Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.5.1.18 (glutathione S-transferase)
 22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The appearance of differentiated hepatocytes in the adult rat pancreas as well as pancreatic-type tissue in the adult rat liver can be experimentally induced (Reddy et al.: J. Cell Biol., 98:2082-2090, 1984; Rao et al., J. Histochem. Cytochem., 34:197-201, 1986). These observations suggest a lineage relationship between cell compartments present in rat liver and pancreas. The present data demonstrate that epithelial cell lines with almost identical phenotypes can be established from adult rat liver and pancreas. The established cell lines showed similar morphologies as established by light- and electron-microscopic studies. The cell lines showed a unique expression pattern of intermediate filament proteins. Vimentin, actin, and beta-tubulin were present in all cell lines. In addition, simple epithelial type II cytokeratins 7 and 8 were found to be coexpressed with the type I cytokeratin 14 in several of the cell lines. Neither the type I cytokeratins 18 and 19, which are the normal partners for cytokeratins 8 and 7 in filament formation, nor the type II cytokeratin 5 could be detected despite the fact that filaments were formed by both cytokeratins 8 and 14. This suggests that cytokeratin 14 acts as an indiscriminate type I cytokeratin in filament formation in the established cell lines. The cell lines expressed the same sets of LDH and aldolase isoenzymes and identical sets of glutathione transferase subunits. In addition, the epithelial cell lines from liver and pancreas were equally sensitive to the growth-inhibitory effects of TGF-beta 1. No expression of tissue- or cell-specific proteins such as alpha-fetoprotein, albumin, amylase, elastase, or gamma-glutamyl transpeptidase were detected. The almost identical phenotypes of the hepatic and pancreatic cell lines suggest that they may be derived from a common primitive epithelial cell type present in both rat liver and pancreas. In contrast to parenchymal cells, these cells have an extended capacity for proliferation in vitro and may represent a progeny from a "precursor" or "stem" cell compartment in vivo.
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PMID:Evidence for a common cell of origin for primitive epithelial cells isolated from rat liver and pancreas. 171 Feb 29

There is already evidence in alcoholic liver disease, mostly from studies of morphology and cytokeratin distribution, that hepatocytes can undergo a variety of phenotypic changes. This study reports findings of immunohistochemistry using antibodies against members of the glutathione S-transferase supergene family of detoxification enzymes. Hepatocytes in severe alcoholic liver disease coexpressed both alpha and pi class glutathione S-transferase. This coexpression has been previously described only in human fetal liver and in chemically-induced preneoplastic foci in rat liver. The use of function associated markers should provide additional information in the investigation of liver disease.
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PMID:Glutathione S-transferases in alcoholic liver disease. 238 16

The effect of a high dietary level of beta-carotene on the formation of preneoplastic and neoplastic respiratory tract lesions was studied in hamsters intratracheally treated with benzo[a]pyrene (B[a]P) attached to ferric oxide (Fe2O3) and suspended in saline. In addition to conventional histopathological examinations, the expression of cytokeratins and the glutathione S-transferase isoenzyme Pi (GST-Pi) was determined in tracheal epithelium using immunocytochemical techniques. B[a]P treatment increased the expression of cytokeratins in tracheal mucous and ciliated epithelial cells as detected by antibody RCK102 (cytokeratins 5 and 8), which normally recognizes basal cells only. The expression of cytokeratins in mucous and ciliated cells as detected by antibody RGE53 (cytokeratin 18) was decreased by B[a]P treatment. Furthermore, the expression of the cytokeratin detected by antibody RKSE60 (cytokeratin 10), characteristic of metaplastic squamous cells, and the expression of the GST-Pi, characteristic of metaplastic changes, was increased in trachael epithelium of hamsters treated with B[a]P. There was no evidence for dietary beta-carotene affecting the expression of cytokeratins or GST-Pi. The incidence of preneoplastic changes and tumors of the respiratory tract was not reduced by dietary beta-carotene. On the contrary, the tumor response of the respiratory epithelium was almost twice as high in hamsters fed the high beta-carotene diet than in hamsters on the low beta-carotene diet. However, this difference was not statistically significant (P = 0.15); hence, the present study did not produce evidence for a clear effect of beta-carotene on B[a]P-induced respiratory tract cancer in hamsters.
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PMID:Benzo[a]pyrene-induced respiratory tract cancer in hamsters fed a diet rich in beta-carotene. A histomorphological study. 747 73

