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)

A specific biochemical phenotype is expressed during chemical hepatocarcinogenesis, which includes increased activity of the various isoenzyme forms of glutathione S-transferase (GST) composed of class alpha (Ya/Yc), class mu (Yb) and class pi (Yp) gene products. In vitro cell lines of normal and chemically transformed rat liver epithelial cells provide an opportunity to examine the regulation of expression of GST isoenzymes. We have studied the effect of the state of proliferation in culture on both the enzymic activity and the isoenzyme-specific mRNA expression. In normal rat liver epithelial cells (WB-F344), basal expression of the Yp subunit decreases, and of the Yb subunit increases, in cells at confluence compared with those in logarithmic-phase growth. In a subline of WB-F344 cells that has been chemically treated in vitro (GN6), there was greater Yp expression; however, the effect of growth status on both subunits was the same as in the nontransformed WB-344 cells, and the Ya subunit was not expressed. Inhibition of RNA synthesis with actinomycin D was limited, demonstrating pronged half-lives of the GST mRNAs, and shows a slightly greater decrease in GST-Yp specific mRNA levels in the confluent cells. Also nuclear run-off experiments demonstrate identical transcription rate in confluent and pre-confluent cells. These data suggest that the increase in Yp steady-state RNA in preconfluent cells is due to increased stability of the GST-Yp mRNA. In tumor cells derived from GN6 cells, the regulatory effects of growth status on the Yb and Yp expressions were absent. However, in these cells Ya subunit was expressed and this was subject to the effects of cell proliferation. We conclude that the growth status of cells in culture exerts a significant regulatory control on the GST isoenzyme gene expression. The effects are probably mediated at independent regulatory sites in each gene. The state of transformation of rat liver epithelial cells may determine responsiveness to this effect.
Carcinogenesis 1991 Nov
PMID:Effect of proliferative state on glutathione S-transferase isoenzyme expression in cultured rat liver epithelial cells. 193 87

The effects of varying the interval of time between initiation with diethylnitrosamine (DEN) and promotion by phenobarbital (PB) on the development of altered hepatic foci (AHF) and hepatomas in female Fischer 344 rats was investigated. The intervals between DEN initiation after a 70% partial hepatectomy and a subsequent 6 month period of promotion by feeding of PB were 1 day, 1 week, 1 month, 2 months, 6 months and 11 months. The number and volume percentage occupied by AHF were determined by quantitative stereologic methods on serial frozen sections stained for the markers gamma-glutamyltranspeptidase (GGT), canalicular adenosine triphosphatase (ATPase), glucose-6-phosphatase (G6Pase) and the placental form of glutathione S-transferase (GST-pi). The number of AHF was greatest when the initiation-promotion interval was only 1 day, and there was a tendency for the number of AHF to decrease as the interval between initiation with DEN and the start of PB promotion was extended. An 11 month delay between initiation and promotion resulted in only 20% fewer AHF than when promotion was begun 1 day after initiation. On the other hand, the volume percentage fraction of AHF did not change when the initiation-promotion interval was increased from 1 day to 2 months. An interval of 6 months roughly doubled the volume percentage fraction, but an interval of 11 months led to a 7- to 8-fold increase in the volume percentage of AHF over that from a 1 day interval. The phenotypic distribution of AHF was significantly lower in relation to certain markers, especially GGT and GST-pi, in those animals only initiated with DEN compared with those initiated with DEN and promoted with PB. When no exogenous promotion was given, there was still a nearly linear increase in both the number and volume percentage occupied by AHF in the liver of rats initiated with DEN. On the other hand, rats subjected to a 1 week interval between DEN initiation and PB promotion exhibited the greatest number of hepatocellular carcinomas 14 months after initiation, compared with other groups. These studies demonstrated a gradually decreasing effectiveness of PB as a promoting agent to stimulate the growth of all AHF initiated by DEN as the interval between initiation and promotion was extended.(ABSTRACT TRUNCATED AT 400 WORDS)
Carcinogenesis 1990 Feb
PMID:Quantitative stereologic study of the effects of varying the time between initiation and promotion on four histochemical markers in rat liver during hepatocarcinogenesis. 196 85

