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)

Tea polyphenols have been demonstrated as chemopreventive agents in a number of experimental models. However, less is known about the mechanism of chemoprevention by black tea compared with that of green tea. Some beneficial properties of theaflavins, the black tea polyphenols, were investigated in the present study. Theaflavins showed inhibitory effects on H(2)O(2)- and tert-butyl hydroperoxide (tBuOOH)-induced cytotoxicity (evaluated by tetrazolium bromide reduction), cellular oxidative stress (detected by oxidation of 2', 7'-dichlorofluorescin), and DNA damage (measured by amount of 8-OHdG and comet assay) in rat normal liver epithelium cell RL-34 cell lines. In addition, theaflavins also exhibited suppression of cytochrome P450 1A1 induced by omeprazole in the human hepatoma HepG2 cell line. Furthermore, when HepG2 cells were pretreated with omeprazole to induce CYP1A1, then exposed to benzo[a]pyrene (B[a]P), DNA damage was observed using the comet assay. However, theaflavins could inhibit this DNA damage. These results indicated that theaflavins could prevent cellular DNA damage by inhibiting oxidative stress and suppressing cytochrome P450 1A1 in cell cultures.
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PMID:Black tea polyphenols, theaflavins, prevent cellular DNA damage by inhibiting oxidative stress and suppressing cytochrome P450 1A1 in cell cultures. 1175 70

To elucidate role of the three enzymes in hepatocarcinogenesis, hMTH1, hOGG1 and hMYH, mRNA expression were examined by using RT/semi-quantitative real-time PCR and 8-O-HdG levels was studied by HPLC/ECD in HCC and non-tumorous liver tissue of 21 patients with hepatocellular carcinoma (HCC). It was found that the 8-OHdG level in non-tumourous liver tissue was significantly higher than in HCC tissue (P = 0.006), and this was correlated with the degree of inflammation. The hMTH1 expression in HCC tissue was significantly higher than in non-tumorous liver tissue (P = 0.014). Inversely, The hMYH alpha expression was significantly increased (P = 0.039) in non-tumorous liver tissue. No difference was seen in hOGG1 expression in non-tumorous liver and HCC tissue. A significant linear correlation between hMTH1 and hOGG1 expression was found both in HCC tissue (r = 0.809, P < 0.001) and in non-tumorous liver tissue (r = 0.883, P < 0.001). Our findings suggested a reactive rather than pathogenic role of the DNA repair enzymes in the hepatocarcinogenesis.
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PMID:[Potential role of human DNA-repair enzymes hMTH1, hOGG1 and hMYHalpha in the hepatocarcinogenesis]. 1463 41

Hepatocellular carcinoma (HCC) frequently develops in patients with chronic viral hepatitis and cirrhosis. In these chronic liver disorders, an increased production of reactive oxygen species (ROS) causing oxidative DNA damage has been reported. In this study, we immunohistologically (LSAB method) demonstrated the presence of 8-hydroxy-2'-deoxyguanosine (8-OHdG) that was generated when oxidative DNA damage was caused by active oxygen species in noncancerous region obtained at hepatectomy for HCC, and investigated the relationship between 8-OHdG and remnant liver recurrence. We found that the 8-OHdG labeling index (LI) for noncancerous region at the time of hepatectomy was significantly higher in recurrent (31.1+/-10.2%) than in nonrecurrent (20.6+/-8.0%) patients (P<0.01). The high 8-OHdG LI (>/=30%) group showed a significantly higher recurrence rate, compared with the low LI (<30%) group (P<0.01). The cancer-free survival curves also showed that the high 8-OHdG LI (>/=30%) group had a significantly poorer prognosis because of remnant liver recurrence than the low 8-OHdG LI (<30%) group (P<0.05). The 8-OHdG LI showed a significant correlation with the histopathologic evaluation of noncancerous region based on the New Inuyama Classification: a higher pathologic Staging and a higher pathologic Grading were associated with a higher 8-OhdG LI. Analysis by Grading and Staging showed that the high 8-OHdG LI group (>/=30%) of Grade A2, Stage F3, or Stage F4 had a significantly higher recurrence rate compared with the low 8-OHdG LI group (<30%) of Grade A2, Stage F3, or Stage F4, respectively. In addition, using multivariate analysis, we compared the influence on recurrence of the histological features that, at the time of hepatectomy, showed significant differences in the rate of remnant liver recurrence, that is, the number of tumors and the presence or absence of portal involvement, and three variables of the Grading, Staging, and 8-OHdG LI of noncancerous regions. The results suggested that 8-OHdG LI (P=0.02) and portal involvement (P=0.04), in this order, were useful as independent prognostic factors for recurrence. From this, we consider that, if patients with high 8-OHdG LI (>/=30%) in noncancerous region at the time of hepatectomy are regarded as being at high risk for remnant liver recurrence (heterochronous multicentric carcinogenesis) and are given careful follow-up treatment with preventive therapy for remnant liver recurrence, the prognosis will be improved.
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PMID:Immunohistochemical study of the relationship between 8-hydroxy-2'-deoxyguanosine levels in noncancerous region and postoperative recurrence of hepatocellular carcinoma in remnant liver. 1269 54

