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)

Short-term treatment of rats with hepatocarcinogens elicits a consistent pattern of phenotypic changes in hepatic drug metabolizing enzymes, the most striking of which is a marked increase in microsomal epoxide hydrolase (EH) activity. The antihistaminic drug methapyrilene induces a high incidence of hepatocellular carcinoma in F-344 rats. The studies reported here were designed to assess the effects of methapyrilene on hepatic EH activity, cytochrome P-450-dependent mixed-function oxidase activities, liver morphology, and liver-derived serum enzymes. Male F-344 rats were treated with three daily oral doses of methapyrilene-HCl, up to 300 mg/kg/day, and were sacrificed 48 hr after the last dose. Hepatic microsomal EH and cytosolic DT-diaphorase activities were increased in a dose-related fashion, to 420 and 230% of control, respectively. Cytochrome P-450 content and benzphetamine-N-demethylase and ethoxycoumarin-O-deethylase activities were concomitantly decreased to 35-50% of control. Serum gamma-glutamyl transpeptidase and alanine aminotransferase activities were elevated 22- to 27-fold, and serum bile acids to 36-fold by treatment with methapyrilene. Periportal lesions, characterized by inflammation, nuclear and nucleolar enlargement, bile duct hyperplasia, and hepatocellular necrosis, were observed following methapyrilene administration. The severity of the periportal lesion correlated with elevations in the serum chemistry parameters. The increases noted in microsomal EH activity supports the suggestion that this enzyme may be a useful biochemical marker for exposure to hepatocarcinogens.
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PMID:Effects of methapyrilene on rat hepatic xenobiotic metabolizing enzymes and liver morphology. 285 28

In an attempt to elucidate the relationship between the antiglucocorticoid effect and the state of differentiation of the target cells, we studied the metabolism of the potent antagonist in cultured liver and hepatoma cells (HTC, FAZA). After incubation of [3H]RU38486 with the cells for different periods of time, the native steroid and its metabolites were extracted and analyzed by thin layer chromatography. We observed that RU38486 was not metabolized in the transformed cell lines after a 3 h incubation. In contrast RU38486 was extensively metabolized in cultured liver cells. The observed degration could help explain why RU38486 inhibited tyrosine aminotransferase induction in hepatoma cells at a concentration 100 times lower than that needed in liver cells. Moreover this catabolism concerned specifically the antagonist RU38486 since other steroids tested (dexamethasone, promegestone) underwent a much slower degradation. Indirect experiments suggest that the alterations of the RU38486 molecule might be at least partially related to the cytochrome P-450 which is very active in the hepatocytes. This study was paralleled by testing the effect of the antagonist on the growth of hepatoma cells. RU38486 exerted an antiproliferative effect in absence of serum. On the basis of the low metabolism of RU38486 and of its antiproliferative effect in hepatoma cells. one can emphasize that RU38486 might represent a potential drug for use in cancer therapy.
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PMID:Metabolism and antiproliferative effect of the glucocorticoid antagonist RU38486 in cultured liver and hepatoma cells. 287 Dec 31

Employing Reuber rat hepatoma cells, H4-II-E, the effects of aflatoxin B1 (AFB1) and sterigmatocystin (STC), which exhibit a similar cytotoxicity but a marked difference in hepatocarcinogenicity, on the hormonal induction of tyrosine aminotransferase (TAT), on glucocorticoid receptors, and on their nuclear acceptor sites were investigated. AFB1 strongly inhibited hydrocortisone-inducible TAT activity. The IC50 value was 0.2 micrograms/ml. AFB1 also showed weak inhibitory effects on insulin- and dibutyryl cyclic AMP-inducible TAT activities. In contrast, the IC50 of STC on hydrocortisone-inducible TAT activity was 3.5 micrograms/ml, about 10 times higher than that of AFB1. Dibutyryl cyclic AMP- and insulin-inductions were not depressed by STC. AFB1 inhibited the formation of cytosolic glucocorticoid receptor-hormone complexes (GRCs) but STC did not. Moreover, AFB1, activated in vitro by the microsomal cytochrome P-450 system, interfered more markedly in the formation of cytosolic GRCs than STC did. Sucrose density gradient analysis of GRCs and Scatchard analysis revealed that AFB1 and STC mainly impaired glucocorticoid receptors and GRC-acceptor sites, respectively. The present data suggest a marked difference between AFB1 and STC with regard to the inhibition of hormonal induction of liver specific enzymes.
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PMID:Modulation of hormonal induction of tyrosine aminotransferase and glucocorticoid receptors by aflatoxin B1 and sterigmatocystin in Reuber hepatoma cells. 290 Jun 79

