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)

Liver microsomes of the rat contain a group of hydroxylating enzymes which are coupled to a greater or lesser degree to the electron flow system. In our studies, enzymes believed to be directly associated with the electron flow chain of NADPH, ferricyanide reduction, cytochrome c, cytochrome P-450 and substrate hydroxylation have been observed in livers obtained from normal, tumor-bearing and whole body irradiated rats as well as in Morris hepatoma 7777 and dimethyl-amino-biphenyl induced breast tumors.A significant difference appeared to exist in the activity of NADPH oxidase, NADP-ferricyanide reductase and benzopyrene hydroxylase when normal liver was compared with the liver obtained from a breast-tumor-bearing animal. Both cytochrome P-450 and cytochrome b(5) were decreased in the tumor-bearing animal.Tissue distribution of benzopyrene hydroxylase in normal, lactating and tumor-bearing Wistar rats has been studied.With the exception of NADPH oxidase, the activities of NADP-cytochrome c reductase, NADPH-ferricyanide reductase, benzopyrene hydroxylase and P-450 were markedly different in liver from Morris hepatoma 7777-bearing Buffalo rat when this was compared with homologous tissue obtained from normal Buffalo rat.Whole-body irradiated animals showed increased P-450 and NADPH oxidase activity in liver as a function of irradiation and there further appeared to be a correlation with decreased ferricyanide reductase activity.
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PMID:Mixed-function oxidation in tumors. 439 26

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

We administered a series of steroid hormones to primary nonproliferating cultures of adult rat hepatocytes and found that dexamethasone and other glucocorticoids but not sex steroid hormones, mineralocorticoids, or derivatives of pregnenolone other than pregnenolone 16 alpha-carbonitrile (PCN) stimulated de novo synthesis of an immunoreactive protein, indistinguishable from the form of cytochrome P-450 (P450PCN) induced by PCN in rat liver. No difference were discerned among purified liver cytochromes from rats treated with dexamethasone, PCN or dexamethasone plus PCN, among proteolytic digests of these proteins, or among the immunoprecipitated cytochromes prepared from cultured hepatocytes treated with these steroids as judged by electrophoresis on polyacrylamide gels containing sodium dodecyl sulfate followed by immunoblot analysis. Of the steroids tested, dexamethasone proved to be the most efficacious inducer increasing the rate of synthesis of P450PCN from 0.05% of total cellular protein synthesis in incubated control cultures (measured as incorporation of [3H]leucine into immunoprecipitable P450PCN) to as much as 9.4% in cultures incubated for 5 days in medium containing dexamethasone (10(-5) M). As with traditional glucocorticoid-responsive liver functions, induction of immunoreactive P450PCN was dependent on the concentration of dexamethasone (10(-8) to 10(-5) M) and was promptly reversed upon withdrawal of the steroid. However, during the 24-h interval between 24 to 48 h of culture age the hepatocytes were refractory to either induction or de-induction of immunoreactive P450PCN even though continuous exposure of the cells to dexamethasone (including this interval) was mandatory for maximal induction of P450PCN at 120 h in culture. Unlike cultured rat hepatocytes, HTC hepatoma cultures failed to exhibit dexamethasone-responsive expression of immunoreactive P450PCN. We conclude that glucocorticoids and PCN constitute a specific "class" of synthetic and endogenous inducers of a single form of cytochrome P-450.
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PMID:Induction of cytochrome P-450 by glucocorticoids in rat liver. I. Evidence that glucocorticoids and pregnenolone 16 alpha-carbonitrile regulate de novo synthesis of a common form of cytochrome P-450 in cultures of adult rat hepatocytes and in the liver in vivo. 614 Nov 67

