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)

Cellular copper metabolism and the mechanism of resistance to copper toxicity were investigated using a wild type hepatoma cell line (HAC) and a copper-resistant cell line (HAC600) that accumulates copper and has a highly elevated level of metallothionein (MT). Of the enzymes involved in reactive oxygen metabolism, only glutathionine peroxidase was elevated (3-4-fold) in resistant cells, suggestive of an increase in the cellular flux of hydrogen peroxide. A majority of the cytoplasmic copper (greater than 60%) was isolated from both cell lines as a GSH complex. Kinetic studies of 67Cu uptake showed that GSH bound 67Cu before the metal was complexed by MT. Depletion of cellular GSH with buthionine sulfoximine inhibited the incorporation of 67Cu into MT by greater than 50%. These results support a model of copper metabolism in which the metal is complexed by GSH soon after entering the cell. The complexed metal is then transferred to MT where it is stored. This study also indicates that resistance to metal toxicity in copper-resistant hepatoma cells is due to increases in both cellular GSH and MT. Furthermore, it is suggested that elevated levels of GSH peroxidase allows cells to more efficiently accommodate an increased cellular hydrogen peroxide flux that may occur as a consequence of elevated levels of cytoplasmic copper.
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PMID:The role of glutathione in copper metabolism and toxicity. 256 91

The metabolism of chemical carcinogens was investigated in liver preparations from 28 captive woodchucks (Marmota monax). Of these, 23 were naturally infected with the woodchuck hepatitis virus (WHV), and eight also had primary hepatocellular carcinoma (PHC). Twenty-nine parameters were investigated in liver subcellular fractions, including cross-reactivity with HBsAg, and biochemical parameters, such as gamma-glutamyl transpeptidase, cytochrome P-450 and microsomal monooxygenases (aryl hydrocarbon hydroxylase, ethoxycoumarin and ethoxyresorufin deethylases, aminopyrine and dimethylnitrosamine demethylases, and testosterone 7 alpha-, 16 alpha- and 6 beta-hydroxylases), uridine 5'-diphosphoglucuronosyl transferase, GSH and related enzymes (peroxidase, reductase and S-transferase), as well as other cytosolic enzyme activities (glucose 6-phosphate and 6-phosphogluconate dehydrogenases, NADPH- and NADH-dependent diaphorases, and DT diaphorase). In addition, liver preparations were used in order to quantify the metabolic activation into bacterial mutagens of five procarcinogens (aflatoxin B1, the pyrolysis products Trp-P-2 and MeIQ, 2-aminofluorene and dimethylnitrosamine) and the decrease of potency of three direct-acting mutagens (sodium dichromate, ICR 191 and 4-nitroquinoline 1-oxide). WHV infection produced a significant stimulation of carcinogen metabolism, as shown by the simultaneous change in detoxification parameters (GSH depletion) and activation indices (enhancement of microsomal monooxygenases and of procarcinogen activation into mutagenic metabolites). There were no significant differences between WHV-positive samples from animals without PHC and the noncancerous tissue of PHC-bearing animals, whereas a decrease of both activation and detoxification indices was recorded in the tumorous tissue. There was a considerable interindividual variability among WHV carriers, which was tentatively ascribed to genetic factors. Pregnancy was the only known factor influencing the results in WHV carriers. However, even by excluding pregnant animals, the effects on carcinogen metabolism produced by WHV infection were still statistically significant. These results, together with previous data obtained in humans, revealed that metabolic factors may play a role in the synergism between viral hepatitis and chemical hepatocarcinogens in the etiopathogenesis of PHC.
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PMID:Enhanced metabolic activation of chemical hepatocarcinogens in woodchucks infected with hepatitis B virus. 272 Sep 3

In previous studies, we have suggested that the selective inhibitory effect of sodium cyanate (NaOCN) on hepatoma metabolism may be due to the lower pH observed in tumors relative to normal tissues. Lower pH might enhance the action of NaOCN by increasing the formation of isocyanic acid and carbamoylation of sulfhydryl groups. In the present work, studies were conducted on the effect of pH on the carbamoylation of sulfhydryl groups. The data indicated that carbamoylation of the sulfhydryl group of glutathione by NaOCN was enhanced by decreasing the pH from 7.4 to 6.6. A less pH-dependent response was observed with organic isocyanates. However, all reactions were reversible after the pH was increased by the addition of base. Kinetic studies showed that the rate of the reaction is very rapid, a maximal effect occurring within the first 10 min. Dose-dependent modifications of cellular glutathione by NaOCN and organic isocyanates were observed in human HT29 colon tumor cells, rat HTC hepatoma cells, and rat hepatocytes. The rate of carbamoylation of the glutathione sulfhydryl group in cells was similar to that of pure glutathione (GSH). The effect of buthionine sulfoxamine on GSH levels in cells was at least as great as that of sodium cyanate, but only the latter showed inhibitory effects on macromolecular synthesis; these were very rapid, pH-dependent, and reversible in tumor cells. Our results suggest that cellular sulfhydryl group(s) other than that of GSH might be involved in the effect of NaOCN on macromolecular synthesis.
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PMID:Influence of pH on the modification of thiols by carbamoylating agents and effects on glutathione levels in normal and neoplastic cells. 273 17

