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: EC:2.5.1.18 (glutathione S-transferase)
22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dehydroepiandrosterone (DHEA), a C19 adrenal steroid hormone, induces peroxisome proliferation in liver cells and is hepatocarcinogenic in the rat. The present study deals with the phenotypic properties of DHEA-induced liver lesions. A majority of the altered areas (80-87%), neoplastic nodules (> 94%) and hepatocellular carcinomas (HCC, 80-100%) lacked the marker enzymes gamma-glutamyltranspeptidase and placental form of glutathione S-transferase (GSTP). Northern blot analysis of HCC from 4 rats revealed no detectable GSTP mRNA. These HCC, however, showed a marked decrease in the staining of glucose-6-phosphatase and adenosine triphosphatase. These results indicate that the phenotypic properties of liver tumors induced by DHEA and amphipathic carboxylate peroxisome proliferators are similar.
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PMID:Phenotypic properties of liver tumors induced by dehydroepiandrosterone in F-344 rats. 133 91

Indocyanine green (ICG) was injected into rat liver nodules induced by 2-acetylaminofluorene (2-AAF) via portal vein. The relationship between ICG staining and cell atypism of liver nodules was examined by means of histology and DNA flow cytometry. After 2-AAF administration, many small nodules appeared on the liver surface. All hyperplastic nodules were ICG stained until 10 weeks after the administration, but some nodules were not stained after 14 weeks. ICG-stained nodules histologically consisted of benign tissues and borderline lesions, and many of them showed "diploidy" in DNA cytometry. ICG-unstained nodules consisted of hepatocellular carcinoma (HCCs) and borderline lesions, and many of them showed "aneuploidy". In this way, it has been suggested that HCC could derive from hyperplastic nodules and that they might lose an ability to take up ICG in the process of hepatocarcinogenesis. Immunohistochemical staining for glutathione-S-transferase alpha (GST-alpha), a carrier protein of ICG in hepatocytes, was well correlated with ICG staining in the nodules, suggesting that the loss of ICG uptake in HCC was partly due to the decrease of GST-alpha. Moreover, the appearance of ICG unstained and aneuploid nodules was significantly inhibited in rats which were fed on diet containing Syosaiko-to after the administration of 2-AAF. Chemopreventive effect of Syo-saiko-to on hepatocarcinogenesis was identified.
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PMID:Rat liver nodules induced by 2-acetylaminofluorene lose an ability to take up indocyanine green in the process of hepatocarcinogenesis. 137 11

P-Glycoprotein (Pgp) has been shown to mediate multidrug resistance in tumor cell lines. Overexpression of Pgp has been detected in clinical cancer samples of many histological types. The basis and biological significance of such increases in Pgp expression are not well understood. In this study, the expression of Pgp during stepwise progression to rat liver cancer was examined to investigate the possible role of Pgp in carcinogenesis. An immunohistochemical technique was used to detect Pgp at the single-cell level, in a large number of liver nodules, hepatocellular carcinoma, and in distant metastases of the carcinomas. The results showed that distinct changes in Pgp expression occurred during stepwise liver carcinogenesis and that these changes were closely associated with the microscopic anatomy of the lesions. In contrast to gamma-glutamyl transpeptidase and glutathione S-transferase-7.7, whose expression appeared to correlate with the early steps of liver carcinogenesis, Pgp expression was higher in the large hyperplastic nodules and in hepatocellular carcinomas than in the early microscopic lesions. A particularly striking finding was the consistent expression of Pgp in the lung metastases. These findings suggested that Pgp was associated with a more progressed malignant phenotype in liver carcinogenesis.
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PMID:P-glycoprotein expression during tumor progression in the rat liver. 138 36

The incidence and phenotype of preneoplastic and neoplastic liver lesions appearing in LEC rats after recovery from severe hereditary hepatitis were studied in comparison with the liver lesions appearing in chemical liver carcinogenesis. The livers of 168 rats (90 male, 78 female) were stained for seven histochemical markers at different time periods from the 20th week to the 122nd week of life. Glucose-6-phosphatase (G6Pase), adenosine triphosphatase (ATPase) and non-specific esterase (ES) were used as negative markers. Gamma-glutamyltransferase (GGT), glutathione S-transferase placental form (GSTP), esterase isozyme L-1 (L1) and alpha-fetoprotein (AFP) were used as positive markers. The study on the incidence of liver lesions in the LEC rats revealed sequential development of liver foci, nodules and hepatocellular carcinomas (HCCs) similar to those seen in chemically induced liver carcinogenesis. These lesions appeared earlier and more frequently in male LEC rats than in female ones, suggesting the importance of hormonal environment in spontaneous HCC development. The histochemical analysis of spontaneous liver lesions in LEC rats showed that GSTP was the most reliable positive marker as previously reported in chemical liver carcinogenesis. There was no essential difference in the expression of the markers in spontaneous and chemically induced liver lesions except for L1, which is considered to be related to xenobiotic metabolism. The results of this study suggest that both spontaneous and chemically induced liver cancer may develop by passing through phenotypically similar preneoplastic processes. In addition, the LEC rat uniquely showed chronic liver damage (hepatocyte death and regeneration) at the promotion stage of carcinogenesis. Such a natural history of HCC development in LEC rats is similar to that of human HCC which is frequently associated with chronic liver damage. Thus, the LEC rat provides a useful model for studying the process and underlying mechanisms of human liver cancer development.
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PMID:Phenotype of preneoplastic and neoplastic liver lesions during spontaneous liver carcinogenesis of LEC rats. 169 69