Incubation of 14C-labeled cis and trans isomers of chlordane with cofactor-fortified mouse hepatic microsomes resulted in binding of insecticide-derived material to endogenous protein and RNA and to added DNA. The microsomes were prepared from male C57BL/6J mice. Chlordane is known to cause hepatocellular carcinoma in a similar strain. The highest concentrations of radioactive material bound to protein, followed by RNA and DNA. The cis isomer produced greater amounts of bound radioactivity, while binding from trans-chlordane was slight and, in the case of DNA, not detectable. Investigation of the effect of microsomal enzyme induction by chlordane isomers and phenobarbital on the yield of bound, chlordane-derived material gave mixed results. Generally, use of induced microsomes increased binding to protein and DNA and had no effect on binding to RNA. The inducers caused increased mixed-function oxidase activity, cytochrome P-450 content, and epoxide hydratase activity in experimental microsomes. Omission of the NADPH generating system from microsomal preparations had a variable effect on binding. Inhibition of epoxide hydratase reduced cis-chlordane-related binding to DNA to unmeasurable levels.
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PMID:Microsomal activation of chlordane isomers to derivatives that irreversibly interact with cellular macromolecules. 616 95

In preneoplastic rat liver nodules produced by 2-acetylaminofluorene, certain uridine diphosphate-glucuronyltransferase (UDP-GT) activities, which are ascribed to a distinct enzyme form, were selectively increased (5-fold). This enzyme form, operationally termed UDP-GT1, accepts 1-naphthol,4-methylumbelliferone, and 3-hydroxybenzo(a)pyrene as substrates and is chiefly inducible in liver by 3-methylcholanthrene-type inducers. Glucuronidation of other substrates (morphine, 4-hydroxybiphenyl, chloramphenicol, bilirubin, and estrone) was only slightly enhanced or decreased in nodular tissue. Differentially increased UDP-GT1 activities were also found in Morris hepatomas 9121 and 7777. Rabbit antibodies to rat liver UDP-GT1, purified from 3-methylcholanthrene-treated rats, demonstrated immunological similarity between the enzymes from liver, nodular tissue, and Morris hepatoma 9121. Rocket immunoelectrophoresis ascertained that enhanced enzyme activity in nodular tissue reflected an increased level of enzyme protein. Increased activity of UDP-GT1 together with decreased cytochrome P-450-dependent monooxygenase may contribute to the resistance of preneoplastic hepatocytes to the cytotoxic actions of chemical carcinogens.
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PMID:Increased uridine diphosphate-glucuronyltransferase activity in preneoplastic liver nodules and Morris hepatomas. 617 9

Cytochrome P-450 content (nmol/g of liver) differed within regions of rat liver according to proximity to intrahepatically implanted Morris hepatoma 7795 or 5123D. Liver adjacent to tumor had higher microsomal cytochrome P-450 content, decreased DNA content (mg/g of liver), and unaltered cytochrome c reductase activity compared to histologically indistinguishable liver far-removed from the tumor. Liver either adjacent to or far-removed from tumor contained markedly more cytochrome P-450 and higher cytochrome c reductase activity but less DNA than transplanted Morris hepatomas 7795 and 5123D that were grown intrahepatically. Compared to intramuscular implants of these same tumors, intrahepatically implanted Morris hepatomas 7795 and 5123D had increased cytochrome P-450 content. Tumor-containing liver from two human subjects revealed regional changes in cytochrome P-450-mediated monooxygenases similar to those observed in rats. These results suggest that histomorphically nontumorous mammalian liver directly adjacent to intrahepatic tumors exhibits previously unsuspected biochemical alterations.
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PMID:Enhanced drug-metabolizing capacity within liver adjacent to human and rat liver tumors. 624 68

The incorporation of lysophosphatidylcholine into biological membranes and its effect on some membrane-bound enzymes of mitochondria and microsomes from rat liver and hepatoma were studied. It was shown that in the presence of lipid-exchange proteins of the liver a far greater amount of lysophosphatidylcholine is incorporated into the membranes than in the-iv absence. The increase of the lysophosphatidylcholine content in the membranes has no effect on the activity of mitochondrial monoamine oxidase, inhibits the activity of microsomal cytochrome P-450 and activates glucose-6-phosphatase.
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PMID:[New method of lysophospholipid incorporation into biological membranes. Effect of lysophosphatidylcholine on the activity of membrane-bound enzymes]. 626 66

