analysis, to be associated with the development of liver injury in mice and to increase with age between 1 and 12 months. Cyp3a expression was also increased in HBV-transgenic mice, but the increase was not as clearly related to age. GST YaYa levels were the same in HBV-transgenic mice and their nontransgenic littermates of all ages. These results show that expression of specific cytochrome P450s is altered in association with overexpression of HBV large envelope protein and liver injury in this model. This may have general relevance to human HCC, the etiology of which is associated with a diverse range of liver-damaging agents.
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PMID:Induction of specific cytochrome P450s involved in aflatoxin B1 metabolism in hepatitis B virus transgenic mice. 791 95

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 association of hepatitis B virus (HBV) infection with human hepatoma is well established. However, no consensus regarding the etiology of hepatocellular carcinoma was elucidated. In this paper, the genomic stability and gene expression of HBV DNA-integrated and non-integrated hepatoma cells by Transcript Profile (TP)-PCR and RT-PCR are characterized. The additional DNA bands generated from TP-PCR of HBV integrated genomes were not correlated with the sequence of HBV, suggesting that the variations may result from genomic instability of the host cells. Moreover, differential genes expressed in HBV DNA-integrated cells were sequenced. A cDNA generated from the integrated cells exhibited 99.3% homology with the sequences of ATP synthase 6 and cytochrome C oxidase III, but the sequences were abnormally linked together. Since HBV infection may alter the energy metabolism of the cell, the results suggest that the integration may cause mitochondriae defects in the ATP synthase 6 and cytochrome C oxidase III genes.
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PMID:Variations in gene expression and genomic stability of human hepatoma cells integrated with hepatitis B virus DNA. 962 67

A great number of epidemiological data have identified chronic alcohol consumption as a significant risk factor for upper alimentary tract cancer, including cancer of the oropharynx, larynx, and the esophagus, and for the liver. In contrast to those organs, the risk by which alcohol consumption increases cancer in the large intestine and in the breast is much smaller. However, although the risk is lower, carcinogenesis can be enhanced with relatively low daily doses of ethanol. Considering the high prevalence of these tumors, even a small increase in cancer risk is of great importance, especially in those individuals who exhibit a higher risk for other reasons. The epidemiological data on alcohol and other organ cancers are controversial and there is at present not enough evidence for a significant association. Although the exact mechanisms by which chronic alcohol ingestion stimulates carcinogenesis are not known, experimental studies in animals support the concept that ethanol is not a carcinogen, but under certain experimental conditions is a cocarcinogen and/or (especially in the liver) a tumor promoter. The metabolism of ethanol leads to the generation of acetaldehyde and free radicals. These highly reactive compounds bind rapidly to cell constituents and possibly to DNA. Acetaldehyde decreases DNA repair mechanisms and the methylation of cytosine in DNA. It also traps glutathione, an important peptide in detoxification. Furthermore, it leads to chromosomal aberrations and seems to be associated with tissue damage and secondary compensatory hyperregeneration. More recently, the finding of considerable production of acetaldehyde by gastrointestinal bacteria was reported. Other mechanisms by which alcohol stimulates carcinogenesis include the induction of cytochrome P4502E1, associated with an enhanced activation of various procarcinogens present in alcoholic beverages, in association with tobacco smoke and in diets, a change in the metabolism and distribution of carcinogens, alterations in cell cycle behavior such as cell cycle duration leading to hyperregeneration, nutritional deficiencies such as methyl, vitamin A, folate, pyrridoxalphosphate, zinc and selenium deficiency, and alterations of the immune system, eventually resulting in an increased susceptibility to certain viral infections such as hepatitis B virus and hepatitis C virus. In addition, local mechanisms in the upper gastrointestinal tract and in the rectum may be of particular importance. Such mechanisms lead to tissue injury such as cirrhosis of the liver, a major prerequisite for hepatocellular carcinoma. Thus, all these mechanisms, functioning in concert, actively modulate carcinogenesis, leading to its stimulation.
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PMID:Alcohol and cancer. 975 43

