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)

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

The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) may produce its effects by altering gene expression in susceptible cells. In mouse hepatoma cells, TCDD induces the transcription of the cytochrome P1-450 gene, whose product, aryl hydrocarbon hydroxylase, contributes both to the detoxification and to the metabolic activation of carcinogenic polycyclic aromatic hydrocarbons. A DNA fragment containing sequences flanking the 5' end of the cytochrome P1-450 gene was isolated and analyzed. This DNA fragment contains a cis-acting control element with at least three functional domains: a putative promoter, an inhibitory domain upstream from the promoter that blocks its function, and a TCDD-responsive domain still farther (1265 to 1535 base pairs) upstream of the promoter. These findings, together with results from earlier studies, imply that transcription of the cytochrome P1-450 gene is under both positive and negative control by at least two trans-acting regulatory factors.
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PMID:Control of cytochrome P1-450 gene expression by dioxin. 385 21

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

Fifteen polychlorinated dibenzofuran (PCDF) congeners were administered in a dose-response fashion to immature male Wistar rats and ED50 values for body weight loss, thymic atrophy and the induction of the hepatic microsomal cytochrome P-448-dependent monooxygenases, aryl hydrocarbon hydroxylase (AHH) and 4-chlorobiphenyl hydroxylase were determined. There was an excellent correlation between the in vivo quantitative structure-activity relationships for these PCDFs and their in vitro activities as AHH inducers in rat hepatoma H-4-II E cells and as ligands for the 2,3,7,8-TCDD receptor protein. A comparison of isomers which differ at all 4 positions in the dibenzofuran ring system indicated that chlorine substitution at each position contributed differentially to the overall molecular activity [C-3 (or C-7) greater than C-2 (or C-8) greater than C-4 (or C-6) greater than C-1 (or C-9)]. There was also an excellent linear correlation between a plot of the -log ED50 for body weight loss vs. -log EC50 for in vitro AHH induction (correlation coefficient, r = 0.96) and -log ED50 for thymic atrophy vs. -log EC50 for in vitro AHH induction (correlation coefficient, r = 0.88). Since body weight loss and thymic atrophy in the rat are representative toxic responses to PCDFs and related toxic halogenated aryl hydrocarbons, the correlations noted above support the use of the in vitro AHH induction assay as a short term quantitative test system for this class of toxic halogenated aryl hydrocarbons.
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PMID:Polychlorinated dibenzofurans (PCDFs): correlation between in vivo and in vitro structure-activity relationships. 393 43

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

Aryl hydroxylase activity has been demonstrated to depend on the pattern of tumor cell structural organization. The activity of microsomal monoxygenases in the ascitic forms of sarcoma MC-11, hepatoma 22a and Ehrlich's tumor was much lower than in the corresponding solid tumors. Aryl hydroxylase was activated after the animals received 3-MC, but the magnitude of the activity induced did not correlate with the basic activity in the different tumors. In in vitro experiments, 7,8-benzoflavone inhibited the enzyme in all the tumors, whereas metyrapone did not affect BP-hydroxylation. It is assumed that all the tumors investigated contain hemoprotein that is similar to cytochrome P1-450.
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PMID:[Differing microsomal monoxygenase activity in the cells of ascitic and solid forms of transplantable tumors]. 402 74

The contents of mitochondrial inner membrane protein complexes were compared in normal liver and in Zajdela hepatoma mitochondria by the immunotransfer technique. Antibodies against core proteins 1 and 2, cytochrome c1, the iron-sulfur protein of Complex III, subunits I and II of cytochrome oxidase, and the alpha and beta subunits of the F1-ATPase were used. In addition, antibodies against a primary dehydrogenase, beta-hydroxybutyrate dehydrogenase, as well as the outer membrane pore protein were used. The results indicate that the components of the cytochrome chain and porin are greatly enriched in hepatoma mitochondria compared to normal rat liver mitochondria. This enrichment was also reflected in the rates of respiration in tumor mitochondria using a variety of substrates. Enrichment of porin may partially account for increased hexokinase binding to tumor mitochondria. In contrast to the respiratory chain components, the F1-ATPase and F0 (measured by DCCD binding) were not increased in tumor mitochondria. Thus, Zajdela hepatoma mitochondria components are nonstoichiometric, being enriched in oxidative capacity but relatively deficient in ATP synthesizing capacity. Finally, beta-hydroxybutyrate dehydrogenase, which is often decreased in hepatoma mitochondria, was shown here by immunological methods to be decreased by only 40%, whereas enzyme activity was less than 5% of that in normal rat liver.
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PMID:Immunochemical analysis of the membrane proteins of rat liver and Zajdela hepatoma mitochondria. 609 64

