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

---

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.
...
PMID:Evidence for a common cell of origin for primitive epithelial cells isolated from rat liver and pancreas. 171 Feb 29

Rat liver epithelial cells resistant to the growth-inhibitory effects of transforming growth factor beta 1 (TGF-beta 1) were isolated after 3 h exposure to 1.5 micrograms/ml of N-methyl-N'-nitro-N-nitrosoguanidine followed by continuous treatment with 1 ng/ml TGF-beta 1 for 6 weeks. In comparison to the parental or N-methyl-N'-nitro-N-nitrosoguanidine-exposed rat liver epithelial cells (concentration causing 50% inhibition of the rate of DNA synthesis, 0.25 ng/ml), these cells were 10-fold more resistant to the antiproliferative effects of TGF-beta 1 and exhibited resistance to growth inhibition by a highly purified liver-derived growth inhibitor, recombinant human tumor necrosis factor, and transforming growth factor beta 2. Single cell cloning of these resistant cells led to the isolation of a nontransformed clonal cell population (clone 11) which maintained stable resistance in the absence of TGF-beta 1 treatment. Binding of 125I-labeled TGF-beta 1 to rat liver epithelial cells and clone 11 cells was similar. Clone 11 cells exhibited a 5-10-fold resistance to the cytotoxins Adriamycin and vinblastine as assessed by a clonogenic assay. This drug resistance was accompanied by an increase in the steady state levels of the mRNAs for multidrug resistance gene (MDR-1), glutathione S-transferase-P, TGF-beta 1, and c-myc genes. The data presented here suggest an association between resistance to the growth-inhibitory effects of TGF-beta 1- and MDR-1-mediated multidrug resistance.
...
PMID:Isolation and characterization of a rat liver epithelial cell line resistant to the antiproliferative effects of transforming growth factor beta (type 1). 211 Dec 9

A multidrug-resistant cell line (A2780/ADM) of human ovarian carcinoma which can resist 0.8 microgram.ml-1 of adriamycin (ADM) was obtained by step-wise selection exposure to increasing doses of ADM. A2780/ADM cells showed 17-fold higher resistance to ADM than A2780 cells. The doubling times were 43.8 h in A2780/ADM and 26.3 h in A2780 cells. Colony formation rates were 15%-20% in A2780/ADM and 65%-75% in A2780 cells. A2780/ADM cell line was also shown to significantly cross-resistant to vincristine (VCR) and VP-16, but no cross-resistance was found to 5-Fu, PDD or Mel. A further investigation showed that intracellular accumulation of ADM in A2780/ADM was significantly decreased. Expressions of P-glycoprotein and GST-pi were increased in A2780/ADM by means of immunohistochemical method. Verapamil (Ver) combined with ADM was found to increase the sensitivity and reverse the resistance to ADM in A2780/ADM. This study indicates that A2780 ADM has the peculiarity of multidrug resistance and there may be other mechanism of drug-resistance besides MDR related to P-170.
...
PMID:[Establishment of adriamycin-resistant human ovarian carcinoma cell line and its mechanism of multidrug resistance]. 766 Jul 93

Hepatocyte resistance against inhibition of DNA synthesis by transforming growth factor beta 1 (TGF-beta 1) was studied in vitro. Hepatocytes were isolated from rats that had received diethylnitrosamine (DEN) for 6 weeks. The effect of TGF-beta 1 and phenobarbital (PB) on DNA synthesis in different cell populations was studied using bromodeoxyuridine (BrdU) incorporation and placental glutathione S-transferase (GST-P) as markers. It was found that GST-P-positive cells were resistant to the growth inhibitory effect of TGF-beta 1 and PB, whereas GST-P-negative cells were inhibited. It is concluded that resistance to TGF-beta 1-dependent growth control may develop early during DEN-induced hepatocarcinogenesis.
...
PMID:Different inhibition of DNA synthesis by transforming growth factor beta and phenobarbital on GST-P-positive and GST-P-negative hepatocytes. 842 66

