Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Several inner membrane proteins from rat liver mitochondria have been translated for the first time in rabbit reticulocyte lysates. These include the Rieske iron-sulfur protein, cytochrome c1 and core protein I of the cytochrome bc1 complex, the alpha and beta subunits of F1 ATPase, and subunit IV of cytochrome oxidase. All were translated from free polysomes as larger-molecular-mass precursors, and were processed to their mature forms by isolated liver mitochondria or by the isolated mitochondrial matrix fraction. In vitro processing, catalyzed by the isolated matrix fraction, is inhibited by rhodamine 6G. The latter is a fluorescent probe, which accumulates specifically in mitochondria of whole cells and which is used extensively to visualize mitochondrial morphology. The concentration of rhodamine 6G required for inhibition in vitro is similar to that of o-phenanthroline. Rhodamine 6G inhibits matrix-catalyzed processing of all precursors tested, indicating that the mechanism of inhibition is common for a variety of functionally unrelated precursors. The novel action of rhodamine 6G reported here can form the basis for its inhibition of precursor processing in intact hepatoma cells [Kolarov, J. & Nelson, B.D. (1984) Eur. J. Biochem. 144, 387-392].
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PMID:Rhodamine 6G inhibits the matrix-catalyzed processing of precursors of rat-liver mitochondrial proteins. 286 95

Inhibition of protein synthesis superinduces transcription of the cytochrome P1-450 gene in Hepa 1c1c7 mouse hepatoma cells. The superinduced transcription rate is 10-15-fold higher than the maximal rate of transcription induced by the known inducer 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alone. Superinduction is maximal within 30-40 min and remains maximal for at least 90 min. Cytochrome P1-450 mRNA is the same length in TCDD-induced and superinduced cells. Superinduction does not occur in variant cells in which TCDD-receptor complexes bind weakly to nuclei and which do not transcribe the cytochrome P1-450 gene in response to TCDD. Inhibition of protein synthesis does not alter several properties of TCDD-receptor complexes. The results imply that a second control mechanism modulates the action of the TCDD-receptor complex in regulating cytochrome P1-450 gene transcription.
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PMID:Superinduction of cytochrome P1-450 gene transcription by inhibition of protein synthesis in wild type and variant mouse hepatoma cells. 298 7

The relationship of glucose intolerance and indocyanine green clearance to respiratory enzyme levels in liver mitochondria was studied along with standard liver function tests in 40 patients (8 cirrhosis, 19 cirrhosis with hepatoma, 13 non-cirrhotic with hepatoma). There was a negative correlation between cytochrome a(+a3) concentrations and phosphorylative activity per unit of cytochrome a(+a3) (r = -0.75, p less than 0.01), but no correlation between ICG-K and cytochrome a(+a3) concentrations. Cytochrome a(+a3) concentrations in cirrhotic patients with linear oral glucose tolerance pattern, characterized with no return toward normal glucose levels within 120 minutes after an oral glucose load, increased to 1.45 +/- 0.11 (10(-10) mol/mg of protein) compared with 0.90 +/- 0.07 in cirrhotic patients with parabolic OGTT pattern, characterized with a return toward normal glucose levels within 120 minutes (p less than 0.01) (0.82 +/- 0.02 in control patients without liver diseases). The former had high operative mortality regardless of ICG-K value and the latter had virtually uneventful clinical courses. It was suggested that increased cytochrome a(+a3) concentrations and impaired glucose tolerance might be responsible for decreased hepatic functional reserve and poor prognosis in cirrhotics.
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PMID:Relationship of glucose intolerance and indocyanine green clearance to respiratory enzyme levels in human cirrhotic liver. 299 74

We analyzed the function and sequence of a dioxin-responsive genomic element flanking the 5' end of the cytochrome P1-450 gene in high-activity variant mouse hepatoma cells. The element can regulate the mouse mammary tumor virus promoter. The element retains responsiveness to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) when the distance, the 5' or 3' position, and/or the 5' or 3' orientation with respect to the promoter are varied. The function of the element requires TCDD-receptor complexes. The element remains responsive to TCDD when transfected into cells from either a heterologous mouse tissue or a heterologous species (human). The DNA element and TCDD receptors together constitute a dioxin-responsive enhancer system.
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PMID:Control of cytochrome P1-450 gene expression: analysis of a dioxin-responsive enhancer system. 301 Mar 18