The import and processing of cytochrome c1 and the iron sulfur protein of the cytochrome b-c1 complex were studied in Zajdela hepatoma ascites cells. Both peptides were synthesized as larger percursor molecules which were approximately 2-3 kDa and 5-6 kDa larger than the mature forms of apocytochrome c1 and apo-iron sulfur protein, respectively. Comparison of these precursors to those reported for functionally homologous peptides in yeast and Neurospora indicate significant size changes have occurred in mammals. Rhodamine 6G, a specific vital stain for mitochondria, is a potent inhibitor of precursor processing in isolated hepatoma cells. Both precursor to cytochrome c1 and precursor to FeS accumulate in the soluble and particulate fractions obtained by digitonin treatment of tumor cells treated with Rhodamine 6G. Appearance of the mature peptides was abolished. The precursors are unstable, however, and disappear from the cytosolic and membrane fractions during a 10 min chase. Comparison of the effects of Rhodamine 6G and carbonylcyanide m-chlorophenylhydrazone on precursor processing shows that: (a) Rhodamine 6G is a more effective inhibitor of processing, (b) it has less of an inhibitory effect on cellular protein synthesis, and (c) it inhibits processing under conditions in which it appears to have little influence on coupled respiration in whole cells. The data suggest that the most likely mode of action of Rhodamine 6G is on the matrix processing step.
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PMID:Import and processing of cytochrome b-c1 complex subunits in isolated hepatoma ascites cells. Inhibition by Rhodamine 6G. 609 71

The induction by phenobarbital (PB) of aldrin epoxidase (AE) and aryl hydrocarbon hydroxylase (AHH), markers of cytochrome P-450- and cytochrome P-448-dependent monooxygenases, was studied in cell lines derived from Reuber H35 rat hepatoma which differ widely in their degree of differentiation. The following results were obtained: (1) PB induced AE 2-6-fold and AHH 2-4-fold in the differentiated clones, Fao, 2sFou, and C2Rev7 during an exposure period of 72 h. The barbiturate increased AHH but not AE in the dedifferentiated clone H5, the poorly differentiated line H4IIEC3/T, and in the well differentiated line H4IIEC3/G-. (2) Continuous presence of the barbiturate was required for maintaining the induction of the two monooxygenase activities in C2Rev7 cells. (3) Maximum induction of AE was observed at a PB concentration of 1.5-3.0 mM. (4) The effects of 7,8-benzoflavone on AHH-activities induced by phenobarbital in C2Rev7 and H5 cells suggested that they are mediated by cytochrome P-450- and cytochrome P-448-dependent monooxygenase forms, respectively. Thus, the flavonoid had only a slight inhibitory effect on PB-induced AHH in C2Rev7 cells, but strongly inhibited PB-induced AHH in H5 cells. The induction of AE and of 7,8-benzoflavone-inhibitable AHH in 2sFou cells indicated that PB is capable of inducing cytochromes P-450 and cytochrome P-448 in the same cell.
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PMID:Phenobarbital induces cytochrome P-450- and cytochrome P-448-dependent monooxygenases in rat hepatoma cells. 609 35

Two closely related hepatoma cell lines were examined for their response to carcinogens requiring metabolic activation: H5, a dedifferentiated line expressing cytochrome P-448-dependent monooxygenase(s); and HF1-4, a differentiated line which also expresses cytochrome P-450-dependent monooxygenase(s). The hepatocarcinogens dimethyl- and diethylnitrosamine and aflatoxin B1, preferred substrates for cytochrome P-450-dependent monooxygenase(s), and the non-hepatocarcinogen benzo[a]pyrene, which is preferentially metabolized by cytochrome P-448-dependent monooxygenase forms, were used as test agents. Their effects were compared to those of the directly alkylating agents N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and N-ethyl-N-nitrosourea (ENU). The cytotoxicity was evaluated by plating efficiency, the genotoxicity by the appearance of alkaline labile DNA sites. The nitrosamines had a cytotoxic and genotoxic effect on the differentiated HF1-4 cells, but had no effect on H5 cells. Aflatoxin B1 affected both cell lines, but was approximately 10-times more potent in the HF1-4 than in the H5 cells. In contrast to the nitrosamines and the mycotoxin, benzo[a]-pyrene exerted a stronger effect on the dedifferentiated cell line. Pretreatment of cultures with dexamethasone increased both the cytotoxicity and genotoxicity of the hepatotoxic agents. MNNG and ENU induced a similar degree of DNA-damage after short-term (2 h) exposure in the two cell lines. When cells were allowed to recover for 16 h HF1-4 cells, but not H5 cells, regained their full growth potential suggesting a marked capacity for the repair of MNNG- and ENU-induced lesions in the HF1-4 cells. The results indicate that continuous lines of mammalian cells may retain a considerable degree of organ-specific response to chemical carcinogens. Hepatoma cells of the type described above may be useful for screening the wide spectrum of chemicals which are potentially genotoxic in liver and in extrahepatic tissues and for analyzing their metabolic activation and mechanism of action.
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PMID:Geno- and cytotoxicity of nitrosamines, aflatoxin B1, and benzo[a]-pyrene in continuous cultures of rat hepatoma cells. 629 36


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