The potential role of transforming growth factor-beta in in vivo resistance was examined by administration of transforming growth factor-beta-neutralizing antibodies to animals bearing the EMT-6/Parent tumor or the antitumor alkylating resistance tumors, EMT-6/CTX or EMT-6/CDDP. Treatment of tumor bearing animals with anti-TGF-beta antibodies by intraperitoneal injection daily on days 0-8 post-tumor cell implantation increased the sensitivity of the EMT-6/Parent tumor to cyclophosphamide (CTX) and cisplatin (CDDP) and markedly increased the sensitivity of the EMT-6/CTX tumor to CTX and the EMT6/CDDP tumor to CDDP, as determined by tumor cell survival assay. Bone marrow granulocyte-macrophage colony-forming units (CFU-GM) survival was determined from these same animals. The increase in the sensitivity in the tumors upon treatment with the anti-TGF-beta antibodies was also observed in increased sensitivity of the bone marrow CFU-GM to CTX and CDDP. Treatment of non-tumor-bearing animals with the anti-TGF-beta regimen did not alter blood ATP or serum glucose level but did decrease serum lactate levels. This treatment also decreased hepatic glutathione, glutathione S-transferase, glutathione reductase, and glutathione peroxidase in non-tumor bearing animals by 40-60% but increased hepatic cytochrome P450 reductase in these normal animals. Animals bearing the EMT-6/CTX and EMT-6/CDDP tumors had higher serum lactate levels than normal or EMT-6/Parent tumor-bearing animals; these were decreased by the anti-TGF-beta regimen. Treatment of animals bearing any of the three tumors with the anti-TGF-beta regimen decreased by 30-50% the activity of hepatic glutathione S-transferase and glutathione peroxidase, and increased by 35-80% the activity of hepatic cytochrome P450 reductase. In conclusion, treatment with transforming growth factor-beta-neutralizing antibodies restored drug sensitivity in the alkylating agent-resistant tumors, altering both the tumor and host metabolic states.
...
PMID:Transforming growth factor-beta in in vivo resistance. 861 16

Interleukin 1 (IL-1) potently activates human glomerular mesangial cells (HMC). In cytosolic extracts of IL-1-stimulated HMC or in anion exchange chromatography fractions we could not find any change in phosphorylation of myelin basic protein (MBP), a good substrate for extracellular regulated kinase (ERK). In contrast, IL-1 stimulated GST-jun kinase activity at least 10-fold. The jun kinase activity could be characterised as JNK1 and JNK2 at the protein and mRNA level. IL-1, TNF, UV light and osmotic stress, but not PMA, LPS, IL-3, IL-4, IL-6, IL-8, IL-10, IL-13, GM-CSF, PDGF, bFGF, TGF-beta and interferon-gamma were able to stimulate jun kinase activity in HMC, suggesting that jun kinase is selectively mediating signal transduction of the proinflammatory cytokines IL-1 and TNF as well as of cellular stress in HMC.
...
PMID:Interleukin 1 activates jun N-terminal kinases JNK1 and JNK2 but not extracellular regulated MAP kinase (ERK) in human glomerular mesangial cells. 883 Jun 57

Dichloroacetic acid (DCA) and trichloroacetic acid (TCA) are metabolites of the industrial solvent and environmental contaminant trichloroethylene (TCE), as well as contaminants of chlorinated drinking water. Human exposure to these chemicals is of concern as all three have been shown to increase liver tumor incidence in mice. Differences in dose-response curves, progression to cancer, and postexposure regression of lesions suggest that TCA and DCA work through different mechanisms. The purpose of this study was to further characterize the proliferative hepatocellular lesions promoted by TCA and DCA using biomarkers of cell growth, differentiation, and metabolism in liver sections to better delineate the distinctions in the mechanism of the two chloroacetates. Fifteen-day-old female mice were initiated with 25 mg/kg N-methyl-N-nitrosourea. The initiated mice were administered DCA or TCA (20.0 mmol/L) in drinking water from age 49 days until euthanasia at age 413 days. The pathologic assessment showed that the foci of altered hepatocytes and tumors occurring in the animals promoted with DCA were eosinophilic and positive immunohistochemically for TGF-alpha, c-jun, c-myc, CYP 2E1, CYP 4A1, and glutathione S-transferase-pi (GST-pi). The DCA lesions also were essentially negative for c-fos and TGF-beta, but nontumor hepatocytes were consistently TGF-beta-positive. In contrast, tumors promoted by TCA were predominantly basophilic, lacked GST-pi, and stained variably; usually, more than 50% of the tumor hepatocytes were essentially negative for the other biomarkers. This study demonstrates some striking differences in certain molecular biomarkers of cell growth, differentiation, and metabolism between DCA and TCA. The results also suggest some potential growth signal transduction pathways that may contribute to the DCA promotion of tumors, further support the premise that these two chloroacetates promote hepatocarcinogenesis in different ways, and provide a rational basis for a similar comparison with TCE. Such a comparison should give some insight as to whether DCA, TCA, or both are playing a significant role in the murine liver carcinogenesis of the parent compound, TCE.
...
PMID:Dissimilar characteristics of N-methyl-N-nitrosourea-initiated foci and tumors promoted by dichloroacetic acid or trichloroacetic acid in the liver of female B6C3F1 mice. 932 30

