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)

The effects of hepatocarcinogens (ethionine, thioacetamide, phenobarbital), non-hepatocarcinogens [N-ethyl-N-(4-hydroxybutyl)nitrosamine (EHBN), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)] and a hepatoinhibitor [(butylated hydroxyanisole (BHA)] were compared in medium- and long-term in vivo systems. In experiment I, 2 weeks after a single injection of diethylnitrosamine (DEN) groups of male F344 rats received chemical administration for 6 weeks, combined with partial hepatectomy at week 3 and were killed at the end of week 8. In experiment II, animals were treated in the same manner and then given basal diet and tap water (group 1) or chemical continuously (group 2) until the 2 year timepoint. Numbers and areas of glutathione S-transferase placental form (GST-P)-positive foci developing in the liver under medium-term bioassay conditions (experiment I) were found to closely correlate with eventual hepatocellular carcinoma incidences after continuation of test chemical administration (experiment II). Thus all of the hepatocarcinogens enhanced both the induction of GST-P-positive focal lesions and liver tumors. While non-hepatocarcinogens exerted no such effects, their influence being limited to inducing lesions in their own respective target organs such as urinary bladder cancers in the EHBN case and glandular stomach adenocarcinomas with MNNG, BHA demonstrated inhibition potential in both experiments. The observed correlation between long- and medium-term results strongly indicates the applicability of our medium-term bioassay system for detection of liver carcinogens.
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PMID:Correlation between medium-term liver bioassay system data and results of long-term testing in rats. 232 97

Liver tissues of LEC rats, which develop fulminant hepatitis and hepatocellular carcinoma (hepatoma), were examined by Northern blot analysis using a cDNA probe of rat placental glutathione S-transferase (GST-P). GST-P gene expression was observed not only during hepatocarcinogenesis but also in fulminant hepatitis before development of chronic hepatitis and hepatoma in LEC rats. Cholangiofibrosis in LEC rats also showed high GST-P expression. A transplantable cell line derived from spontaneous LEC hepatoma exhibited a remarkably high expression. By contrast, very weak expression was observed in the livers of young LEC rats before development of hepatitis and control strain rats. Thus, spontaneous hepatic lesions in LEC rats may provide a new clue to elucidate the mechanism of GST-P gene expression.
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PMID:Gene expression of placental glutathione S-transferase in hereditary hepatitis and spontaneous hepatocarcinogenesis of LEC strain rats. 248 61

The effect of clofibrate (CF) on proliferation of diethylnitrosamine (DEN)-initiated glutathione S-transferase placental form (GST-P)-positive preneoplastic and neoplastic lesions as studied in male F344 rats. Animals were given a single i.p. injection of 200 mg/kg body weight of DEN, and then from 2 weeks later were given a diet containing 0.3% CF (group 1), or no supplement (group 2) until week 64. Group 3 received an injection of 0.9% NaCl instead of DEN and then a diet containing 0.3% CF, like group 1. Animals in all groups were subjected to partial hepatectomy at week 3 and killed at weeks 8, 20, 32, 49 or 64. The results showed that development of GST-P-positive lesions was significantly less in group 1 than in group 2 from week 8 (P less than 0.05). However, in group 1, morphologically distinguishable GST-P-negative preneoplastic lesions increased from week 20 (P less than 0.05), and the total number of GST-P-positive and -negative lesions was significantly greater than that in group 2 from week 32 (P less than 0.05). The induction of hepatocellular carcinoma (HCC) was greater in group 1 than in group 2 from week 49. All the HCCs induced in group 2 were GST-P-positive, whereas 38.9% (7/18) of those in group 1 were GST-P-negative. In group 3, only a few GST-P-positive and/or -negative preneoplastic lesions developed by week 64. These results suggest that CF has tumor-promoting activity, and that GST-P-positive cells induced by DEN changed to GST-P-negative cells on subsequent treatment with CF.
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PMID:Modulation of diethylnitrosamine-initiated placental glutathione S-transferase positive preneoplastic and neoplastic lesions by clofibrate, a hepatic peroxisome proliferator. 268 52

Some reports link human hepatic porphyria with a risk of hepatocellular carcinoma. Hepatic protoporphyria and uroporphyria were induced in mice by feeding griseofulvin and hexachlorobenzene (HCB), respectively. These chemicals also cause liver cancer. Hepatic immunoreactive cytosolic levels of heme-binding Z protein (HBP) were reduced by 81% (griseofulvin) and 55% (HCB). In contrast, both treatments caused a greater than 4-fold increase in the immunoreactive levels of glutathione S-transferase isozymes (GST) which like HBP also bind heme. Unlike in vitro studies in the presence of porphyrins, no cross-linking of HBP was observed in vivo.
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PMID:Modulation of hepatic heme-binding Z protein in mice by the porphyrogenic carcinogens griseofulvin and hexachlorobenzene. 273 Nov 54