This study deals with the role of glutathione transferase (GST)-mediated conjugation of (+)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-oxy-7,8,9,10- tetrahydrobenzo[a]pyrene (BPDE) in two mammalian cell lines, human mammary carcinoma cells (MCF-7) and rat hepatoma cells (H4IIE), in relation to their capacity to metabolize (-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene [(-)-BP-7,8-diol] to products that induce mutations in co-cultivated V79 cells. Both MCF-7 and H4IIE cells metabolized (-)-BP-7,8-diol to BPDE, but mutations in co-cultivated V79 cells were only detected with MCF-7 cells. However, depletion of glutathione (GSH) in H4IIE cells increased the mutagenicity of (-)-BP-7,8-diol to a similar level to that found with MCF-7 cells. Measurements of GST activity using GSH and post-microsomal supernatants from H4IIE, V79 and MCF-7 cells indicated a substantial difference in conjugation capacity. Although preparations from all three cell-lines showed GST activity with 1-chloro-2,4-dinitrobenzene as the substrate, GST activity towards BPDE could only be detected in supernatants from H4IIE cells. This is consistent with the presence of GST 7-7 an isoenzyme highly efficient in catalysing BPDE-GSH conjugation. The difference in GSH-conjugation activity towards BPDE was confirmed using intact H4IIE and MCF-7 cells in culture. These results indicate that GSH-conjugation plays a pivotal role in mutagenesis induced by polycyclic aromatic hydrocarbons (PAH). Accordingly, a deficiency in GSH-conjugation capacity may be regarded as one important factor in defining a target cell population with an increased risk for tumour initiation following exposure to PAH.
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PMID:Effects of glutathione transferase activity on benzo[a]pyrene 7,8-dihydrodiol metabolism and mutagenesis studied in a mammalian cell co-cultivation assay. 276 61

Glutathione peroxidase (GSH-Px) activity, one of the scavenger enzymes of oxygen active radicals, has been measured in hepatocellular carcinoma (HCC) of 17 patients and the values compared with the activity of adjacent tumor-free tissue and with those of 30 histologically normal livers. The results demonstrate a reduced GSH-Px activity in neoplastic tissue (21.19 vs 33.74 U/g prot.; P less than 0.001). However, the adjacent tumor-free liver also had a reduced activity when compared with normal tissue (23.15 vs 33.74 U/g prot.; P less than 0.01), but this value did not differ from that of HCC tissue. These data suggest that HCC might develop in a GSH-Px-deficient condition.
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PMID:Decreased activity of liver glutathione peroxidase in human hepatocellular carcinoma. 299 47

Catalase (CAT), glutathione-peroxidase (GSH-Px) activity and reduced glutathione content (GSH) were measured in patients who had hepatocellular carcinoma, and values compared with those of normal liver and liver adjacent to neoplastic tissue. The results showed a remarkable reduction of CAT in tumor and corresponding tumor-free tissue (P less than 0.001 and P less than 0.02, respectively). All neoplastic samples had a significant lower activity of CAT than the corresponding adjacent tumor-free tissue (P less than 0.05). The GSH-Px activity of tumor tissue also was lower than normal (P less than 0.001) but similar to that of adjacent tissue. No correlation was noted between the two enzyme activities. Glutathione content was extremely low in tumor (P less than 0.001) and even in tumor-free tissue (P less than 0.05) when compared with normal liver. In all cases the content of GSH in neoplastic tissue was lower than that of the corresponding tumor-free tissue (P less than 0.05). Whereas in normal liver the activity of GSH-Px was positively correlated with the content of GSH, in the neoplastic tissue such a relationship disappeared. All these findings suggest that the antioxidant system of hepatocellular carcinoma cell is severely impaired.
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PMID:Severe impairment of antioxidant system in human hepatoma. 301 7

Twelve adults with hepatocellular carcinoma (HCC) and 8 individuals with histologically normal liver, were measured for serum selenium concentration and glutathione peroxidase (GSH-Px) of liver tissue. It was found a reduced serum selenium and liver GSH-Px in patients with HCC. Serum selenium concentration and the enzyme activity were positively correlated (p less than 0.01). The increased risk of carcinoma in selenium deficiency may be partially due to a reduced activity of GSH-Px, one of the most important scavenger enzymes of oxygen toxic radicals.
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PMID:Reduction of liver glutathione peroxidase activity and deficiency of serum selenium in patients with hepatocellular carcinoma. 302 33