The dose dependence of the hepatopromoting effects of phenobarbital (PB) was investigated in a rat liver medium-term bioassay (Ito test) to elucidate a practical threshold level. F344 rats were given a single i.p. injection of diethylnitrosamine (200 mg/kg body wt) and subjected to two-thirds partial hepatectomy at week 3. Commencing 2 weeks from the start, PB at doses of 0, 1, 2, 4, 7.5, 15 or 500 p.p.m. in experiment 1 and 0, 0.01, 0.1 or 0.5 p.p.m. in experiment 2 were fed to the rats for 6 weeks. Experiment 3 was conducted to confirm previous data using the same medium-term bioassay, with PB at doses of 0, 1, 2, 4, 7.5, 15, 30, 60, 125, 250 or 500 p.p.m. fed to the rats. All surviving animals were killed at week 8 in these experiments and their livers were immunohistochemically examined for expression of glutathione S-transferase placental form (GST-P). Quantitative values for GST-P-positive foci in the liver were increased dose dependently in rats given 60-500 p.p.m. PB. However, those for doses in the range 1-7.5 p.p.m. demonstrated a decrease as compared with the control group (0 p.p.m.), with significant differences observed for 1 and 2 p.p.m.. The results for 15-30 and 0.01-0.5 p.p.m. were comparable with the control values. Examination of transforming growth factor-alpha (TGF-alpha)-positive foci also produced similar results to those for GST-P in experiment 1. Immunohistochemical staining of TGF-alpha and GST-P using serial liver sections demonstrated that the TGF-alpha-positive foci comprised a sub-population of the GST-P-positive lesions, being approximately 1/8-1/10th as common in livers of animals treated with PB. TGF-alpha-positive foci were almost always negative on immunostaining for TGF-beta. Western blotting for proteins CYP2B1, 2C6 and 3A2 revealed a good correlation between changes in GST-P-positive foci and CYP3A2 protein expression. The finding of inhibition effects at low doses of PB confirms the presence of a threshold level for promoting effects by PB on liver carcinogenesis in rats.
...
PMID:Presence of a threshold for promoting effects of phenobarbital on diethylnitrosamine-induced hepatic foci in the rat. 974 45

A comparative study on the possible involvement of several genes in the susceptibility of chemical carcinogenesis was carried out using carcinogen-resistant DRH rat and -sensitive Donryu and F344 rats. Previously, we observed that the induction of glutathione S-transferase placental form (GST-P) in the liver of Donryu rats by 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB) was significantly greater than that of DRH rats. In the present study, we tentatively determined base sequences of the enhancer region including GPE-I and GPE-II (GST-P enhancers I and II) of GST-P genes of DRH, Donryu and F344 rats, but we did not observe any nucleotide polymorphism around these regions. Furthermore, the mRNA levels of silencer binding protein (NFA-1) for the GST-P promoter of rat liver were also similar in the DRH and Donryu rats. Since clonal expansion of putative preneoplastic GST-P-positive foci in the DRH rat liver was significantly suppressed during 3'-Me-DAB administration, we examined whether two opposite growth controlling factors, TGF-alpha and TGF-beta, may participate in such suppression of growth. It was supposed that mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R), at least in part, activates TGF-beta preproprotein. However, we observed that the levels of M6P/IGF2R mRNA in the livers of DRH were not higher than those of Donryu rats after being fed 3'-Me-DAB for 8 weeks. Another important factor in the carcinogenesis is insulin-like growth factor II itself. Although liver tumors induced by 3'-Me-DAB in F344 had high levels of IGF-II mRNA, little IGF-II gene expression existed in normal adult livers of Donryu, F344 and DRH rats. High levels of IGF-II mRNA were detected similarly in the livers of neonates from all these three strains of rats. Finally, we detected a significant increase of AFP (alpha-fetoprotein) mRNA in the livers of Donryu rats around 6 to 8 weeks from the start of 3'-Me-DAB feeding, which is in parallel with detrimental effects of this carcinogen on these rats. A reduced induction of AFP mRNA was observed in DRH rats under the same conditions. Further study will be needed to explain the lower tumor susceptibility in the DRH rat.
...
PMID:Investigation of possible involvement of several genes related to development of hepatocarcinogenesis in rats. 1086 7

Alpha2-macroglobulin (alpha2M) is a major carrier of transforming growth factor-beta (TGF-beta) in vitro and in vivo. By screening glutathione S-transferase (GST) fusion proteins with overlapping sequences, we localized the TGFbeta-binding site to aa 700-738 of the mature human alpha2M subunit. In separate experiments, we screened overlapping synthetic peptides corresponding to aa 696-777 of alpha2M and identified a single 16-mer (718-733) that binds TGF-beta1. Platelet-derived growth factor-BB (PDGF-BB) bound to the same peptide, even though TGF-beta and PDGF-BB share almost no sequence identity. The sequence of the growth factor-binding peptide, WDLVVVNSAGVAEVGV, included a high proportion of hydrophobic amino acids. The analogous peptide from murinoglobulin, a human alpha2M homologue that does not bind growth factors, contained only three nonconservative amino acid substitutions; however, the MUG peptide failed to bind TGF-beta1 and PDGF-BB. These results demonstrate that a distinct and highly-restricted site in alpha2M, positioned near the C-terminal flank of the bait region, mediates growth factor binding. At least part of the growth factor-binding site is encoded by exon 18 of the alpha2M gene, which is notable for a 5' splice site polymorphism that has been implicated in Alzheimer's Disease.
...
PMID:A 16-amino acid peptide from human alpha2-macroglobulin binds transforming growth factor-beta and platelet-derived growth factor-BB. 1110 72


1 2 3 Next >>

---