Lipid peroxidation of microsomal membranes isolated from rat liver, and Morris hepatomas 9618A (slow-growing) and 3924A (fast-growing) was induced by superoxide radicals generated by the action of xanthine oxidase on xanthine. The peroxidation, measured as malondialdehyde and lipid hydroperoxide formation, was optimized with regard to iron concentration and chelation of iron by ADP. In such conditions hepatoma microsomes catalyze lower rates of lipid peroxidation than the normal counterpart. However, while microsomes from hepatoma 3924A show a marked decrease in both the malondialdehyde and hydroperoxide production rates, microsomes from hepatoma 9618A differ moderately from the control, mainly in the long-term production of hydroperoxides. It is also reported here that the 9618A microsomes partially lack cytochrome P-450 (about 40% deficiency), but they have a fatty acid composition similar to that of control. No differences were found in the content of vitamin E between normal and hepatoma 3924A microsomes. Moreover, induction of vitamin E deficiency in hepatoma 3924A microsomes does not influence the rate of either malondialdehyde or lipid hydroperoxide production. On the basis of these results and previous data on the lipid composition of hepatoma 3924A microsomes it is proposed that the high resistance to superoxide-dependent lipid peroxidation of hepatoma 3924A microsomes is related to the low substrate availability rather than the content of membrane antioxidants; and a limitation only in the propagation phase characterizes the hepatoma 9618A microsomal lipid peroxidation and would be due to the partial deficiency of the endogenous propagating agent, cytochrome P-450.
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PMID:Superoxide-dependent lipid peroxidation and vitamin E content of microsomes from hepatomas with different growth rates. 298 56

The quantitative structure-activity relationships (QSARs) for polychlorinated biphenyl (PCB) congeners have been determined by comparing the EC50 values for three in vitro test systems, namely, aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O-deethylase (EROD) induction in rat hepatoma H-4-II-E cells and competitive binding avidities to the rat cytosolic receptor protein (using 2,3,7,8-tetrachlorodibenzo-p-dioxin as a radioligand). For several PCB congeners that are in vivo inducers of rat hepatic microsomal AHH, there was a linear correlation between the -log EC50 values for receptor and the -log EC50 values for AHH (or EROD) induction; moreover, a comparable linear relationship was observed between the -log EC50 values for AHH and EROD induction. Previous in vivo studies have shown that the most active PCB congeners 3,3',4,4'-tetra-, 3,4,4',5-tetra-, 3,3',4,4',5-penta-, and 3,3',4,4',5,5'-hexachlorobiphenyl, cause many of the biologic and toxic effects reported for the highly toxic halogenated aryl hydrocarbon, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Moreover, the monoortho-substituted homologs of the four coplanar PCBs also elicit comparable in vivo biologic and toxic responses. It was evident from the QSARs for PCBs that there was an excellent correspondence between the in vivo and in vitro potencies of the individual PCB congeners. The effects of substituents on both receptor binding and AHH/EROD induction was determined for a series of 4'-substituted (X)-2,3,4,5-tetrachlorobiphenyls (where X = H, Cl, Br, I, OH, OCH3, NO2, COCH3, F, CF3, CH3, C2H5, i-C3H7, n-C4H9 and t-C4H9). Not unexpectedly, there was a linear relationship between the -log EC50 values for AHH and EROD induction, and these results confirm that both enzymatic oxidations are catalyzed by the same cytochrome P-450 isozyme(s). The effects of substituent structure on receptor binding for 12 substituents was subjected to multiple regression analysis which correlates the relative binding affinities of the compounds with the physical chemical characteristics of the substituents. The analysis gave the following equation: log (1/EC50) = 1.53 sigma + 1.47 pi + 1.09 HB + 4.08 for n = 12, s = 0.18, r = 0.978; where n is the number of substituents, s is the standard deviation, r is the correlation coefficient, and sigma = electronegativity, pi = hydrophobicity (log P) and HB = hydrogen bonding capacity for the substituent groups.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effects of structure on binding to the 2,3,7,8-TCDD receptor protein and AHH induction--halogenated biphenyls. 299 47

Mitochondrial ATPase and adenylate kinase activity of hepatoma cells were inhibited by hematoporphyrin derivative (HPD) followed by photoirradiation. Inhibition of ATPase activity was a dose- and time-related event. Malonaldehyde (MDA) content of mitochondrial membranes was markedly increased by HPD plus light. The content of mouse liver microsomal cytochrome P-450 was greatly increased after intraperitoneal injection of HPD for 4 days (5 mg/kg/day). The liver weight, and levels of liver microsomal G-6-phosphatase, MDA and triglyceride (TG) showed no difference in treated vs. control animals. The data presented here demonstrate that mitochondria may be a sensitive site of action of HPD photosensitization, and inactivation of ATPase and adenylate kinase may be an important contributing factor to tumor cell damage and death.
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PMID:Photosensitization of mitochondrial adenosine-triphosphatase and adenylate kinase by hematoporphyrin derivative in vitro. 300 50

Two fat soluble vitamins, Vitamins E and K, when added into culture medium, were found to increase aryl hydrocarbon hydroxylase activity in human cultured cells. The extent of induction in a hepatoma-derived cell line (Hep G2) by these vitamins is of similar magnitude to those cells receiving benz[a]anthracene; whereas in a mammary tumor-derived cell line (MCF-7), benz[a]anthracene is the best inducer for the hydroxylase activity. The increase of the hydroxylase activity is associated with increased levels of a specific mRNA coding for polynuclear aromatic hydrocarbons-induced form of cytochrome P-450 with Vitamins E and K treatment. The size of the induced mRNA is 3.3 kilobase which is the same as that of benz[a]anthracene treatment.
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PMID:Vitamins E and K induce aryl hydrocarbon hydroxylase activity in human cell cultures. 303 86