Nodularin and microcystin-LR are cyanobacterial toxins and environmental hazards. Nodularin inhibits protein phosphatases 1 and 2A with the same potency as does microcystin-LR, which has recently been identified as a potent tumor promoter in rat liver. Our results suggested that nodularin is also a new tumor promoter in rat liver. A two-stage carcinogenesis experiment in rat liver initiated with diethylnitrosamine and without partial hepatectomy revealed that nodularin stimulated glutathione S-transferase placental form-positive foci in rat liver more effectively than did microcystin-LR, and that nodularin alone induced glutathione S-transferase placental form-positive foci as well as did diethylnitrosamine alone. Thus, nodularin itself is a new liver carcinogen, and microcystin-LR is a tumor promoter rather than a carcinogen. Nodularin induced hyperphosphorylation of cytokeratin peptides 8 and 18 in primary cultured rat hepatocytes 20% more effectively than did microcystin-LR, suggesting that nodularin penetrates more easily into the hepatocytes than does microcystin-LR. Nodularin up-regulated induction of c-jun, jun-B,jun-D,c-fos,fos-B, and fra-1 mRNA transcripts in rat liver after i.p. administration, and the accumulation of the mRNA transcripts was sustained for over 9 h after treatment. The environmental hazards of cyanobacterial toxins are discussed in relation to human primary liver cancer in Qidong county in the People's Republic of China. Our results support this hypothesis and indicate the need for prevention measures against cyanobacterial toxins.
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PMID:Nodularin, a potent inhibitor of protein phosphatases 1 and 2A, is a new environmental carcinogen in male F344 rat liver. 752 97

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

Expression of the mouse cytokeratin EndoA gene is regulated by an enhancer that is located 1 kilobases (kb) 3' downstream from the gene. The EndoA enhancer consists of six direct repeats with homology to the PEA3 motif in the polyoma virus enhancer core. The PEA3 motif binds to the proto-oncogene Ets product. In this report we show that GST-c-Ets-1 fusion protein binds specifically to the EndoA enhancer unit sequence by gel shift analysis. Footprinting showed that the Ets-1 binding site consisted of 20 bases in each repeat. Ets-1 also moderately activated the EndoA enhancer. These results demonstrate that Ets-1 binds in a sequence specific fashion to the mouse EndoA enhancer and suggest that c-Ets-1 or other related Ets family genes function in regulating EndoA gene expression.
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PMID:Sequence specific binding of Ets-1 to the mouse cytokeratin EndoA gene enhancer. 768 60

Indole-3-carbinol (I3C) was examined for its ability to inhibit aflatoxin B1 (AFB1)-induced hepatocarcinogenesis in male Fischer rats when administered either before or after the carcinogen. After 13 weeks, animals pretreated with I3C (0.5% in the diet) for 2 weeks prior to administration of AFB1 and with continuing treatment during exposure to the carcinogen were protected from development of preneoplastic lesions, as determined by the classical markers gamma-glutamyltranspeptidase (GGT) and glutathione S-transferase (GST) P. In animals receiving AFB1 for 6 weeks before treatment with I3C, there was no obvious protective effect at 13 weeks compared with animals receiving only AFB1. Using cytokeratin 18 expression as a marker, animals fed AFB1 alone had a small number of positive foci at 13 weeks. However, no cytokeratin-positive foci were visible in the majority of livers from either group receiving I3C in combination with AFB1 and after 43 weeks all animals in these groups were protected from liver tumour formation. These results suggest that expression of cytokeratin 18, a later phenotypic change in foci than induction of GST-P and GGT, correlates more closely with tumour outcome in this model. I3C appeared to retard progression of AFB1-induced carcinogenesis at both the initiation and promotion stages. Continuous treatment with I3C for 13 weeks caused significant induction of CYP1A1, 1A2, 3A and 2B1/2, GST Yc2, aflatoxin B1 aldehyde reductase and quinone reductase. Such alteration of the drug metabolizing capacity of the liver by I3C contributes to blocking of initiation, while the observed inhibition of ornithine decarboxylase, a rate limiting enzyme in polyamine biosynthesis, and of tyrosine kinase activity may contribute to the suppressive effect of I3C.
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PMID:Chemoprevention of aflatoxin B1-induced carcinogenesis by indole-3-carbinol in rat liver--predicting the outcome using early biomarkers. 980 66