We have developed a medium-term bioassay system of 8 weeks duration utilizing male Fischer 344 (F344) rats for detection of liver carcinogens and modifiers of hepatocarcinogenesis. The system consists of a single intraperitoneal injection of diethylnitrosamine (DEN, 200 mg/kg), 6-weeks-administration of test chemical beginning 2 weeks after the DEN injection, and 2/3 partial hepatectomy (PH) performed at week 3. Carcinogenic potency of test chemicals is predicted based on the results of quantitative analyses of immunohistochemically-demonstrated glutathione S-transferase placental form (GST-P) positive liver cell foci. At present, a total of 140 chemicals have been tested using this system, and the findings show a good correlation with reported carcinogenic activities in long-term tests. Furthermore, the reliability of the system has been extensively examined: the results from the medium-term bioassay were compared with those from long-term experiments using the same doses of selected chemicals; the data from presently-used 2-dimensional analysis were compared with calculated values utilizing mathematical formulae for three-dimensional analysis: conformity of phenotypic expression of enzymes in preneoplastic lesions was examined in relation to their growth activity. In conclusion, although the results with non-hepatocarcinogens were less than satisfactory, the present experimental protocol, which requires far fewer animals and shorter duration than a long-term carcinogenicity test, appears of advantage for rapid screening of the large number of environmental chemicals which may possess hazard potential for induction of liver cancer in man.
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PMID:Medium-term bioassay system for detection of carcinogens and modifiers of hepatocarcinogenesis utilizing the GST-P positive liver cell focus as an endpoint marker. 262 99

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

Previously we established that 'LEC rats' have displayed spontaneous fulminant hepatitis with severe jaundice, which progressed to liver cancer, and a single autosomal recessive gene is responsible for the cause of the diseases. The activities of drug metabolizing enzymes were assayed in livers from LEC and control (LEA) rats at 4 weeks and 3 months before the onset of liver cancer. At 4 weeks the cytochrome P-450 content of the LEC rat livers was 43% of the control (LEA) value. At 3 months the level was 65% of the control. Epoxide hydrolase, gamma-glutamyltranspeptidase and UDP-glucuronyltransferase activities were 2.6-, 6.9- and 2.4-times higher than those in the LEA rats at 4 weeks, respectively, while glutathione S-transferase activity was not significantly different between the two strains. The enzyme changes in the LEC rats are quite similar to those observed in hyperplastic foci and nodules in chemical carcinogenesis of hepatocytes.
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PMID:Metabolic predisposition of a novel mutant (LEC rats) to hereditary hepatitis and hepatoma: alterations of the drug metabolizing enzymes. 290 Jul 2

Assay conditions of human liver glutathione S-transferase and its activity in human serum from liver disease patients were investigated. One mmol/l reduced glutathione, and 1 mmol/l-1-chloro-2,4-dinitrobenzene, pH 6.5, were used for the measurement, because of the very low non-enzymatic conjugation. Glutathione S-transferase activity was inhibited by bilirubin, but this inhibition was counteracted by the presence of a low concentration of albumin. The normal human serum glutathione S-transferase activity was 5.2 +/- 2.4 I.U./l (mean +/- S.D.), and was not influenced by any differences of age, sex or leukocyte count. A significant increase in serum enzyme activity was noted in cases of acute hepatitis with GPT exceeding 200 I.U./l, primary hepatoma and metastatic liver cancer. Some of the cases with fulminant hepatitis showed extremely high values. The degree of correlation between serum glutathione S-transferase and GOT or GPT was high in acute hepatitis, with GOT or GPT exceeding 200 I.U./l, in fulminant hepatitis, primary hepatoma and gall stones, while in chronic hepatitis and liver cirrhosis it was low. In cases of acute hepatitis and fulminant hepatitis, the disappearance of serum glutathione S-transferase from the blood was much faster than that of GOT and GPT. Serum glutathione S-transferase measurements will provide new and unique information for the diagnosis of acute liver diseases.
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PMID:Serum glutathione S-transferase activity in liver diseases. 625 85

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

DNA single-strand (ss) breaks were detected in the livers of B6C3F1 mice immediately following exposure to 4000-8000 p.p.m. methylene chloride (MC) for 6 h. This damage was undetectable 2 h after exposure, suggesting an active DNA repair process. Similarly, DNA ss breaks were detected in whole lung homogenates taken from mice exposed to 2000-6000 p.p.m. MC. The DNA of mouse Clara cells incubated in vitro with MC was also damaged at concentrations of 5 mM MC and above. Pre-treatment of mice with the glutathione depletor buthionine sulphoximine (BSO) caused a decrease in the amount of DNA damage detected, suggesting a GST-mediated mechanism. DNA damage was also reduced in Clara cells when incubated in vitro with MC in the presence of BSO. In CHO cells induction of DNA damage was dependent upon exogenous MC metabolism by mouse liver S100 fraction (but not microsomes) in the presence of GSH. DNA ss breaks were not induced by MC in hamster hepatocytes in vitro at concentrations from 5 to 90 mM MC, nor in eight individual samples of normal human hepatocytes exposed to MC at similar concentrations. The ability of MC to induce DNA ss breaks in the four species studied is entirely compatible with the known carcinogenicity of this chemical in animals and offers experimental evidence to suggest that humans would not be susceptible to MC-induced liver cancer. The DNA ss breaks correlate with the metabolism of MC by the GST pathway and provide an explanation for the lack of sensitivity of hamsters and rats to MC-induced liver cancer.
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PMID:Methylene chloride-induced DNA damage: an interspecies comparison. 763 22


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