The pharmacokinetics of 1-(tetrahydro-2-furanyl)-5-fluorouracil (FT) and its conversion into 5-fluorouracil (FUra) in liver tissue were studied in ten patients with hepatocellular carcinoma (HCC). The plasma concentration of FT after its intravenous injection (dosage: 800 mg) was computerfitted to a bi-exponential function (C = Ae-alpha t + Be-beta t), indicating a two-compartment disposition. The pharmacokinetic parameters did not significantly differ between the five patients with, and the five without cirrhosis of the liver. The plasma concentrations of FUra likewise showed no significant difference between the two groups. The rates of FT degradation in the liver tissue homogenate were similar for four of the patients with cirrhosis (0.10 +/- 0.05 mumol/g liver protein/30 min) and four of those without it (0.13 +/- 0.05). The rates of cytochrome P-450-dependent FUra formation in the microsomal fraction of liver tissue from two patients (1.1 and 1.3 nmol/mg microsomal protein/30 min) were dramatically reduced to less than half of those of two control subjects (2.4 and 2.7). The estimated rates of FUra formation in the soluble fraction (105,000 X g supernatant fraction) from the two patients (0.1 and 0.13 nmol/mg protein/30 min) were almost identical to those from the controls (0.12 and 0.14), suggesting that the rate in the soluble fraction from HCC patients may not be as strongly affected as the rate in the microsomal fraction.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hepatic conversion of 1-(tetrahydro-2-furanyl)-5-fluorouracil into 5-fluorouracil in patients with hepatocellular carcinoma. 303 26

The present studies were aimed at evaluating the suitability of the differentiated Reuber hepatoma cells H4IIEC3/G- for monitoring permanent damage to the DNA caused by hepatotrophic chemicals. First we determined the profile of xenobiotic metabolizing enzymes. The cells expressed various cytochrome P-450-dependent monooxygenases, UDP-glucuronosyl-, phenol sulpho- and glutathione S-transferase, cytochrome c (P-450) reductase and carboxylesterases. We then established the conditions for genotoxicity testing in H4IIEC/G- cells. Induction of resistance against 6-thioguanine and appearance of micronuclei served as indicators for mutagenicity and clastogenicity, respectively. 6-Thioguanine-resistant H4IIEC3/G- cells were phenotypically stable for at least 30 cell cycles; recovery of 6-thioguanine-resistant cells was not significantly affected by the number of cells seeded for mutant selection up to at least 10(6) cells/100-mm dish; expression time of chemically induced mutants was 12-15 days; a period of 24 h after treatment appeared to be sufficient to allow for the formation of micronuclei. Finally we tested the genotoxic effects of promutagens which are typically activated or inactivated in liver. Aflatoxin B1, N-nitrosodiethylamine and cyclophosphamide were genotoxic to H4IIEC3/G- cells at concentrations of 10-30 nM, 2-20 mM and 1 mM, respectively. N-Nitrosodimethylamine and benzo[a]pyrene were not or only weakly cytotoxic and genotoxic to the cells, but this appears most likely to be due to protective mechanisms rather than to lack of metabolic activation. The results indicate that differentiated hepatoma cells such as H4IIEC3/G- offer a means of studying the potential of chemicals for inducing permanent DNA damage in liver cells.
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PMID:Mutagenicity, clastogenicity and cytotoxicity of procarcinogens in a rat hepatoma cell line competent for xenobiotic metabolism. 304 89

The continuous rat hepatoma cell line H4IIEC3/G- and rat hepatocyte primary cultures (hpc) were compared with regard to their capacity to metabolize structurally different promutagens. The sensitivities of both activation systems were evaluated by comparing the induction of SCE in H4IIEC3/G- cells themselves with that ih V79 cells co-cultured with hpc. Of the six chemicals tested, aflatoxin B1 (AFB1), cyclophosphamide, dimethylnitrosamine and nitrosomorpholine (NM) were shown to be inducers of SCE in H4IIEC3/G- cells as well as in V79 cells with hepatocyte activation. 7,12-Dimethylbenzanthracene gave positive responses in hpc/V79 co-cultures but not in H4IIEC3/G- cells whereas benzo[a]pyrene was negative in both systems. These results suggest that H4IIEC3/G- cells retain metabolic activities to convert different indirect mutagens into their active forms and clearly indicate the presence of liver specific cytochrome P-450-dependent mono-oxygenases. However, freshly isolated hepatocytes are more efficient in metabolizing the test compounds. Although hpc provide only external activation, the V79 cells system appears to be more sensitive for the detection of promutagens.
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PMID:Induction of SCE by indirect mutagens in cultured rat hepatoma cells and in Chinese hamster V79 cells co-cultivated with hepatocyte primary cultures. 307 Feb 93


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