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)

For the analysis of the molecular mechanism of the action of peroxisome proliferators, we attempted to establish the optimal conditions for obtaining the effects of the chemicals in vitro, employing an established cell line, Reuber rat hepatoma H4IIEC3. Histochemical analyses revealed a marked increase in the number, size, and catalase content of peroxisomes in the cells cultured on a medium containing 0.5 mM ciprofibrate, a peroxisome proliferator. The activity of acyl-CoA oxidase, the initial enzyme of the peroxisomal beta-oxidation system, was increased by more than 10-fold by the same treatment. Catalase was also induced significantly, whereas the activities of glutamate dehydrogenase and lactate dehydrogenase, mitochondrial and cytosolic marker enzymes, did not change upon the treatment. Immunoblotting and RNA-blotting analyses confirmed the increases in the amount of protein and mRNA for all the three enzymes of the peroxisomal beta-oxidation system. Cell fractionation experiments gave a partial separation of peroxisomes from other organelles for the induced culture. Thus, H4IIEC3 cells offer a good in vitro model system of the induction of peroxisomes and peroxisomal beta-oxidation enzymes by peroxisome proliferators.
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PMID:Proliferation of peroxisomes and induction of peroxisomal beta-oxidation enzymes in rat hepatoma H4IIEC3 by ciprofibrate. 212 77

Using an initiation--selection--promotion protocol for induction of liver tumors in Wistar rats, the modulating action of various peroxisome proliferators on neoplasia as well as on selected biochemical parameters was studied. After treatment with diethylnitrosamine (DEN), the animals were subsequently subjected to a selection procedure involving feeding of 2-acetylaminofluorene (2-AAF), and in the middle of the 2-AAF treatment, a single necrogenic dose of carbon tetrachloride. Following a recovery period, the rats were fed a diet containing 0.1% nafenopin (NAF), 0.015% perfluorooctanoic acid (PFOA), 0.05% 2,4-dichlorophenoxyacetic acid (2,4-D), 0.05% 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) or 0.05% phenobarbital (PB) as a positive control. When the animals were killed, 7 months after initiation, the incidence of hepatocellular carcinoma was 83, 33 and 16% in the animals treated with NAF, PFOA or 2,4,5-T respectively. No cancers were observed in controls, or in the 2,4,-D groups. In comparison with controls, NAF and PFOA caused a 60-and 24-fold increase inthe peroxisomal beta-oxidation of fatty acids respectively, but only about a 2-fold increase in the catalase activity, 2,4-D and/or 2,4,5-T were much less active in this respect, giving approximately a doubling in the rate of fatty acid oxidation. The specific activity of D-amino acid and glycolate oxidases were significantly depressed, whereas the urate oxidase levels were apparently unaffected by the NAF and PFOA treatment. The results suggest that the selective induction of peroxisomal fatty acid oxidation is consistent with the hypothesis that imbalance between H2O2 overproduction and its destruction could play a role in the modulation of hepatocarcinogenesis by peroxisome proliferators.
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PMID:Peroxisome proliferation and modulation of rat liver carcinogenesis by 2,4-dichlorophenoxyacetic acid, 2,4,5-trichlorophenoxyacetic acid, perfluorooctanoic acid and nafenopin. 222 20

Photosensitization induced by tetrabromofluorescein (eosin, 3.8 mumol/L) in ascites hepatoma cells or in normal kidney cells of mice was found to be significant. The cytocidal activity increased in proportion to the concentration of fluorescein as well as with irradiation time. ESR signals were not detected using a trapping agent, 2,2,6,6-tetramethyltetrahydroxy-piperidine (TMHP) which functions as a singlet oxygen probe. No effect on photosensitization by superoxide dismutase (SOD), NaN3, histidine, mannitol or beta-carotene were observed. However, catalase did decrease photosensitization. These results indicate that cytocidal activity is not related to 1O2, O2-. or OH., but is related to H2O2. The cytocidal activity of tetrabromofluorescein in ascites hepatoma cells is stronger than that in normal kidney cells.
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PMID:[Mechanism of active oxygen in cytocidal activity of tetrabromofluorescein]. 248 20

