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)

Many structurally unrelated nonmutagenic peroxisome proliferators induce altered areas, neoplastic nodules, and hepatocellular carcinomas in rats. Unlike the lesions induced by genotoxic hepatocarcinogens, these lesions do not stain positively for the phenotypic markers gamma-glutamyl transpeptidase (GGT) and glutathione-S-transferase P (GST-P). To ascertain whether the absence of immunocytochemically detectable GST-P and GGT proteins in peroxisome proliferator-induced neoplastic lesions is due to the absence of specific mRNAs, we analyzed the total RNA isolated from hepatocellular carcinomas induced by three different peroxisome proliferators (ciprofibrate, Wy-14643, and BR-931) and the genotoxic carcinogens, 2-acetylaminofluorene and aflatoxin B1 (AFB), for the presence of GST-P, GGT, and alpha-fetoprotein (AFP) mRNAs. Northern and dot blot analysis of total RNA isolated from liver tumors induced by three different peroxisome proliferators revealed no detectable GST-P, GGT, and AFP mRNAs. GST-P mRNA was also not detected in a transplantable hepatocellular carcinoma established from a liver tumor induced by ciprofibrate. In contrast, GST-P mRNA levels were high in primary liver tumors induced by both 2-acetylaminofluorene and AFB and the two transplantable hepatocellular carcinomas established from such tumors. By immunoblot method, GST-P protein was found to be abundant in both primary and transplantable liver tumors induced by genotoxic carcinogens but not in those derived from peroxisome proliferator treatment. The GGT and AFP mRNAs were also not found in all 18 liver tumors induced by peroxisome proliferators that were analyzed and also in the ciprofibrate-derived transplantable liver tumor. The expression of GGT and AFP genes in liver tumors induced by 2-acetylaminofluorene and AFB was variable. These studies with peroxisome proliferators show that the GST-P and GGT gene derepression is not essential for the hepatocarcinogenesis or successful tumor transplantation. Further characterization of the molecular basis for the differential expression, particularly of the GST-P gene in liver tumors, may help identification of the critical event(s) in hepatocarcinogenesis by genotoxic carcinogens and nongenotoxic peroxisome proliferators.
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PMID:Lack of expression of glutathione-S-transferase P, gamma-glutamyl transpeptidase, and alpha-fetoprotein messenger RNAs in liver tumors induced by peroxisome proliferators. 245 33

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

This study deals with the role of glutathione transferase (GST)-mediated conjugation of (+)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-oxy-7,8,9,10- tetrahydrobenzo[a]pyrene (BPDE) in two mammalian cell lines, human mammary carcinoma cells (MCF-7) and rat hepatoma cells (H4IIE), in relation to their capacity to metabolize (-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene [(-)-BP-7,8-diol] to products that induce mutations in co-cultivated V79 cells. Both MCF-7 and H4IIE cells metabolized (-)-BP-7,8-diol to BPDE, but mutations in co-cultivated V79 cells were only detected with MCF-7 cells. However, depletion of glutathione (GSH) in H4IIE cells increased the mutagenicity of (-)-BP-7,8-diol to a similar level to that found with MCF-7 cells. Measurements of GST activity using GSH and post-microsomal supernatants from H4IIE, V79 and MCF-7 cells indicated a substantial difference in conjugation capacity. Although preparations from all three cell-lines showed GST activity with 1-chloro-2,4-dinitrobenzene as the substrate, GST activity towards BPDE could only be detected in supernatants from H4IIE cells. This is consistent with the presence of GST 7-7 an isoenzyme highly efficient in catalysing BPDE-GSH conjugation. The difference in GSH-conjugation activity towards BPDE was confirmed using intact H4IIE and MCF-7 cells in culture. These results indicate that GSH-conjugation plays a pivotal role in mutagenesis induced by polycyclic aromatic hydrocarbons (PAH). Accordingly, a deficiency in GSH-conjugation capacity may be regarded as one important factor in defining a target cell population with an increased risk for tumour initiation following exposure to PAH.
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PMID:Effects of glutathione transferase activity on benzo[a]pyrene 7,8-dihydrodiol metabolism and mutagenesis studied in a mammalian cell co-cultivation assay. 276 61