Reactive oxygen species may be involved in the progression of chronic liver disease and the occurrence of hepatocellular carcinoma (HCC). To clarify whether clinicopathological findings in liver diseases are related to oxidative DNA damage, hepatic expression of the 8-hydroxy-2'-deoxyguanosine (8-OHdG) was examined in 75 liver disease patients, which included 32 chronic hepatitis (CH), 13 liver cirrhosis (LC) and 30 HCC patients. The CH patients had higher 8-OHdG-positive hepatocytes than LC (P < 0.05). In CH and LC, the number of 8-OHdG-positive hepatocytes was correlated with alanine aminotransferase and asparate aminotransferase (P < 0.01 and P < 0.05, respectively). Of 30 HCC cases, 25 cases (83%) showed stronger immunoreactivity than non-cancerous counterparts. The patients with poorly differentiated HCC had a larger tumor size and higher levels of AFP, and exhibited higher labeling indices of PCNA-, TUNEL- and 8-OHdG-positive cells than those with well and moderately differentiated HCC. Our findings suggest that oxidative DNA damage is increased in association with necroinflammation in chronic liver disease and determination of 8-OHdG is useful in assessing high-grade malignancy in HCC.
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PMID:Expression of 8-hydroxy-2'-deoxyguanosine in chronic liver disease and hepatocellular carcinoma. 1470 94

Oxidative stress (OS) plays a major role in chronic hepatitis C. Various OS markers have been found to be elevated in hepatitis C virus (HCV)-related liver disease. This study detected the presence of OS in serum and liver biopsy specimens of HCV patients. Reactive oxygen molecules (ROM) in sera of 54 HCV patients were compared with 23 controls. OS markers 8-hydroxydeoxyguanosine (8-OHdG), 4-hydroxy-2-nonenal, malondialdehyde, and thioredoxin were measured in liver biopsy specimens of 18 HCV patients with fibrosis staging F1 (six); F2 (two), F3 (four), and F4 (six). The interferon (IFN) response and hepatocellular carcinoma (HCC) occurrence in the presence of OS markers were also evaluated. The level of ROM in HCV patients was 318 +/- 56.7 Carr compared with 248 +/- 40.8 Carr in controls (p=0.032). Multivariate analysis found age (p=0.0236) to be the only independent variable associated with increase in ROM in sera. In liver biopsy specimens, OS markers were found mainly around the area of piecemeal necrosis or the periportal area. The presence of OS markers seemed to increase with fibrosis staging, although not significantly. The OS DNA damage marker 8-OHdG was detected in the nucleus of hepatocytes. Thirteen patients received IFN therapy. During the 4-year follow-up period, HCC developed in four nonresponders to IFN and in one untreated patient. OS markers were stained in both HCC cells and non-HCC cells in HCC patients. OS markers were found in serum and liver specimens of HCV-associated liver disease and in HCC tissue. Detection of OS markers may be important for monitoring disease progression in HCV patients. Antioxidant therapy in combination with antiviral therapy may minimize liver damage and aid in the prevention and subsequent development of HCC.
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PMID:Immunohistochemical evaluation of oxidative stress markers in chronic hepatitis C. 1471 33