The cytotoxic properties of quinone drugs such as menadione and adriamycin are thought to be mediated through one-electron reduction to semiquinone free radicals. Redox cycling of the semiquinones results in the generation of reactive oxygen species and in oxidative damage. In this study the toxicity of mitozantrone, a novel quinone anticancer drug, was compared with that of menadione in human Hep G2 hepatoma cells. Mitozantrone toxicity in these cells was not mediated by the one-electron reduction pathway. In support of this, inhibition of the enzymes glutathione reductase and catalase, responsible for protecting the cells from oxidative damage, did not affect the response of the Hep G2 cells to mitozantrone, whereas it exacerbated menadione toxicity. In addition, the toxicity of menadione was preceded by depletion of reduced glutathione which was probably due to oxidation of the glutathione. Mitozantrone did not cause glutathione depletion prior to cell death. DT-diaphorase activity and intracellular glutathione were found to protect the cells from the toxicity of both quinones. Inhibition of epoxide hydrolase potentiated mitozantrone toxicity but did not affect that of menadione. Our experiments indicate that mitozantrone toxicity may involve activation to an epoxide intermediate. Both quinone drugs inhibited cytochrome P-450-dependent mixed-function oxidase activity, although menadione was more potent in this respect.
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PMID:The toxicity of menadione and mitozantrone in human liver-derived Hep G2 hepatoma cells. 253 22

Liver catalase activity, one of the free-radical scavenger enzymes, has been measured in 22 normal subjects and compared with that of 13 patients suffering from hepatocellular carcinoma. The activity was estimated both in tumor tissue and in tumor-free tissue. A significant reduction of catalase activity was noted in tumor tissue (p less than 0.001) as well as in the adjacent tumor-free tissue (p less than 0.02). In patients with hepatoma, the serum iron level was lower than in normal (p less than 0.01) and was correlated with enzyme activity (r = 0.958). These findings suggest that in hepatocarcinoma the free radical scavenger system is impaired.
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PMID:Catalase activity in human hepatocellular carcinoma (HCC). 283 48

Effect of superoxide radical (O2-) produced extracellularly by hypoxanthine (HX) and xanthine oxidase (XO) on invasive capacity of rat ascites hepatoma cells was studied. Invasive capacity was estimated in vitro by counting the number of tumor cell colonies penetrated underneath cultured mesothelial cell monolayer. When the tumor cells had been treated with non-toxic doses of HX and XO, the formation of penetrated colonies increased with increasing concentrations of XO. This increment was completely inhibited by scavengers of active oxygen radicals, superoxide dismutase (SOD) in combination with catalase (CAT) added simultaneously at the time of HX-XO treatment.
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PMID:Superoxide radical potentiates invasive capacity of rat ascites hepatoma cells in vitro. 301 47

In vitro and in vivo invasive capacities of rat ascites hepatoma cells (AH 130) that had been cultured on the feeder layers of rat macrophages were examined. The in vitro invasive capacity of the tumor cells was measured by their ability to form tumor cell colonies underneath cultured mesothelial cell monolayers; in vivo invasive capacity was examined by the implantation of the tumor cells into the rat peritoneal cavity. When the tumor cells were precultured on a macrophage feeder layer, the in vitro invasive capacity of the tumor cells increased almost 10 times as much as that of uncocultred control cells. The cocultured tumor cells, when implanted in rat peritoneal cavity, infiltrated extensively in the peritoneum and formed many tumor nodules and enlarged metastatic lymph nodes. Implantation of the uncocultured tumor cells did not develop any macroscopically detectable nodules. The effect of macrophages was reversed by subculturing the cocultured tumor cells without macrophages. Treatment of the tumor cells with the medium conditioned by macrophage culture did not result in the increase in invasive capacity. Almost 50% of the macrophage-mediated enhancement of the in vitro invasive capacity was inhibited by the simultaneous addition of superoxide dismutase and catalase at the time of tumor cell-macrophage coculture.
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PMID:Macrophage potentiation of invasive capacity of rat ascites hepatoma cells. 303 May 45