The importance of some glutathione metabolic pathways was examined in two highly dedifferentiated hepatomas, Yoshida AH-130 and Morris 3924 A hepatomas, and in normal liver in relation to their role against oxidative stress. The cytosol prepared from Yoshida hepatoma cells decreased the peroxidation rate in normal liver microsomes and mitochondria, but this antioxidant property was not displayed by Morris hepatoma. Glutathione peroxidase and glutathione-S-transferases activities were extremely low in both hepatomas; glutathione reductase activity values were about half the normal liver values. The large decrease in glutathione peroxidase and glutathione-S-transferases suggests that in these two tumors only small amounts of GSH can be used in reduction or conjugation reactions, such as the reduction of hydrogen peroxide and lipid hydroperoxides or the conjugation of GSH with the end products of lipoperoxidation, aldehydes or ketones. The hypothesis of a more efficient GSSG reduction in hepatomas, due to the low glutathione peroxidase/glutathione reductase activity ratio, is also discussed. The described changes in glutathione related enzymes do not seem to have any correlation with the protective effect against the lipoperoxidative processes displayed by some tumors since these enzymatic activities were similar in both hepatomas whereas only Yoshida hepatoma showed antioxidant properties.
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PMID:Analysis of glutathione-dependent enzyme activities in two different rat hepatomas and in normal liver in relation to their role in resistance to oxidative stress. 323 5

A large proportion of the metabolites formed from benzo[a]pyrene (BP) in cell cultures from rodents, fish and humans result from conjugation of an oxidized metabolite of BP with sulfate, glucuronic acid or glutathione (GSH). To improve the analysis of these metabolites, a reversed-phase ion-pair h.p.l.c. system using a step gradient of methanol:tetrabutyl-ammonium bromide in ammonium formate buffer has been developed for the separation of these three classes of conjugates. This system separated 3-hydroxy-BP glucuronide and sulfate conjugates and resolved them from GSH conjugates of BP 4,5-oxide, 7,8-oxide and 7,8-diol-9,10-epoxide. Cultures of early passage Syrian hamster, Wistar rat and Sencar mouse embryo cells, a bluegill fry (BF-2) cell line and a human hepatoma cell line (HepG2) were exposed to [3H]BP for 24 h. Medium samples from each were extracted with chloroform: methanol:water, and the water-soluble metabolites were analyzed by ion-pair h.p.l.c. The largest peak of metabolites in the media from cell cultures from rodents and the bluegill fry cell line co-eluted with the glucuronic acid conjugate of 3-hydroxy-BP. These phenol-glucuronides represented 48-62% of the total water-soluble metabolites in the fish and rodent cell cultures. Treatment of this material with beta-glucuronidase released 3-hydroxy-BP and 9-hydroxy-BP in ratios from 3:4 to 13.3:1 in various cultures. Media from the bluegill fry cell line and the mouse embryo cell cultures also contained a peak of BP-diol glucuronides; treatment of these peaks with beta-glucuronidase released mainly BP-7,8-diol. In HepG2 cells, 40% of the water-soluble metabolites were identified as sulfate conjugates of 3-hydroxy-BP and 9-hydroxy-BP. No glucuronic acid conjugates of BP metabolites were detected in HepG2 cells. Only small amounts of the water-soluble metabolites from these cell cultures eluted in the same volumes as the synthetic GSH conjugate of BP-4,5-oxide, BP-7,8-oxide and BP-7,8-diol-9,10-oxide. These studies indicate that conjugation with glucuronic acid represents a major pathway of formation of water-soluble metabolites from BP in cells derived from a number of species and demonstrate the value of this ion-pair h.p.l.c. system for the analysis of conjugates formed from BP.
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PMID:Separation by ion-pair high-performance liquid chromatography of the glucuronide, sulfate and glutathione conjugates formed from benzo[a]pyrene in cell cultures from rodents, fish and humans. 380 96

A 20 h pre-treatment of human cells from normal (foetal lung) or malignant origin (glioma, lines U118 MG and U251 MG and bladder carcinoma, line EJ) with dexamethasone failed to increase their radiation resistance in vitro despite a 2-fold increase in the GSH content of a glioma cell line, U251 MG, and a small but significant increase in the GSH content of EJ bladder carcinoma cells. In contrast, there was a correlation between an increase in radiation resistance and an elevated GSH content of rodent cells (Chinese hamster lung, line V-79-379A; ovary, line CHO; rat hepatoma, line HTC, and mouse neuroblastoma, line NB413A) after a similar pre-treatment. The results suggest that enhancement of radiation resistance cannot be directly ascribed to an elevated GSH content in steroid-treated cells. On the basis of these data it is unlikely that the efficacy of radiotherapy will be diminished amongst patients receiving concomitant treatment with dexamethasone. However, in vivo testing is required to confirm these findings.
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PMID:Studies on the relationship between the radiation resistance and glutathione content of human and rodent cells after treatment with dexamethasone in vitro. 387 26


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