Although peroxisome proliferators are considered non-genotoxic agents, most of them, nevertheless, were found to promote and/or induce, hepatocellular carcinoma (HCC) in rodents. The aim of the present study is, first, to investigate whether the peroxisome proliferator perfluorooctanoic acid (PFOA) possesses inherent liver cancer promoting activity, and second, to study the possible mechanisms involved. To acheive these aims two protocols have been applied, a biphasic protocol (initiation by diethyl-nitrozamine (DEN) 200 mg/kg i.p. followed by treatment with 0.005% or 0.02% perflourooctanoic acid (PFOA) for 14 and 25 weeks) and a triphasic initiation, selection-promotion (IS) protocol (initiation by giving 200 mg/kg DEN i.p. followed by a selection procedure for 2 weeks consisting of giving 0.03% 2-acetylaminofluorene (2-AAF) in diet). In the middle of this treatment a single oral dose of carbon tetrachloride (2.0 ml/kg) was given, followed by giving diet containg 0.015% of PFOA for 25 weeks. After applying both protocols, our results showed slight increase in the catalase activity while acyl CoA oxidase activity was markedly increased. Both experiments indicated that PFOA has a liver cancer promoting activity. Other groups of rats were given either basal diet or diet containing 0.02% PFOA. Five or nine weeks later they were sacrificed and the levels of 8-hydroxydeoxyguanosine in the isolated DNA were estimated. The data showed a slight nonetheless insignificant increase in 8-hydroxydeoxyguanosine. From the present data, it is concluded that PFOA is a true liver cancer promoter that may not require extensive initial DNA damage for its promoting activity.
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PMID:Peroxisomal enzymes and 8-hydroxydeoxyguanosine in rat liver treated with perfluorooctanoic acid. 1475 43

Expression of multiple drug resistant (MDR) phenotype and over-expression of P-glycoprotein (P-gp) in the human hepatocellular carcinoma (HCC) cell clone P1(0.5), derived from the PLC/PRF/5 cell line (P5), are associated with strong resistance to oxidative stress and a significant (p < 0.01) increase in intracellular vitamin E content as compared with the parental cell line. This study evaluates the role of vitamin E in conferring resistance to drugs and oxidative stress in P1(0.5) cells. Parental drug-sensitive cells, P5, were incubated in alpha-tocopherol succinate (alpha-TS, 5 microM for 24 h) enriched medium to increase intracellular vitamin E content to levels comparable to those observed in P1(0.5) cells at basal conditions. Susceptibility to lipid peroxidation and oxidative DNA damage were assessed by measuring the concentration of thiobarbituric-reactive substances (TBARS) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) at basal and after experimental conditions. Cell capacity to form colonies and resistance to doxorubicin were also studied. P5 cells, treated with alpha-TS, became resistant to ADP-Fe3+ and to ionizing radiation-induced lipid peroxidation as P1(0.5) cells. Exposure to ADP-Fe3+ or ionizing radiation increased TBARS and the 8-OHdG content in the P5 cells, while vitamin E enrichment abolished these effects. Irradiation doses at 5 cGy increased TBARS and 8-OHdG. They also inhibited cell capacity to form colonies in the untreated P5 cells. Incubation with alpha-TS fully reverted this effect and significantly (p < 0.01) reduced the inhibitory effect of cell proliferation induced by irradiation doses at >500 cGy. Resistance to doxorubicin was not affected by alpha-TS. These observations demonstrate the role of vitamin E in conferring protection from lipid peroxidation, ionizing radiation and oxidative DNA damage on the human HCC cell line. They also rule out any role of P-gp over-expression as being responsible for these observations in cells with MDR phenotype expression.
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PMID:Vitamin E protects DNA from oxidative damage in human hepatocellular carcinoma cell lines. 1545 40