Hydrogen peroxide produced by stimulated phagocytic cells or during the metabolism of drugs, is toxic to various cell types. The aim of this study was to investigate its toxicity against normal vs. tumor rat hepatocytes. Isolated normal hepatocytes and tumor hepatocytes from three hepatocarcinoma cell lines, Fao, C2 (Faof1C2) and HTC, were incubated in the presence of a H2O2-generating system consisting of glucose and varied concentrations of glucose oxidase. The toxicity of H2O2 was quantified by measuring the percentage of lactate dehydrogenase activity released in the culture medium after various times of incubation. By comparison to normal hepatocytes, tumor hepatocytes exhibited an increased susceptibility to lysis by H2O2. At a concentration of 100 mU per ml, glucose oxidase induced a lactate dehydrogenase activity release of only 6.1 +/- 2.2% (mean +/- S.E.) from normal hepatocytes and of 71.0 +/- 2.9, 45.5 +/- 2.5 and 34.7 +/- 3.4% from Fao, C2 and HTC cells, respectively, after an 18-hr incubation. At a concentration of 10 mU per ml, glucose oxidase had no toxic effect to normal hepatocytes or HTC cells, whereas it induced a lactate dehydrogenase activity release of 58.7 +/- 7.6 and 51.2 +/- 5.6% from Fao and C2 cells, respectively. In addition, the time courses of lactate dehydrogenase activity release, studied with 500 mU per ml glucose oxidase, demonstrated that Fao cells, C2 cells and, to a lesser degree, HTC cells were lysed more rapidly than normal hepatocytes. The toxicity of glucose oxidase was suppressed by the addition of catalase, indicating that it was actually mediated by H2O2.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:In vitro toxicity of hydrogen peroxide against normal vs. tumor rat hepatocytes: role of catalase and of the glutathione redox cycle. 319 84

The H-35 rat hepatoma is relatively insensitive to the anthracycline antibiotic, daunorubicin (DNR), requiring 0.25 microM daunorubicin for inhibition of cell proliferation by 50%. Studies were undertaken to investigate the basis for the apparent intrinsic resistance in this cell line. The relative insensitivity of the H-35 cells to DNR is not a function of metabolic inactivation of DNR to deoxyaglycone derivatives; after a 2-h incubation, less than 10% of drug is metabolized, exclusively by conversion to daunorubicinol. The limited toxicity of DNR to the rat hepatoma may be explained, in part, by the absence of DNA strand breaks at daunorubicin concentrations up to 1 microM while higher (supraclinical) DNR concentrations (5 and 10 microM) produce direct, "non-protein-associated" DNA strand breaks. Limited daunorubicin toxicity in this tumor cell line may also be related to the apparent absence of free radical-mediated cellular damage as the free radical scavengers dimethyl sulfoxide, catalase, methanol, and mannitol fail to reverse the inhibitory effect of 1 microM DNR on cell proliferation. Daunorubicin does not induce leakage of the cytoplasmic enzyme, glutamic oxaloacetate transaminase, or diminish mitochondrial enzyme function. Conversely, while drug effects on RNA synthesis are small, and protein synthesis is minimally diminished, inhibition of cell proliferation corresponds closely with inhibition of DNA synthesis.
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PMID:Evidence for inhibition of growth related to compromised DNA synthesis in the interaction of daunorubicin with H-35 rat hepatoma. 335 5

Fischer F-344 male rats, fed a choline-devoid diet that leads to a highly reproducible sequence of biochemical and biological changes with an ultimate development of hepatocellular carcinoma, show elevated levels of glutathione in the liver at 3, 6 and 8 days. Several enzymes related to the metabolism of free radicals, including superoxide dismutase, catalase, glutathione peroxidase, glutathione S-transferase and DT-diaphorase show neither increased nor decreased activity as measured between 12 h and 8 days on the diet. Thus, of several known cellular components related to the possible scavenger of free radicals in the liver, only glutathione responded to the feeding of the CD diet. It is tentatively concluded that a decrease in the levels of possible scavengers for free radicals is not a major basis for the nuclear and mitochondrial lipid peroxidation seen early in rats fed a choline-devoid diet.
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PMID:Glutathione and enzymes related to free radical metabolism in liver of rats fed a choline-devoid low-methionine diet. 339 Aug 3


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