The synthesis of the glutathione S-transferase Ya subunit is induced in the mammalian liver by chemicals such as phenobarbital and 3-methylcholanthrene. To study the mechanism of this induction, the 5'-flanking region of a mouse glutathione S-transferase Ya subunit gene was fused to the structural gene for chloramphenicol acetyltransferase. The fusion gene was introduced into hepatoma cells for the assay of the expressed acetyltransferase activity. At least two cis-regulatory elements were identified in the 5'-flanking region of the Ya gene: one, responsible for the basal level of expression, is present in the sequence up to -0.2 kb; another, responsible for the inducible expression by aromatic compounds such as beta-naphthoflavone and 3-methylcholanthrene, is located in the sequence from -0.2 kb to -1.6 kb. The inducible element was functional only in cells with normal aromatic compound receptors, and it retained responsiveness to beta-naphthoflavone when transfected into homologous (mouse) or heterologous (rat, human) hepatoma cells. A 150-bp region upstream from the transcription initiation site of the mouse Ya gene was investigated for cis-acting transcriptional elements that are recognized by specific DNA-binding proteins. We show by DNase I foot-printing assays using extracts from liver nuclei that the Ya gene promoter contains, in addition to the TATA and CCAAT boxes, a more distal element that binds a protein which is probably related to the family of nuclear factor 1 (NF1).
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PMID:Regulatory elements controlling the basal and drug-inducible expression of glutathione S-transferase Ya subunit gene. 277 26

Spontaneous occurrence of placental glutathione S-transferase (GST-P)-positive foci was observed in the livers of 5-month-old LEC rats. Quantitative studies revealed that GST-P foci appeared after the onset of hepatitis. The number and size of GST-P foci increased with age and more foci were induced in males than in females. No sex difference, however, was found in the incidence of hepatitis. Although hepatitis is necessary for the induction of GST-P foci, it is insufficient for their further growth. Since hereditary hepatitis first appears at around 4 months of age, leading to a high incidence of hepatocellular carcinomas in later life, the spontaneous occurrence of the foci may be related to the development of hepatocellular carcinoma.
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PMID:Spontaneous occurrence of placental glutathione S-transferase-positive foci in the livers of LEC rats. 289 58

A cDNA library prepared from poly(A)+ RNA of 2-acetylaminofluorene (AAF) induced rat hepatocellular carcinoma was screened by synthetic DNA probes deduced from a partial amino acid sequence of glutathione S-transferase P subunit that had been isolated from the tumor by two-dimensional gel electrophoresis. One of the four clones analyzed contained an mRNA region encoding the total amino acid sequence of this enzyme subunit and the complete 3'-noncoding region. The nucleotide sequence indicates that this enzyme subunit has 209 amino acids (calculated Mr=23,307) distinct from other glutathione S-transferase subunits such as Ya and Yc. Comparison of the amino acid sequences between these proteins indicates that glutathione S-transferase P subunit gene has been evolved from the ancestral gene at an earlier stage than the separation of Ya and Yc and that there are at least three domains having a considerable homology with each other in these enzymes. The very large increase of this mRNA in chemically induced hepatocellular carcinoma suggests a characteristic derepression of this gene during hepatocarcinogenesis.
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PMID:Cloning and the nucleotide sequence of rat glutathione S-transferase P cDNA. 299 15

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 effect of 30 week intake of a choline-deficient (CD) diet on cytosolic glutathione S-transferase (GST) activity was investigated in rats of both sexes. GST activities in choline-supplemented (CS) control male cytosol were higher than those in CS-female cytosol for five test substrates--1-chloro-2, 4-dinitrobenzene (CDNB), 1,2-epoxy-3-(p-nitrophenoxy)-propane, trans-4-phenyl-3-buten-2-one, p-nitrobenzyl chloride (PNBC) and 1,2-dichloro-4-nitrobenzene (DCNB). The CD dietary regimen produced a relatively uniform decrease in GST activities in male liver to 37-59% of CS-control. With the exception of CDNB conjugation, GST activities in CD-male and CS-female cytosols were not significantly different. On the other hand, in female rats, the CD diet increased GST activity with PNBC and DCNB as substrates to 153 and 204% of respective CS-control female activities; other GSTs were unchanged. Hepatic cytosols from female rats were subfractionated on Whatman CM-52 and subjected to electrophoresis on polyacrylamide gels. The principal finding was that the relative concentration of GST subunit 3 (mol. wt approximately 27 kd) was apparently increased in CD-female rat cytosol; a finding that is consistent with the observed increase in DCNB- and PNBC-conjugation. Thus it is apparent that intake of the tumorigenic CD diet by male rats results in the feminization of GST activity, whereas in females GST subunit 3 is upregulated. The impaired regulation of these enzymes in CD-rats is an early event in relation to the development of hepatocellular carcinoma.
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PMID:Sex- and substrate-dependent changes in hepatic cytosolic glutathione S-transferase enzymes produced by dietary choline-deficiency. 334 83

Fischer F-344 male rats, fed a choline-devoid diet that leads to a highly reproducible sequence of biochemical and biological changes with an ultimate development of hepatocellular carcinoma, show elevated levels of glutathione in the liver at 3, 6 and 8 days. Several enzymes related to the metabolism of free radicals, including superoxide dismutase, catalase, glutathione peroxidase, glutathione S-transferase and DT-diaphorase show neither increased nor decreased activity as measured between 12 h and 8 days on the diet. Thus, of several known cellular components related to the possible scavenger of free radicals in the liver, only glutathione responded to the feeding of the CD diet. It is tentatively concluded that a decrease in the levels of possible scavengers for free radicals is not a major basis for the nuclear and mitochondrial lipid peroxidation seen early in rats fed a choline-devoid diet.
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PMID:Glutathione and enzymes related to free radical metabolism in liver of rats fed a choline-devoid low-methionine diet. 339 Aug 3


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