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

We have studied the expression of aldrin eposidase (AE), 7-ethoxycoumarin-O-deethylase (ECDE), and aryl hydrocarbon (benzo[a]pyrene) hydroxylase (AHH) in nine differentiated or dedifferentiated cell lines derived from H4IIEC3 rat hepatoma cells. The nature of the cytochromes P-450 mediating AE, ECDE and AHH activities was analysed using monoclonal antibodies (MAb) made to the major 3-methylcholanthrene-induced cytochrome P-450 (MAb-MC) or phenobarbital-induced cytochrome P-450 (MAb-PB) from rat liver. The cells were treated with 5 microM dexamethasone for 30 h to increase the levels of the monoxygenase activities. (a) The six differentiated cell lines examined (Faza967, Fao, HF1-4, 2sFou, C2Rev7, and H4IIEC3/G-) contained MAb-PB-sensitive AE comprising 30-75% of the total AE activity. In most of these cell lines MAb-PB also markedly inhibited ECDE; however, the antibody had a considerably weaker effect on AHH. (b) MAb-PB-sensitive AHH, ECDE and AE activities were also observed in untreated and phenobarbital-treated cells. (c) MAb-MC inhibited AHH and ECDE in the two dedifferentiated lines HF1 and H5 by 50-80%. The antibody also inhibited AHH activities in the poorly differentiated line H4IIEC3/T and in the majority of the differentiated lines by 40-65%. MAb-MC-sensitive AHH was found in Fao cells after treatment with benz[a]anthracene but induced AHH in H4IIEC3/T, H4IIEC3/G-, and 2sFou cells 20-30-fold and in Faza967 and Fao cells 3-5-fold. Benz[a]anthracene remained without effect on AHH activity in C2Rev7 cells. The results show that the hepatoma cells examined express to various degrees phenobarbital-inducible cytochrome P-450 and/or 3-methylcholanthrene-inducible cytochrome P-450. These cell lines are versatile tools for studying the regulation of monooxygenase activities and analysing their role in the activation and inactivation of xenobiotics such as carcinogens, drugs and pesticides.
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PMID:Expression of cytochromes P-450 in rat hepatoma cells. Analysis by monoclonal antibodies specific for cytochromes P-450 from rat liver induced by 3-methylcholanthrene or phenobarbital. 633 5

We have investigated the responsiveness of established rat hepatocyte cell cultures to inducers of cytochrome P-450. One Reuber hepatoma-derived line (Fu5-C8), which under normal culture conditions produces no detectable cytochrome P-450(MC) or cytochrome P-450(PB)--the major cytochrome P-450 isozymes induced by 3-methylcholanthrene and phenobarbital, respectively--was tested for the ability to accumulate either cytochrome P-450 isozyme in response to treatment with various xenobiotics. By immune-precipitation from [35S]-methionine-labeled cell extracts, using monospecific anticytochrome P-450(MC) antibody or monoclonal anticytochrome P-450(PB) antibody, it was demonstrated that these cells possess the capability to synthesize cytochrome P-450(MC) in response to 3-methylcholanthrene treatment, while none of the drug treatments caused the synthesis of detectable quantities of cytochrome P-450(PB). RNA extracted from Fu5-C8 cells directed the in vitro synthesis of immune-precipitable cytochrome P-450(MC) only after treatment of the cells with 3-methylcholanthrene. Kinetic analysis of the response of these cells to 3-methylcholanthrene induction revealed detectable levels of immune-precipitable cytochrome P-450(MC) 2 h after drug treatment with maximal induction occurring between 12 and 16 h of exposure. Another cell line (HF 1.5), obtained originally by hybridization of Fao X H5 variants of a Reuber H35 hepatoma, produces cytochrome P-450(MC) and also cytochrome P-450(PB) constitutively, as determined by specific immune-precipitation from labeled cell extracts. Exposure of confluent monolayers to either phenobarbital or 3-methylcholanthrene resulted in an induction of cytochrome P-450(PB) or cytochrome P-450(MC), respectively. Double-labeling immunofluorescence studies indicate that all cells in the culture produce albumin and most of the cells produce cytochrome P-450(MC), but only a subset of cells synthesize cytochrome P-450(PB). Our results demonstrate that some continuously dividing hepatocyte cell cultures retain the capacity to respond to xenobiotics, including phenobarbital, a response which is typically exhibited by fully differentiated liver cells. Such established hepatocyte cell cultures should prove useful for investigating the mechanism of induction of cytochrome P-450(PB).
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PMID:Induction of cytochrome P-450 isozymes in rat hepatoma-derived cell cultures. 637 29


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