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)

Messenger RNA is released preferentially from isolated rat liver nuclei in the presence of the ATP-generating system and cytosol. The release is suppressed by spermidine, while cytoplasmic RNase inhibitor was ineffective and PCMB like some other thiol-blocking agents inhibitory. Cytoplasmic SOD added to the system strongly suppressed RNA release. A similar effect could be obtained by anaerobiosis due to addition of SMP. In both cases the inhibition is reversed by cyanide. In contrast to normal liver where the generation of superoxide radicals takes place almost exclusively in microsomes and is coupled with the oxidation of NADPH, in mouse ascites hepatoma 22a the generation of superoxide radicals occurs mainly in the nuclear envelope and is coupled wih the oxidation of both NADPH and NADH and inhibited by cyanide.
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PMID:Some features of nucleo-cytoplasmic RNA transport from isolated nuclei. 626 58

NADPH-cytochrome P-450 reductase was purified to homogeneity from hepatoma 5123t.c.(H) microsomes from phenobarbital and hydrocortisone-treated rats by detergent solubilization and affinity chromatography with an overall 8% recovery. The purified enzyme has a minimum subunit molecular weight of 79 000 and contains one molecule each of FMN and FAD per 79 000 molecular weight. The purified hepatoma cytochrome P-450 reductase catalyzes electron transfer to artificial electron acceptors with Km values similar to those of purified liver reductase. The Km value of the hepatoma reductase for NADPH, 13 microM, is also similar to that of purified liver reductase. The tumor reductase appears immunochemically identical to liver reductase by Ouchterlony double-diffusion analysis and inhibition of activity. Peptide maps of the hepatoma and hepatic enzymes after proteolysis demonstrate the identity of the two proteins.
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PMID:Preparation of homogeneous NADPH-cytochrome P-450 reductase from rat hepatoma. 681 99

Tissue contents of NADPH and NADP+ were measured in freeze-clamped samples of normal rat liver and in four transplantable rat hepatomas covering a wide range of growth rates. Lowry cycling procedures were employed for analysis, using alkaline extracts for NADPH and acid extracts for NADP+. The mean NADPH content in 33 normal livers was 515 nmol/g wet weight, and mean NADP+ content was 311 nmol/g wet weight. In the four hepatomas, the amounts of both NADPH and NADP+ were low, and the extent of decrease correlated with tumor growth rate. In the slowly growing hepatoma 9618A, total NADP was slightly decreased (63% control) and more extensive decreases were observed in the medium growth rate tumors 47C and 8999 (38% and 19%, respectively, of control). In the rapidly growing hepatoma 3924A, total NADP was drastically decreased to 3% of the control liver value. Measurement of NADPH and NADP+ recovery from extracts of hepatoma 3924A showed that there were no inhibitors that might have blocked the activity of the assay enzymes. The NADPH/NADP+ ratio was close to the normal liver value in all four hepatomas. A 30-sec period of ischemia did not cause significant change in NADPH, but gave 33% decrease in liver NADP+. A 5-min period of ischemia decreased NADP+ to 50% of the zero-time value in liver, and to 71% in hepatoma 3924A, but was without effect on NADPH.
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PMID:Decreased content of reduced and oxidized nicotinamide-adenine dinucleotide phosphate in rat hepatomas. 715 Oct 32

It was shown that in contrast to normal liver cells the electron transport in the nuclear membranes of ascite hepatoma 22a cells proceeds much faster than that in microsomes. Using superoxide dismutase-sensitive adrenaline oxidation as an index of O2 formation, it was found that the hepatoma nuclear membranes contain an active O2-producing enzymatic system of a new type. This system differs from those described previously, e.g. it utilizes not only NADPH but also NADH as electron donors and reveals a high sensitivity to cyanide ([I] 50% approximately 10 mkM) and azide ([1] 50% approximately 0.2 mM). It is assumed that the site of cyanide-sensitive generation of O2 radicals in hepatoma 22a nuclei is the cytochrome fraction of the b5 type; the latter is activated by terminal desaturase of fatty acids. The high activity of O2 formation in ascite hepatoma nuclei associated with a low superoxide dismutase activity typical for the tumours suggests a shift in the equilibrium between generation and dismutation of O2 radicals in ascite hepatoma cells. The role of this shift in the selective action of some anticarcinogenic antibiotics, whose effects are mediated by O2 radicals, is discussed.
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PMID:[Electron transport systems in the membranes of rat liver nuclei and microsomes and of hepatoma 22a]. 728 78

