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)

We have previously demonstrated the inducibility of both cytochrome P-448- and P-450-dependent monooxygenases in the differentiated rat hepatoma cell line MH1C1. Further experiments with these cells on the expression of different forms of cytochrome P-450, inducible not only by phenobarbital (PB) and 3-methylcholanthrene (MC), but also by metyrapone (MP), ethanol (E), and beta-naphthoflavone (BNF) are reported here. The effects of the in vitro addition of the inhibitors alpha-naphthoflavone and beta-naphthoflavone on the aryl hydroxylase activity (AHH) and the influence of protein synthesis on the induction of cytochrome P-450 were also assessed. Cultures were exposed to the inducers PB, MC, BNF, and MP during the last 6 days of culture and to E for 10 days. The inhibition of protein synthesis was obtained by adding cycloheximide (CY) to the cultured cells during the last 24 hr. The exposure of MH1C1 cells to various concentrations of MP resulted in a dose-dependent increase in AHH activity. The treatment of MH1C1 cells with different concentrations of ethanol produced a significant dose-dependent increase of monooxygenases. AHH activity, induced by the various treatments, was inhibited in a dose-dependent way by alpha-naphthoflavone and beta-naphthoflavone. Cy reduced the concentration of cytochrome P-450 and the AHH activity induced by the various treatments, thus indicating an implication of the protein synthesis in the mechanism(s) of induction.
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PMID:Biochemical properties of carcinogen-metabolizing enzymes in cultured hepatoma cells. 357 79

Gas-liquid chromatography was used to investigate the hepatic and intestinal metabolism of T-2 toxin, a cytotoxic and immunodepressive trichothecene produced by species of Fusarium. The hepatic S-9 and microsomal fractions of various species hydroxylated T-2 toxin to form 3'-hydroxy-T-2. HT-2 toxin, a deacetylated metabolite of T-2 toxin formed by reactions involving microsomal esterases, was also hydroxylated, to 3'-hydroxy HT-2 toxin. Experiments with inhibitors and inducers of the cytochrome P-450-dependent system revealed that these two hydroxylation reactions were catalysed by the cytochrome P-450-dependent monooxygenase system. Species comparisons using rats, mice, guinea-pigs, rabbits, pigs, cows and chickens showed that the rate of the hydroxylation reaction was highest in the hepatic microsomes of guinea-pigs, followed by mice. Chickens possessed a low activity both in the hydrolysis and hydroxylation reactions. No hydroxylated metabolites were produced by the intestinal microsomes of rabbits. These two hydroxylated metabolites were far less cytotoxic to Reuber hepatoma cells than the parent compound, T-2 toxin.
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PMID:The cytochrome P-450-dependent hydroxylation of T-2 toxin in various animal species. 362 44

The induction of cytochrome P-450 (c+d) messenger RNAs in rat liver by 3-methyl cholanthrene follows a biphasic pattern. Administration of cycloheximide blocks the induction of cytochrome P-450 (c+d) messenger RNAs by 3-methylcholanthrene as well as cytochrome P-450 (b+e) messenger RNAs by Phenobarbitone. Transcription of these messenger RNAs in isolated nuclei is also blocked by cycloheximide administration. Thus cycloheximide not only fails to mimic the superinduction effects reported in hepatoma cell cultures, but actually blocks the specific transcription process. Exogenous hemin, while counteracting the effects of CoCl2 (heme biosynthetic inhibitor) on cytochrome (c+d) messenger RNA induction by the hydrocarbon, fails to counteract the effects of cycloheximide. It is suggested that a positive labile transcription factor is involved in the regulation of cytochrome P-450 gene expression in vivo.
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PMID:Differential effects of cycloheximide on rat liver cytochrome P-450 gene transcription in the whole animal and hepatoma cell culture. 368 89

Microsomal membranes from the slow-growing Morris hepatoma 9618A catalyze, in the presence of t-butyl hydroperoxide, lower rates of lipid peroxidation than rat liver microsomes. The cytochrome P-450 content of hepatoma microsomes is about 40% that of the liver. SKF 525-A, an inhibitor of mixed-function oxidase, produces in hepatoma microsomes a P-450 type I binding spectrum similar to that of hepatic microsomes. The concentration of the inhibitor required for half-maximal spectral change is about 2 microM in both microsome types. SKF 525-A or ethylmorphine inhibit lipid peroxidation of normal and tumor microsomes to the same extent (about 60%). Treatment of the tumor-bearing rats with 3-methylcholanthrene increases the hepatoma cytochrome P-450 to values comparable to those of control membranes, although the hemoprotein has a peak in the CO-reduced difference absorption spectrum at 448 nm. The cytochrome P-448 induction is accompanied by an almost complete restoration of the hydroperoxide-dependent lipid peroxidation.
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PMID:Restoration of hydroperoxide-dependent lipid peroxidation by 3-methylcholanthrene induction of cytochrome P-448 in hepatoma microsomes. 379 50