Perfluorooctanoic acid (C8HF15O2, PFOA) is widely used in various industrial fields for decades and it is environmentally bioaccumulative. PFOA is known as a potent hepatocarcinogen in rodents. But it is not yet clear whether it is also carcinogenic in humans, and the genotoxic effects of PFOA on human cells have not yet been examined. In this study, the genotoxic potential of PFOA was investigated in human hepatoma HepG2 cells in culture using single cell gel electrophoresis (SCGE) assay and micronucleus (MN) assay. In order to clarify the underlying mechanism(s) we measured the intracellular generation of reactive oxygen species (ROS) using dichlorofluorescein diacetate as a fluorochrome. The level of oxidative DNA damage was evaluated by immunocytochemical analysis of 8-hydroxydeoxyguanosine (8-OHdG) in PFOA-treated HepG2 cells. PFOA at 50-400 microM caused DNA strand breaks and at 100-400 microM MN in HepG2 cells both in a dose-dependent manner. Significantly increased levels of ROS and 8-OHdG were observed in these cells. We conclude that PFOA exerts genotoxic effects on HepG2 cells, probably through oxidative DNA damage induced by intracellular ROS.
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PMID:Genotoxic risk and oxidative DNA damage in HepG2 cells exposed to perfluorooctanoic acid. 1621 84

Curcumin is extensively used as a spice and pigment and has anticarcinogenic effects that could be linked to its antioxidant properties. However, some studies suggest that this natural compound possesses both pro- and antioxidative effects. In this study, we found that curcumin induced DNA damage to both the mitochondrial and nuclear genomes in human hepatoma G2 cells. Using quantitative polymerase chain reaction and immunocytochemistry staining of 8-hydroxydeoxyguanosine, we demonstrated that curcumin induced dose-dependent damage in both the mitochondrial and nuclear genomes and that the mitochondrial damage was more extensive. Nuclear DNA fragments were also evident in comet assays. The mechanism underlies the elevated level of reactive oxygen species and lipid peroxidation generated by curcumin. The lack of DNA damage at low doses suggested that low levels of curcumin does not induce DNA damage and may play an antioxidant role in carcinogenesis. But at high doses, we found that curcumin imposed oxidative stress and damaged DNA. These data reinforce the hypothesis that curcumin plays a conflicting dual role in carcinogenesis. Also, the extensive mitochondrial DNA damage might be an initial event triggering curcumin-induced cell death.
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PMID:Mitochondrial and nuclear DNA damage induced by curcumin in human hepatoma G2 cells. 1653 56

The fatty liver Shionogi (FLS) mouse is a new inbred strain that spontaneously develops fatty liver with infiltration of mononuclear cells. Moreover, this mouse is known to frequently develop spontaneous hepatic cancers. Recently, human non-alcholic steatohepatitis (NASH) has been focused of attention regarding hepatocellular carcinoma. Therefore, this mouse has potential as a model for human hepatic cancer due to steatosis. It is of interest therefore, whether it exhibits elevated susceptibility not only regarding spontaneous tumor development but also to chemical hepatocarcinogens. To examine this concern, we examined diethylnitrosamine (DEN) hepatocarcinogenesis in FLS mice with 30ppm in drinking water for 26 weeks in comparison to two other strains of mice, C3H and C57. The induction of spontaneous and DEN-induced hepatic tumors was clearly increased in the FLS case, along with levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, as compared to the other strains, with or without DEN treatment. These results indicate that the oxidative DNA stress is intimately involved in hepatocarcinogenesis in FLS mice and provide further support for use of this mouse as a useful model for investigating hepatocarcinogenesis due to human hepatic steatosis.
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PMID:High sensitivity of fatty liver Shionogi (FLS) mice to diethylnitrosamine hepatocarcinogenesis: comparison to C3H and C57 mice. 1656 78


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