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

We have analyzed the cis-acting regulatory DNA elements of the placental rat glutathione S-alkyltransferase (GST-P) gene. Various regions of the 5' flanking sequence were fused with a bacterial chloramphenicol acetyltransferase gene. The transcriptional activity of each construct was determined by the transient expression assay after introduction into a hepatoma cell line. Multiple regulatory elements were identified. Two enhancing elements were located 2.5 and 2.2 kilobases upstream from the transcription start site and designated GST-P enhancers I and II (GPEI and GPEII, respectively). A consensus sequence of the phorbol 12-O-tetradecanoate 13-acetate responsive elements was present in the GPEI and at position -61. GPEII contained two of the simian virus 40 and one of the polyoma enhancer core-like sequences. A silencing element was also found 400 base pairs upstream from the cap site. In accordance with the above observation, endogenous GST-P gene was found to be stimulated when the rat fibroblast line 3Y1 was treated with phorbol 12-O-tetradecanoate 13-acetate. Phorbol 12-O-tetradecanoate 13-acetate enhanced the expression of the transfected GST-P gene to a much higher degree in HeLa cells than in the hepatoma cells, which constitutively expressed the endogenous GST-P. The results are discussed in terms of the specific derepression of GST-P gene during hepatocarcinogenesis in the rat.
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PMID:Multiple regulatory elements and phorbol 12-O-tetradecanoate 13-acetate responsiveness of the rat placental glutathione transferase gene. 320 Aug 31

We have used a rat glutathione S-transferase P (GST-P) complementary DNA as a probe to screen a human placenta complementary DNA library constructed in the lambda gt11 vector. One of the positive clones contained the complete coding region (630 base pair) and the entire 3'-noncoding region (78 base pair) of the putative human glutathione S-transferase pi (GST-pi) subunit mRNA. From the nucleotide sequence we deduced the complete amino acid sequence of the GST-pi subunit. It contained 209 amino acids with the relative molecular mass of Mr 23,224. Comparison of the amino acid sequences between GST-pi and GST-P subunits suggests that they are the corresponding enzymes in these species. GST-pi and GST-P both consist of 209 amino acids and differ in only 30 amino acids (85.6% homology). The difference in amino acid composition can explain the large difference in isoelectric point between GST-pi subunit (pI 5.5) and GST-P subunit (pI 6.9). The expression of GST-pi mRNA in some normal and cancerous tissues, including some hepatoma cell lines, hepatoma, and colon carcinoma specimens was determined using complementary DNA as a probe. The results indicate that the mode of the expression of GST-pi in humans is different from that of GST-P in rats.
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PMID:Structure and expression of a human class pi glutathione S-transferase messenger RNA. 366 69

The dose-dependent effects of three hepatocarcinogens were investigated by measuring the number and area of glutathione S-transferase placental form (GST-P)-positive foci and nodules appearing in the liver under short-term conditions (Experiment I) and evaluating the incidence of hepatocellular carcinoma after long-term chronic administration (Experiment II). For these purposes, three different doses of 2-acetylaminofluorene (2-AAF), 3'-methyl-4-dimethy-laminoazobenzene (3'-Me-DAB), and DL-ethionine (ethionine) were given to male F344 rats for 6 weeks after a single injection of diethylnitrosamine (DENA) in Experiment I or for 104 weeks without initiation by DENA in Experiment II. In Experiment I, the induction of GST-P-positive foci and nodules by 2-AAF and 3'-Me-DAB was clearly dose-dependent. In contrast, ethionine showed enhancing effects inducing GST-P-positive foci and nodules only in groups given the highest dose level. Similarly, in Experiment II, induction of hepatocellular carcinomas by 2-AAF and 3'-Me-DAB was clearly dose-dependent, whereas liver neoplasms were only induced by the highest dose level of ethionine. These results indicate that degree of induction of GST-P positive foci and nodules in a short-term in vivo test for liver carcinogens corresponds with the incidences of hepatocellular carcinomas revealed in a long-term in vivo assay.
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PMID:Comparative effects of carcinogens on the induction of placental glutathione S-transferase-positive liver nodules in a short-term assay and of hepatocellular carcinomas in a long-term assay. 383 82