We have examined the suitability of the continuous rat hepatoma cell line 2sFou for testing the genotoxicity of chemicals in comparison with that of primary rat hepatocyte cultures (HPC). The capacity of the cells for metabolic activation was assessed by measuring induction of DNA-repair synthesis and inhibition of replicative DNA synthesis by the test compounds dimethylnitrosamine (DMN), diethylnitrosamine (DEN), hydroxyurea (HU) and benzo[a]pyrene (BaP), which are substrates for major hepatic and extrahepatic forms of cytochrome P-450 dependent monooxygenases. The cellular capacity for DNA-repair synthesis was assessed using UV-light as a DNA-damaging agent. Repair-specific incorporation of [3H]deoxycytidine (3H-dCyd) caused by UV-light was higher in 2sFou cells than in HPC. In contrast, background repair incorporation of 3H-dCyd in 2sFou cells was only 1/3 that found in HPC. All the test agents induced DNA repair and inhibited DNA synthesis in both 2sFou cells and HPC. The two nitrosamines were more effective in HPC than in 2sFou cells. HU and BaP affected DNA repair and DNA synthesis in the two cell systems at a similar range of concentrations. In general, DNA repair in the 2sFou cells increased near linearly with the concentrations of the test compounds. The data indicate that 2sFou cells are capable of activating hepatotropic pro-mutagens/carcinogens such as dialkylnitrosamines, and are sensitive indicators of DNA damage. In contrast, BaP, a non-hepatotoxic compound, caused only little DNA repair in these cells. Thus, continuously growing cells, such as 2sFou, show a qualitatively similar response to genotoxic chemicals as HPC and offer a potential alternative to HPC for genotoxicity testing.
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PMID:Comparison of the continuous rat hepatoma cell line 2sFou with primary rat hepatocyte cultures for the induction of DNA repair synthesis by nitrosamines, benzo[a]pyrene and hydroxyurea. 380 38

Two forms of cytochrome P-450 (hepatoma P-450MCI and P-450MCII) were purified from hepatoma 5123D microsomes of tumor-bearing rats treated with 3-methylcholanthrene. Hepatoma P-450MCI had a specific content of 18.4 nmol/mg protein and showed a main protein band with a minimum molecular weight of 56,000 on sodium dodecyl sulfate-polyacrylamide gel. Hepatoma P-450MCII had a specific content of 7.38 nmol/mg protein and a minimum molecular weight of 50,000. The carbon monoxide-reduced difference spectral peak of hepatoma P-450MCI was at 446.5 nm, whereas the peak of hepatoma P-450MCII was at 451 nm. In the reconstituted system, hepatoma P-450MCI catalyzed 3-hydroxylation of benzo[a]pyrene and O-deethylation of 7-ethoxycoumarin, but showed low activities for N-demethylation of benzphetamine and aminopyrine, O-demethylation of p-nitroanisole, and p-hydroxylation of aniline. On the other hand, hepatoma P-450MCII did not catalyze hydroxylation of any of the substrates tested. By Ouchterlony double-diffusion analysis, hepatoma P-450MCI was immunologically indistinguishable from rat liver cytochrome P-450c, but hepatoma P-450MCII was distinct from hepatoma P-450MCI and rat liver cytochrome P-450c. Peptide maps of hepatoma P-450MCI and rat liver cytochrome P-450c after proteolysis with Staphylococcus aureus V8 protease demonstrated the similarity of the two cytochromes P-450.
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PMID:Microsomal monooxygenase system in Morris hepatoma: purification and characterization of cytochromes P-450 from Morris hepatoma 5123D of 3-methylcholanthrene-treated rats. 391 48

To evaluate the effects of anaerobic conditions and inducers for the mixed-function oxidase system on the metabolism of mitomycin C, a bioreductive alkylating agent widely used for the treatment of hepatocellular carcinoma, experiments so designed were performed in rats and mice. Metabolism of mitomycin C by microsomes from normal rat liver and diethyl-nitrosamine-induced mouse hepatocellular carcinoma tissue was assessed from the disappearance of the quinone portion of mitomycin C and by measurement of alkylating metabolites using 4-(p-nitrobenzyl)pyridine as a trapping agent. The metabolism of mitomycin C measured by the two independent methods was strikingly increased under anaerobic conditions in both intact and tumor tissues. Since involvement of cytochrome P-450 in the metabolic activation of mitomycin C was shown recently, effects of representative inducers for the mixed-function oxidase system on the metabolism of mitomycin C were also studied. Phenobarbital treatment resulted in a significant increase in the metabolism of mitomycin C in both intact and tumor tissues under anaerobic conditions. The markedly enhanced formation of active metabolites of mitomycin C under anaerobic conditions may explain on a metabolic basis, at least in part, our recent clinical observations that chemoembolizations with microcapsular forms of mitomycin C is more effective than conventional bolus administration of this agent in the treatment of hepatocellular carcinoma. Combination of anaerobic conditions and induction of the mixed-function oxidase system may be applicable to chemotherapy of hepatic malignancy.
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PMID:Effects of hypoxia and phenobarbital treatment on the metabolism of mitomycin C in experimental animals. 393 61