In laboratory animals and in mouse hepatoma cells in culture the Ah receptor previously has been shown to mediate induction of aryl hydrocarbon hydroxylase (cytochrome P1-450) by 3-methylcholanthrene, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds. We examined human lung cytosols to determine whether the Ah receptor was present in human tissues. Cytosol was prepared from grossly normal lung tissue obtained at pulmonary lobectomy for presumed lung cancer from 53 consecutive adult patients including 32 males (42-77 years old) and 21 females (18-81 years old). Ah receptor in the cytosols was identified and quantitated by specific binding of [3H]TCDD after separation by ultracentrifugation on sucrose gradients. Specific binding of [3H]TCDD to a component which met the criteria for Ah receptor was detected in 10 of the 53 specimens. As previously established in tissues from laboratory animals, the specific [3H]TCDD-binding component sedimented approximately 9S. Binding of [3H]TCDD to the 9S component was competitively inhibited by incubation in the presence of 2,3,7,8-tetrachlorodibenzofuran, dibenz(a,h)anthracene, and nonradioactive TCDD, all known to be potent agonists for Ah-receptor-mediated induction of aryl hydrocarbon hydroxylase. Specific Ah receptor also was detected in some specimens by direct binding of [3H]-3-methylcholanthrene. The human population studied exhibited striking heterogeneity in Ah receptor concentrations. Only 10 of the 53 individuals studied had detectable Ah receptor. In specimens with detectable specific binding, the mean concentration of binding sites was 6.9 +/- 1.2 (SE) fmol/mg cytosolic protein. These concentrations are approximately 10-30% of the concentrations of Ah receptor found in lung cytosols from laboratory animals. Our experiments indicate that the Ah receptor can be detected in lung cytosol from some humans and suggest that the regulatory mechanism mediating human cytochrome P1-450 induction may be similar to that in the murine model. Aryl hydrocarbon hydroxylase, the major enzyme induced under control of the Ah receptor, plays an important role in the metabolism of several carcinogens including polycyclic aromatic hydrocarbons such as benzo(a)pyrene. It is possible that differences in the Ah receptor content within the human population may be genetically based and that variation at the Ah receptor level may be an important determinant of individual susceptibility to certain chemically induced cancers.
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PMID:Ah receptor mediating induction of aryl hydrocarbon hydroxylase: detection in human lung by binding of 2,3,7,8-[3H]tetrachlorodibenzo-p-dioxin. 301 Dec 54

Ketoconazole, an imidazole derivative, is a member of a class of metabolic inhibitors acting specifically at cytochrome-P450 mediated reactions. We studied the effects of this compound on cholesterol synthesis, and on HMG-CoA reductase and LDL receptor activities, in cultures of human hepatoma cell line Hep G2. Ketoconazole, added in concentrations of 2-100 microM, inhibited cholesterol synthesis, and caused accumulation of lanosterol and dihydrolanosterol. Total mass formation of sterols was depressed. After 20 hr preincubation of the cells with the drug in these concentrations, activity of HMG-CoA reductase was markedly decreased, while the receptor-mediated binding, uptake and degradation of human LDL were increased. This increase is at least partly due to a higher affinity of LDL for its receptor. Ketoconazole prevented the fall in LDL-receptor activity caused by preincubation with LDL, whereas it did not affect the suppression caused by preincubation with exogenous mevalonate. These findings are discussed with respect to the involvement of endogenous sterol and non-sterol effectors of reductase and receptor activities.
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PMID:Effect of ketoconazole on cholesterol synthesis and on HMG-CoA reductase and LDL-receptor activities in Hep G2 cells. 303 62

A mouse hepatoma cell line, Hepa-1, is highly sensitive to the toxic effects of Aflatoxin B1 (AFB1). Half maximal survival (LD50) of cells occurs at 0.068 ug AFB1/ml. Benzo(a)anthracene, which induces aryl hydrocarbon hydroxylase and cytochrome P1-450 in Hepa-1, causes a slight increase in the toxicity of AFB1 (LD50 = 0.034 ug/ml). An aryl hydrocarbon hydroxylase- and cytochrome P1-450-deficient mutant of Hepa-1 is, however, over 100 times more resistant to AFB1 than Hepa-1. Almost no decline in survival is observed at 5 ug AFB1/ml. Cytochrome P1-450 thus effects strongly on the cytotoxicity of AFB1 in these cells. The basal activity in Hepa-1 is enough to elicit an almost full toxic effect. AFB1, although a substrate for cytochrome P1-450, does not act as an inducer of aryl hydrocarbon hydroxylase.
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PMID:Mechanism of cytotoxicity of aflatoxin B1: role of cytochrome P1-450. 310 20

The presence and location of cytochrome P-450 in Donryu rat hepatocyte culture lines, Ac2F cells and 3 other cell lines were assessed by indirect immunofluorescence examination using anti-cytochrome P-450 monoclonal antibodies. Ac2F cells and other hepatocyte cell lines were selectively stained at their nuclear envelope, but not the cytoplasm, with a monoclonal antibody selective to a high-spin form of cytochrome P-448 (P-448H), although this monoclonal antibody stained primary cultured normal rat hepatocytes at both cellular components and did not stain hepatoma cells of 2 transplantation lines. The results of unscheduled DNA synthesis assay with Ac2F cells using several carcinogenic aromatic amines (4-aminoazobenzene derivatives and amino acid pyrolysis products) suggested that this nuclear envelope-associated cytochrome P-450 activates a restricted portion of these aromatic amines, i.e., a tryptophan pyrolysis component and a glutamic acid pyrolysis component. These results indicate that rat hepatocyte culture lines lack (or contain a reduced amount of) the cytoplasmic cytochrome P-450 but maintain a characteristic type of cytochrome P-450, probably a kind of cytochrome P-448H in their nuclear envelope, and this may be involved in oxidative metabolism of a restricted portion of aromatic amines.
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PMID:Immunochemically detected nuclear envelope-associated cytochrome P-450 component(s) in rat hepatocyte culture lines. 311 63