Induction of Phase II enzymes of the [Ah] gene battery by L-buthionine (S,R)-sulfoximine (BSO) and other agents was examined in mouse hepatoma Hepa-1c1c7 cells. BSO, a nonelectrophilic inhibitor of gamma-glutamylcysteine synthetase (GCS), is routinely used to examine the toxicological implications of GSH depletion. Exposure to BSO for 24 h produced a 75-85% depletion of GSH levels, proportional to the inhibition of GCS activity, as well as small increases in the UDP-glucuronosyltransferase (UGT, 60%) and glutathione transferase (GST, 30%) enzyme activities in Hepa-1 wild-type (wt) cells. However, for the NAD(P)H:menadione oxidoreductase (NMO1) and cytosolic aldehyde dehydrogenase class 3 (AHD4) enzyme activities, BSO produced larger increases (110% and 170%, respectively). The mechanisms of NMO1 and AHD4 induction were examined further. In Hepa-1 wt cells, NMO1 and AHD4 activities were increased by the aromatic hydrocarbon inducer 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and by the electrophile tert-butylhydroquinone (tBHQ), known inducing agents for these enzymes. However, NMO1 and AHD4 were induced in Ah receptor nuclear translocation-defective mutant (c4) cells by BSO and tBHQ, but not by TCDD, suggesting that the induction by BSO and tBHQ is not Ah receptor-mediated. In wt cells, N-acetylcysteine produced a concentration-dependent increase in intracellular cysteine levels, but not GSH levels, in the absence or presence of BSO. Furthermore, N-acetylcysteine had no effect on NMO1 activity under any conditions examined, suggesting that GSH levels per se, rather than change in overall thiol status, might be mediating increased NMO1 activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Enzyme induction by L-buthionine (S,R)-sulfoximine in cultured mouse hepatoma cells. 757 30

The cells derived from the human embryo liver tissue were transfected with a plasmid pSV3neo containing both the large and small T-antigen gene of the early region of simian virus 40 (SV40), and two cell strains, OUMS-21 and -22, were obtained. OUMS-22 cells, to date, have reached over 100 population doublings through a culture crisis and are considered to have become an immortal cell line. However, OUMS-21 cells failed to become an immortal cell line. Both OUMS-21 and -22 cells were SV40 T-antigen-positive, epithelial-like, and immunoreactive against an anti-keratin 18 monoclonal antibody but against neither an anti-vimentin nor an anti-von Willebrandt factor VIII monoclonal antibody. The staining pattern of cytokeratin in these cells was similar to that in the differentiated human hepatoblastoma and hepatocellular carcinoma cell lines but not to that in the human cholangiocellular carcinoma cell lines. OUMS-21 and -22 cells expressed neither alpha-fetoprotein nor albumin mRNAs. These cells showed no tyrosine aminotransferase activity. However, both OUMS-21 and -22 cells were sensitive to cytotoxicity of aflatoxin B1, 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole, and benzo[a]pyrene, whereas human embryo lung fibroblasts were insensitive to the cytotoxicity of these carcinogens. These findings suggest that OUMS-21 and -22 cells may arise from undifferentiated liver stem cells or from hepatocytes that lost their ability to express the liver-specific functions prior to immortalization. Both OUMS-21 and -22 cells expressed glutathione S-transferase pi (GST-pi) mRNA. The expression of GST-pi mRNA highly increased in OUMS-22 cells with their immortalization. Karyotypic analysis showed that numerical and structural aberrations of the chromosomes were profound, but neither specific events nor marker chromosomes were found in OUMS-21 and -22 cells. Both OUMS-21 and -22 cells could grow in soft agar, but they were not tumorigenic when transplanted into nude mice.
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PMID:Immortalization of epithelial-like cells from human liver tissue with SV40 T-antigen gene. 768 77


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