A single dose of 15 mg/kg dimethylnitrosamine is an initiator of hepatic tumour formation in rats but does not produce tumours without further treatment. Subsequent promotion by Na phenobarbitone (1000 micrograms/ml drinking water) leads to 40% or more of the rats developing hepatocellular carcinoma. Four days of dietary treatment designed to produce a wave of DNA synthesis at the time of initiation leads to an even greater yield of tumours and nodules after promotion. This effect of phenobarbitone does not appear to be directly related to its ability to induce enzyme activity in the liver because lower doses of phenobarbitone (100 micrograms/ml or less) did not promote tumour development in spite of being adequate for the induction of cytochrome P-450 and associated enzyme activity. A similar incidence of hepatocellular carcinoma was found in both the groups given DMN and the top dose of Na phenobarbitone (1000 micrograms/ml) whether or not they had been given the dietary pretreatment. However, hyperplastic nodules were seen only in the diet pre-treated group. This is discussed in relation to the hypothesis that hyperplastic nodules are precursors of hepatic carcinoma.
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PMID:Dose-response relationship for phenobarbitone promotion of liver tumours initiated by single dose dimethylnitrosamine. 394 31

Lipid peroxidation of microsomes from rat liver and Morris hepatoma 9618A was induced by means of tert-butyl hydroperoxide (t-BuOOH). In rat liver microsomes t-BuOOH stimulated an early formation of lipid hydroperoxides (LOOH) and an increasing accumulation of malondialdehyde; t-BuOOH was completely consumed and cytochrome P-450 was rapidly destroyed. In hepatoma microsomes (60% deficiency of cytochrome P-450) a remarkable inhibition of both malondialdehyde and LOOH was observed; t-BuOOH was consumed only partially and cytochrome P-450 was destroyed slowly. In the presence of aminopyrine, malondialdehyde production was inhibited to the same extent (about 70%) in normal and tumour microsomes. The concentration of t-BuOOH required to achieve half-maximal velocity of malondialdehyde accumulation was comparable in the two microsome types. It is proposed that the deficiency of cytochrome P-450 limits the activation of t-BuOOH to the free radical species which initiate lipid peroxidation. Low cytochrome P-450 content would also affect the LOOH-dependent propagation of lipid peroxidation.
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PMID:Cytochrome P-450 deficiency and resistance to t-butyl hydroperoxide of hepatoma microsomal lipid peroxidation. 395 61

Two closely related hepatoma cell lines were examined for their genotoxic response to benacridines and their metabolites by the appearance of alkaline labile DNA sites: H5, a dedifferentiated line expressing cytochrome P-448-dependent mono-oxygenase(s); and HF1-4, a differentiated line expressing cytochrome P-450-dependent monooxygenase(s). The parent heterocycles had no effect on both cell lines. In contrast to the 3,4-dihydrodiol of benz[c]acridine the 3,4-dihydrodiol of benz[a]acridine induced no DNA strand breaks in both cell lines. All diol epoxides, however, induced DNA-damage in both cell lines, the syn derivatives in the same order of magnitude as the dihydrodiol of benz[c]acridine. The antidiol epoxides (epoxide group on the opposite side to the benzylic hydroxyl group) were the most potent to induce DNA-single strand breaks. The diol epoxide of benz[c]acridine was three times more efficient in HF1-4 than in H5, whereas for the diol epoxide of benz[a]acridine, the reverse was true. The results indicate that benz[c]acridine-3,4-diol is oxidized to metabolites which can induce DNA-damage. This is consistent with the hypothesis that the benz[a]acridine and derivatives are not easily metabolized to active mutagens but more likely are converted to inactive metabolites, possibly via N-oxidation. This is illustrated with 3,4-diol-1-2 anti-diol epoxide of benz[a]acridine which is inactivated in cell line HF1-4 due to the reactivity of the epoxide ring in the bay region. Since all diol epoxides show similar activity in both hepatoma cell lines, they are of great interest because of their ability to detect DNA-damaging agents and to analyse their metabolic activation and mechanism of action.
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PMID:Differentiated genotoxic response of carcinogenic and non-carcinogenic benzacridines and metabolites in rat hepatoma cells. 397 58


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