Hepatitis B virus (HBV) and aflatoxins are major risk factors for hepatocellular carcinoma (HCC) exhibiting a synergistic interaction in the development of this disease. The molecular mechanisms of this interaction remain to be elucidated but an altered carcinogen metabolism in the presence of hepatitis-induced liver injury is one hypothesis. The availability of biomarkers of aflatoxin exposure and metabolism permits this hypothesis to be examined in human populations whilst animal models, such as HBV transgenic mice permit parallel studies in an experimental setting. The hepatitis B virus X protein (HBx) is suspected to play a role in the hepatocarcinogenic process by virtue of its capacity to transactivate oncogenes and several other cellular genes via cis-acting elements. In previous studies in HBV transgenic mice expressing the HB surface antigen and X genes we observed a marked induction of specific cytochrome P450s (CYP) (Kirby et al., 1994a). In the current study we investigated the status of CYP, glutathione S-transferases (GST) and antioxidant enzymes in mice carrying only the X gene under the control of the alpha-1 antitrypsin regulatory elements (ATX mice). Livers of ATX mice showed no major pathological alterations compared to age-matched non-transgenic control mice. Immunohistochemical staining for CYP1A, 2A5 and GST expression and determination of related enzymatic activities (7-ethoxyresorufin O-deethylation, 7-methoxyresorufin O-deethylation, coumarin 7-hydroxylation and GST activities) revealed no differences between control and ATX mice. In addition, no differences in antioxidant enzymes were observed. Overall, these results support the conclusion that HBx expression alone is insufficient to induce transactivation of CYP and GST genes or to alter the antioxidant system and that the induction in other HBV models is a result of inflammatory injury in the liver, a feature absent in ATX mice. These data are compared to biomarker studies of enzyme activities in aflatoxin-exposed human populations with and without HBV infection.
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PMID:Hepatitis B virus-induced liver injury and altered expression of carcinogen metabolising enzymes: the role of the HBx protein. 1002 19

As a mitochondrial membrane death ligand, Bid oligomerises Bak to release cytochrome C and its deficiency renders hepatocytes resistant to apoptosis induced by Fas. The Bid level in hepatocellular carcinoma (HCC) is unknown. In this report, we examined the expression of Bid protein and mRNA in HCC cancerous tissues and their corresponding non-cancerous ones. The effect of the hepatitis B x protein (HBx) on the expression of Bid was also evaluated by transfecting hepatoma cells with the HBx gene. The results showed that the expression of Bid was significantly lower in cancerous tissues than that in their corresponding non-cancerous tissues. Immunohistochemical study revealed that Bid molecule was mainly localised in hepato-cytoplasm. Some nuclei were also positive for Bid antigen though to a lesser degree. In vitro experiments demonstrated that the expression of Bid in cells transfected with HBx was significantly lower than that in the cells without HBx transfection. This finding suggests that HBx may play a causative role in the reduction of Bid expression in HCC. This in vitro result is, to some degree, supported by clinical data that all the HCC examined are positive for hepatitis B virus (HBV). We conclude from this data that the expression of Bid in HCC is significantly decreased and the reduction of Bid may result from a mechanism associated with HBx, a major hepatocarcinogenic product from HBV. The imbalance of increased anti-apoptosis and decreased pro-apoptosis seen in HCC is a critical mechanism leading to the uncontrolled growth of tumour cells. Therefore, this study suggests that a deficiency in the expression of Bid may contribute to the development of such an imbalance in HCC.
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PMID:Decreased expression of Bid in human hepatocellular carcinoma is related to hepatitis B virus X protein. 1152 98

A case-control study was carried out to investigate the impact of factors including virus infection, aflatoxin B1, microcystins, smoking/drinking and dietary habits as well as genetic polymorphisms of aldehyde dehydrogenase 2 (ALDH2) and cytochrome P4502E1 (CYP2E1), on susceptibility to hepatocellular carcinoma (HCC) in Haimen, China. A total of 248 patients with HCC and 248 sex-, age- and residence-matched population-based controls were recruited into the study. Virus infection, and ALDH2 and CYP2E1 gene polymorphisms were assessed in 134 paired cases and controls. By univariate analysis, hepatitis B virus (HBV) infection (odds ratio [OR]=9.75; 95% confidence interval [CI]=4.71-20.2), history of intravenous injection (OR=1.50; 95%CI=1.02-2.22), average income (OR=0.63; 95%CI=0.43-0.92), frequent intake of foods rich in protein, e.g., egg (OR=0.6; 95%CI=0.42-0.87), chicken (OR=0.53; 95%CI=0.35-0.79), pork (OR=0.67; 95%CI=0.46-0.98) and fresh fish (OR=0.58; 95%CI=0.39-0.87) significantly differed between cases and controls. However, peanut intake (OR=0.66; 95%CI=0.43-1.01), source of drinking water, including tap (OR=1.33; 95%CI=0.81-2.20), deep well (OR=0.94; 95%CI=0.56-1.55), shallow well (OR=0.85; 95%CI=0.55=1.30), river (OR=0.95; 95%CI=0.65-1.38), ditch (OR=1.09; 95%CI=0.76-1.55) and pond water (OR=1.0; 95%CI=0.14-7.10) were not significantly associated with risk. Univariate analysis also indicated that the 1-1 genotype of ALDH2 (OR=1.38; 95%CI=0.86-2.23) as well as the Pst1- and Rsa1-digested c1/c1 genotype of CYP2E1 (OR=1.36; 95%CI=0.81-2.28), was slightly more frequent in the case group. On multivariate analysis, HBV infection (OR=13.9; 95%CI=5.78-33.6) and history of intravenous injection (OR=2.72; 95%CI=1.24-6.00) were still associated with significantly increased risk of HCC, while frequent intake of fresh fish (OR=0.32; 95%CI=0.12-0.86) decreased this risk. These findings suggest that whereas peanut intake, water sources as well as genetic polymorphisms in ALDH2 and CYP2E1 do not significantly correlate with the risk of HCC, HBV infection is a main risk factor, and dietary items rich in protein, especially fresh fish, might protect against the risk of HCC in Haimen, China.
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PMID:Hepatitis B and C viruses infection, lifestyle and genetic polymorphisms as risk factors for hepatocellular carcinoma in Haimen, China. 1249 67