We have shown previously that 2,3,4,5-tetrachlorobiphenyl is ineffective as an inducer of rat liver microsomal cytochrome P-450. Addition of a single para-chloro substituent in the otherwise unsubstituted phenyl ring, to give 2,3,4,4',5-pentachlorobiphenyl, produces a potent cytochrome P-450 inducer with both phenobarbital- and 3-methylcholanthrene-type characteristics. In the present study, 2,3,4,5-tetrachlorobiphenyl was substituted in the para(4') position with 12 other functional groups. The 4'-X-C12H5Cl4 derivatives were tested as inducers of cytochromes P-450a--P-450e and epoxide hydrolase, by immunochemical analysis of liver microsomes prepared 4 days after a single treatment (500 mumol/kg) of 1-month-old male Long Evans rats. When the para' substituent was a halogen (F, Cl, Br or I), the derivative induced both cytochromes P-450b and P-450e, and cytochromes P-450c and P-450d, which are the major phenobarbital- and 3-methylcholanthrene-inducible isozymes, respectively. A similar type of induction was observed with a second group of derivatives substituted with CN, NO2 or CF3. However, a derivative containing CH3CO--(which is also a meta-directing, ring-activating substituent) failed to induce cytochromes P-450a-P-450e at the dosage and time tested. Members of a third group of derivatives, which contained an ortho/para-directing, ring-activating substituent) were either ineffective inducers (OH, CH3, CH3O--), or were inducers of cytochromes P-450c and P-450d (isopropyl or t-butyl). Hence, 4'-substitution with a bulky lipophilic substituent conferred 3-methylcholanthrene- but not phenobarbital-type characteristics on 2,3,4,5-tetrachlorobiphenyl. Some of the derivatives tested, namely those substituted with Cl, Br, I and CF3, were remarkably effective inducers of cytochrome P-450a, causing a 10-11-fold induction of this isozyme. Data on the induction of cytochrome P-450c were analyzed by multiparameter linear regression in an attempt to correlate the biological activity of the 4'-X-C12H5Cl4 derivatives with the physiochemical properties of the various substituents. From these results, and those reported recently, we propose that binding of the 4'-X-C12H5Cl4 derivatives to the rat cytosolic Ah receptor is favored by increasing the electronegativity, lipophilicity and hydrogen bonding characteristics of the 4' substituent, whereas enzyme induction (both in vivo and in cultured rat hepatoma cells) is also governed by a fourth characteristic, the STERIMOL factor, which gives a measure of the width of the substituent.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Induction of rat liver microsomal cytochrome P-450 isozymes and epoxide hydrolase by a series of 4'-substituted-2,3,4,5-tetrachlorobiphenyls. 314 31

The identification of etiological agents in feral fish neoplasia epizootics has been hampered in part by the lack of suitable fish models, and complicated by the likely existence of environmental agents which can act to stimulate or reduce population responses to genotoxin insult. The response of fish to tumor inhibitors and promoters, and the underlying mechanisms of modulation, have been studied in the rainbow trout model. Dietary treatment of trout with the compounds indole-3-carbinol (I3C), beta-naphthoflavone (BNF), or the polychlorinated biphenyl (PCB) complex Aroclor 1254, before and during exposure to aflatoxin B1 (AFB1), was shown to reduce the final incidence of hepatocellular carcinoma after 12 months, compared to fish receiving AFB1 only. By contrast, treatment of trout with BNF or I3C following AFB1 initiation led to a significant enhancement of ultimate tumor response. Similarly, simultaneous treatment of trout with PCB and the carcinogen N-nitrosodiethylamine led to syncarcinogenic enhancement, rather than inhibition, of tumor response. Mechanisms of inhibition of AFB1 carcinogenesis by PCB, BNF, and I3C were investigated. PCB and BNF, but not I3C, are known to be strong inducers of trout cytochrome P448 and associated activities. Dietary induction by BNF or PCB was shown to be accompanied in isolated hepatocytes by considerably altered AFB1 metabolism, and by significantly reduced rates of DNA adduct formation for all three agents. All agents differentially altered in vivo AFB1 pharmacokinetics, enhanced bile elimination of AFB1 as the aflatoxicol-M1 glucuronide, and significantly reduced peak levels of liver DNA adduct formation. No effects were seen on repair of AFB1-DNA adducts, which was very slow in trout.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Initiation, promotion, and inhibition of carcinogenesis in rainbow trout. 329 57


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