The aromatic amines 2-aminofluorene (2AF), 2-acetylaminofluorene, and 2-aminoanthracene, and the heterocyclic amines 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline, and 3-amino-1-methyl-SH-pyrido[4,3-b]indole (Trp-P-2) were activated by rat liver cytosolic fractions to form mutagenic metabolites in Salmonella typhimurium strains TA98, TA98NR, and TA98/1,8-DNP6. In the case of the Trp-P-2, the cytosolic activation was even more potent than the microsomal activation, which is classically ascribed to N-hydroxylation and subsequent esterification. The cytosolic activation was a) NADPH-dependent, b) induced by pretreatment of rats with 3-methylcholanthrene and especially Aroclor 1254 but not by phenobarbital, and c) inhibited by dicoumarol. The hypothesis is that, following a preliminary oxidative step in the cytosol (pure cytosolic activation) or in microsomes via prostaglandin H synthase (mixed microsomal-cytosolic activation), an oxidized intermediate of amino compounds may serve as substrate for DT diaphorase activity and bielectronically reduced to the corresponding N-hydroxyamino derivative. Purified DT diaphorase, in the presence of either NADPH or NADH as electron donor, produced mutagenic derivatives from IQ and Trp-P-2. An NADPH-dependent activation of Trp-P-2 also occurred in the liver cytosol of woodchucks (Marmota monax), but was not inhibited by dicoumarol. As previously demonstrated with liver S-12 fractions in both humans and woodchucks, the cytosolic activation of Trp-P-2 was enhanced in animals affected by hepatitis B virus infection. This enhanced metabolism, which persisted even after appearance of primary hepatocellular carcinoma in virus carriers, is likely to be ascribed to mechanisms other than DT diaphorase induction, such as glutathione depletion.
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PMID:Cytosolic activation of aromatic and heterocyclic amines. Inhibition by dicoumarol and enhancement in viral hepatitis B. 753 25

Fatty acid synthase (FAS; EC 2.3.1.85) was purified to near homogeneity from a human hepatoma cell line, HepG2. The HepG2 FAS has a specific activity of 600 nmol of NADPH oxidized per min per mg, which is about half that of chicken liver FAS. All the partial activities of human FAS are comparable to those of other animal FASs, except for the beta-ketoacyl synthase, whose significantly lower activity is attributable to the low 4'-phosphopantetheine content of HepG2 FAS. We cloned the human brain FAS cDNA. The cDNA sequence has an open reading frame of 7512 bp that encodes 2504 amino acids (M(r), 272,516). The amino acid sequence of the human FAS has 79% and 63% identity, respectively, with the sequences of the rat and chicken enzymes. Northern analysis revealed that human FAS mRNA was about 9.3 kb in size and that its level varied among human tissues, with brain, lung, and liver tissues showing prominent expression. The nucleotide sequence of a segment of the HepG2 FAS cDNA (bases 2327-3964) was identical to that of the cDNA from normal human liver and brain tissues, except for a 53-bp sequence (bases 3892-3944) that does not alter the reading frame. This altered sequence is also present in HepG2 genomic DNA. The origin and significance of this sequence variance in the HepG2 FAS gene are unclear, but the variance apparently does not contribute to the lower activity of HepG2 FAS.
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PMID:Human fatty acid synthase: properties and molecular cloning. 756 99

Normal human liver tissue and cultured human hepatocytes are valuable models to study xenobiotic metabolism and toxicity, but they only have a limited in vitro life-span and are not readily available. This report describes the establishment of replicative cultures of human adult liver epithelial cells in serum-free medium. The longevity of three of these cultures, derived from different donors, was extended by introduction of the simian virus 40 large T antigen gene. Two cell lines, THLE-2 and -3, established with a recombinant simian virus 40 large T antigen virus have undergone > 100 population doublings, are nontumorigenic when injected into athymic nude mice, have near-diploid karyotypes, and do not express alpha-fetoprotein. The cells express cytokeratin 18 and albumin in early passage, whereas higher-passage cells in logarithmic-phase growth also express cytokeratin 19. THLE-2 and -3 cells metabolize benzo[a]pyrene, N-nitrosodimethylamine, and aflatoxin B1 to their ultimate carcinogenic metabolites that adduct DNA, which indicates functional cytochrome P450 pathways. Other enzymes involved in metabolism of chemical carcinogens, such as epoxide hydrolase, NADPH cytochrome P450 reductase, superoxide dismutase, catalase, glutathione S-transferases, and glutathione peroxidase are also retained by THLE cells. Thus, these immortalized human liver cells constitute an in vitro model for pharmacotoxicological studies and for the investigation of etiology and pathogenesis of human hepatocellular carcinoma.
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PMID:Simian virus 40 large tumor antigen-immortalized normal human liver epithelial cells express hepatocyte characteristics and metabolize chemical carcinogens. 768 15