The expression of glutathione (GSH)-dependent enzymes and cytochrome P450 (P450) proteins in freshly isolated proximal tubular cells from human kidney (hPT), and the effect of primary culture on these enzymes, were determined. Freshly isolated hPT cells had relatively high activities of gamma-glutamyltransferase, gamma-glutamylcysteine synthetase, glutathione S-transferase (GST), glutathione disulfide reductase, and GSH peroxidase. Cytochrome P450 4A11 was detected in freshly isolated hPT cells, whereas CYP2E1 was not. Freshly isolated hPT cells also expressed GSTA, GSTP, and GSTT but not GSTM. Primary cultures of hPT cells maintained their epithelial-like nature and diploid status, based on measurements of morphology, cytokeratin expression, and flow cytometric analysis. hPT cells retained GSH-dependent enzyme activities during primary culture, whereas cells that had undergone subsequent passage exhibited a loss of activities of most GSH-dependent enzymes and no longer expressed P450s or GSTs. CYP4A11 expression in primary cultures of hPT cells was significantly increased after treatment for 48 h with either ethanol (50 mM) or dexamethasone (7 nM). GSTA, GSTP, and GSTT contents, although still detectable, were decreased compared with those of freshly isolated hPT cells. Our data show that hPT cells express enzymes involved in xenobiotic disposition, and that they thus provide a model suitable for studies of human renal drug metabolism. Furthermore, primary cultures of hPT cells may afford the opportunity to study factors regulating P450 enzyme expression in human kidney.
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PMID:Expression of glutathione-dependent enzymes and cytochrome P450s in freshly isolated and primary cultures of proximal tubular cells from human kidney. 1077 44

Primary cultures of renal proximal (PT) and distal tubular (DT) cells from control and uninephrectomized (NPX) Sprague-Dawley rats were established to characterize factors that are responsible for the altered susceptibility to nephrotoxicants that occurs after compensatory renal cellular hypertrophy. Cells were grown in serum-free, hormonally defined medium and parameters were measured on days 1, 3, and 5 of primary culture. PT and DT cells from control and NPX rats appeared to maintain epithelial characteristics in culture, as shown by cytokeratin staining, morphology, protein and DNA content, and enzyme activities. Activities of several glutathione-dependent enzymes, including gamma-glutamyltransferase, glutathione S-transferase, glutathione peroxidase, and gamma-glutamylcysteine synthetase, were significantly greater in PT cells from NPX rats than in PT cells from control rats when factored by protein content. Rates of alpha-methylglucose uptake across the basolateral and brush-border membranes and sodium-dependent uptake of glutathione across the basolateral membrane were 2- to 3-fold higher in PT cells from NPX rats than in PT cells from control rats. These results are consistent with the hypertrophied phenotype being maintained in primary cultures of PT cells from NPX rats. The marked alterations in transport may play central roles in the delivery of nephrotoxicants to the target cell, and thus, increases the probability of chemically induced injury or death. These findings also suggest that these cell cultures may be useful for the study of biochemical processes associated with compensatory renal cellular hypertrophy.
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PMID:Biochemical and functional characteristics of cultured renal epithelial cells from uninephrectomized rats: factors influencing nephrotoxicity. 1116 Jun 4

Mass spectrometry-based proteomics can reveal protein-protein interactions on a large scale, but it has been difficult to separate background binding from functionally important interactions and still preserve weak binders. To investigate the epidermal growth factor receptor (EGFR) pathway, we employ stable isotopic amino acids in cell culture (SILAC) to differentially label proteins in EGF-stimulated versus unstimulated cells. Combined cell lysates were affinity-purified over the SH2 domain of the adapter protein Grb2 (GST-SH2 fusion protein) that specifically binds phosphorylated EGFR and Src homologous and collagen (Shc) protein. We identified 228 proteins, of which 28 were selectively enriched upon stimulation. EGFR and Shc, which interact directly with the bait, had large differential ratios. Many signaling molecules specifically formed complexes with the activated EGFR-Shc, as did plectin, epiplakin, cytokeratin networks, histone H3, the glycosylphosphatidylinositol (GPI)-anchored molecule CD59, and two novel proteins. SILAC combined with modification-based affinity purification is a useful approach to detect specific and functional protein-protein interactions.
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PMID:A proteomics strategy to elucidate functional protein-protein interactions applied to EGF signaling. 1257 67


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