Patients with human immunodeficiency virus (HIV) most often have hepatitis C virus (HCV) or hepatitis B (HBV) virus coinfection, or both, as a cause of their liver disease. Recent survival statistics show that patients infected with HIV treated with highly active antiretroviral therapy (HAART) can expect a significant prolongation of life by interfering with the natural progression of HIV to acquired immune deficiency syndrome (AIDS). Therefore, HIV-positive patients experiencing complications of liver failure are at greater immediate risk of dying from their end-stage liver disease (ESLD) rather than their HIV. Many transplant centers still consider HIV infection as a contraindication for orthotopic liver transplantation (OLT). At our two institutions, we believe that patients with HIV suffering from ESLD should be considered for OLT. This study evaluates the survival of patients undergoing OLT with HIV under HAART therapy. OLT was performed in 16 patients with HIV suffering from ESLD as a result of chronic HCV, chronic HBV, or fulminant hepatic failure (FHF). Collected data include patient demographics, patient and graft survival, pre-OLT assessments, and postoperative complications (including opportunistic infections). Ten patients at Pittsburgh and 6 patients at Miami received OLT. Of the 16 patients who received OLT, 14 remain alive to date. Thirteen of 16 patients are more than 12 months post-OLT, whereas the last patient is currently 6 months post-OLT. Five patients at Miami and 9 of 10 patients at Pittsburgh received HAART therapy before OLT, although 2 of the Pittsburgh patients had their HAART therapy discontinued before OLT because of significant liver dysfunction. The pre-OLT viral loads were undetectable in 13 of 16 patients. The cluster determinant (CD)4 count was less than 200 in 6 patients and greater than 100 in 2 patients before OLT. In all patients, CD4 counts increased above 200 in the post-OLT period. Tacrolimus toxicity associated with the pharmacologic inhibition of cytochrome p450 metabolism caused by protease inhibitors occurred in 6 patients after OLT. Six patients (38%) experienced acute cellular rejection immediately after OLT. Our experience suggests that OLT is effective in selected HIV-positive patients suffering from ESLD. Patient and graft survival was similar to non-HIV-positive patients suffering from the same indications for OLT. Acute cellular rejection was no less frequent that seen in non-HIV-positive patients. Given the complex pharmacologic interactions between the protease inhibitors and tacrolimus, careful monitoring, and attention is required to prevent toxicity or underdosing.
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PMID:Orthotopic liver transplantation in patients with human immunodeficiency virus and end-stage liver disease. 1261 20

A population-based case-control study was carried out to investigate risk factors for hepatocellular carcinoma (HCC) in Nagoya, Japan, including hepatitis virus infections, drinking and smoking habits and genetic polymorphisms in aldehyde dehydrogenase2 (ALDH2) and cytochrome P4502E1 (CYP2E1). A total of 84 patients with HCC and 84 sex, age and residence pair-matched controls were recruited for this study. By univariate analysis, hepatitis B virus (HBV) (OR=5.14; 95%CI=2.29-11.6) and hepatitis C virus (HCV)(OR=32.00; 95%CI=7.83-130.7) infections, having a history of blood transfusion (OR=5.25; 95%CI=1.80-15.29), and habitual smoking (OR=2.36; 95%CI=1.17-4.78) were significantly linked to cases; by multivariate analysis, HCV infection (OR=23.5; 95%CI=5.07-108.9) and habitual smoking (OR=5.41; 95%CI=1.10-26.70) were still associated with a significantly increased risk. The c1/c1 genotype of CYP2E1 (odds ratio [OR]= 0.45; 95% confidence interval [CI]=0.21-0.99), detected by Pstl and Rsal digestion was significantly more prevalent in the control group, while 1-1 genotype of ALDH2 (OR=1.24; 95%CI=0.70-2.20) did not demonstrate variation. There were no statistically significant interactions between habitual smoking/drinking and genetic polymorphisms of ALDH2/P4502E1 with reference to HCC development. These findings suggest that viruses, especially HCV infection, and habitual smoking are major independent risk factors, while genetic polymorphisms of ALDH2 and CYP2E1 have only limited contribution to the risk of HCC in Nagoya, Japan.
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PMID:HBV/HCV Infection, Alcohol, Tobacco and Genetic Polymorphisms for Hepatocellular Carcinoma in Nagoya, Japan. 1271 71


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