The supernatant from human Hep G2 hepatoma cells was examined for typical enzymatic activities involved in the metabolism of xenobiotics. Neither cytochrome P-450 nor b5 was detectable, but associated enzymatic activities were found especially after induction with hydrocortisone (HC) and benzanthracene (BA) suggesting that this Hep G2 supernatant contains cyt P-450 IA1 and IA2. Other critical enzymes are also present, but, as expected, at lower activities than in Aroclor 1254 rat liver S9, except for NADH and NADPH cytochrome c reductase. Results of the Ames test indicate that the induced Hep G2 supernatant is a suitable activator for the evaluation of genotoxicity of indirect mutagens.
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PMID:Metabolic activation by a supernatant from human hepatoma cells: a possible alternative in mutagenic tests. 769 57

Mammalian organisms possess a variety of enzymes that catalyze the biotransformation of numerous chemicals with diverse structure. The gene superfamily comprising the cytochrome P-450 monooxygenases (P-450) are key participants in these reactions, and certain P-450 genes are highly inducible upon xenobiotic exposure. Many of the standard techniques used in the study of these systems rely on the disruption of tissues and cells, together with the preparation of subcellular particles. We have adopted a sensitive new technique, scanning laser cytometry, to monitor P-450-mediated O-dealkylation activities directly in cultured cells. Metabolism in single cells was quantified by fluorescence detection of resorufin, the P-450-mediated O-dealkylation product of alkoxyresorufin ether substrate probes. Functional activities associated with P-4501A1 and NADPH DT-diaphorase were compared among a human hepatoma (Hep G2) cell line and cells derived from mouse (Hepa 1clc7 wt) and rat (H4-II-E) hepatomas. Pretreating cells with the polyaromatic hydrocarbon inducer beta-naphthoflavone resulted in 50- to 100-fold increases in single cell rates of O-dealkylation of ethoxyresorufin (EROD activity). The use of scanning laser cytometry enabled in situ analysis of both constitutive and inducible biotransformation activities without disruption of cells or intracellular processes that determine the toxicologic fate of exogenous chemicals in vivo.
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PMID:Direct determination of functional activity of cytochrome P-4501A1 and NADPH DT-diaphorase in hepatoma cell lines using noninvasive scanning laser cytometry. 769 59

The protein-bound polysaccharide of Coriolus versicolor QUEL (PS-K) expresses superoxide dismutase (SOD) mimicking activity. Examination was made of the suppressive effects of PS-K on cancer cell lines cultured in vitro. SOD activity of incorporated PS-K was 5.88 u/mg in LLC-WRC-256 (Walker 256 fibrosarcoma) cells and 4.73 u/mg in NRK-49F (rat normal kidney fibroblast) cells. SOD activity in both cell types was enhanced about 7-8 times that of the original PS-K. PS-K was not incorporated into H4-11-E or H4-11-E-C3 (rat hepatoma) cells. SOD activity of 1 mg/ml PS-K incubated with cell homogenates of LLC-WRC-256 cells for 6 hours increased from 0.68 u/mg to 1.35 u/mg. SOD activity of PS-K 1 mg/ml in 0.05 M phosphate buffer incubated with 50 microM NADPH increased from 0.68 u/mg. The consumption of NADPH at the same concentration was confirmed spectrophotometically by incubation with PS-K. The mechanism for the enhancement of SOD activity associated with PS-K is considered to be collaboration with NADPH as an electron donor in the cytoplasm of cancer cells whose SOD and coupling enzyme activities are significantly lower than in normal cells.
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PMID:Suppressive effects on cancer cell proliferation of the enhancement of superoxide dismutase (SOD) activity associated with the protein-bound polysaccharide of Coriolus versicolor QUEL. 781 65


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