We used double-label immunofluorescence to evaluate the expression of glutathione-S-transferase-P (GST-P) and gamma-glutamyl transferase (gamma GT) in individual liver cells in rats placed on a modified Solt-Farber hepatocarcinogenesis protocol. Four days after treatment with diethylnitrosamine (DEN), single GST-P+ cells were found in the centrilobular and midzonal regions. Most of these were gamma GT-, but the percentage of gamma GT+ cells increased with DEN dose to a high of 32%. At later times (7-8 days) doublets and small clusters of GST-P+ cells predominated; all cells in each pair or cluster displayed the same phenotype (GST-P+ or GST-P+/gamma GT+). Following administration of acetylaminofluorene and partial hepatectomy, lesions were larger and a greater percentage were GST-P+/gamma GT+. However, within these lesions individual cells displayed different phenotypes. These results indicate that the expression of GST-P and gamma GT is discordant in individual cells and small clusters soon after treatment, and suggest that different molecular events may be involved in their expression.
Carcinogenesis 1990 Mar
PMID:Immunofluorescent analysis of gamma-glutamyl transpeptidase and glutathione-S-transferase-P during the initial phase of experimental hepatocarcinogenesis. 196 86

Female adult rats were as responsive as males to initiation by diethylnitrosamine (DEN) as measured by numbers of GST-P positive hepatocytes appearing early, and do develop hepatocellular cancers. However, when females and males were exposed to four promotion regimens including orotic acid (OA), choline deficiency, deoxycholic acid (DOC), or selection for resistance (to 2-acetylaminofluorene; 2-AAF) after DEN initiation, very significant sex differences were observed with respect to oval cell proliferation and growth rates of hepatocytic foci. These results suggest that responses to promotion such as growth of foci and oval cell proliferation can accompany carcinogenesis but may not be essential to the development of hepatocellular cancer.
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PMID:Sex differences in response to four promotion regimens in spite of common first cellular steps in the hepatocellular cancer process initiated by diethylnitrosamine. 197 Feb 74

The initiating potential of the secondary bile acids, deoxycholic acid (DCA) and lithocholic acid (LCA), for rat hepatocarcinogenesis was investigated using the development of hyperplastic nodules and/or glutathione S-transferase placental form (GST-P)-positive liver foci as the end point. Five week old male F344 rats were given either basal diet, or diets containing 0.5% DCA or 0.5% LCA for 3 weeks in conjunction with partial hepatectomy performed midway, followed by a selection regimen consisting of 2 weeks feeding of 0.02% 2-acetylaminofluorene diet and a single gastric intubation of carbon tetrachloride. The animals were then placed on either basal diet or a diet containing 0.05% phenobarbital (PB) for 52 weeks. Significantly higher numbers of hyperplastic liver nodules developed in the DCA-treated rats irrespective of PB promotion as compared with the respective control groups. No such increase was evident in the LCA-treated rats. In contrast, both DCA and LCA treatments enhanced the development of GST-P-positive liver foci with or without subsequent PB promotion. Only one hepatocellular carcinoma was diagnosed in a control group animal. The present data indicate that a short period of feeding of DCA and LCA in the initiation stage in conjunction with partial hepatectomy results in enhanced development of preneoplastic liver lesions under selection pressure conditions with or without subsequent PB promotion. They thus confirm and extend our previous finding of enhanced gamma-glutamyltranspeptidase-positive liver foci development in a short-term assay of DCA and LCA, and suggest that these secondary bile acids either possess possible initiating activity or some other priming effect for rat hepatocarcinogenesis.
Carcinogenesis 1990 Aug
PMID:Enhanced preneoplastic liver lesion development under 'selection pressure' conditions after administration of deoxycholic or lithocholic acid in the initiation phase in rats. 197 29

Four novel nontransformed epithelial cell lines, isolated from fetal or adult mouse liver, were tested: (a) to determine the profile of xenobiotic metabolizing enzymes; (b) to evaluate the inducibility of the polysubstrate (cytochrome P-450-dependent) monooxygenase system by various classes of inducers; and (c) to assess the capacity of the cells to metabolize structurally different procarcinogens. With regard to the phase I pathway, the cells expressed various P-450 (class IA, IA2, IIB, IIE1, IIIA) and flavin adenine dinucleotide-containing monooxygenase-dependent bio-transformation enzyme activities at levels (in lines C2.8 and C6) comparable with those present in murine adult liver preparations. The expression of various P-450s was demonstrated also by immunoprecipitation assays using rabbit polyclonal antibodies. For the phase II pathway, cells expressed substantial levels of glutathione S-transferase, glutathione S-epoxide transferase, and UDP-glucuronosyltransferase. Low expression of epoxide hydrolase was observed. Induction of P-450 function by sodium phenobarbital, beta-naphthoflavone, isosafrole, ethanol, and pregnenolone 16 alpha-carbonitrile, monitored using specific P-450-linked activities, was considerably elevated (over 5-fold in class IIB with the C2.8 and C6 cell lines). The most competent C2.8 and C6 cell lines were able to activate benzo(a)pyrene, cyclophosphamide, dimethylnitrosamine, diethylstilbestrol, and 2-naphthylamine as shown by the significantly increased frequencies of mitotic gene conversion, mitotic crossing-over, and point [reverse] mutation in the diploid D7 strain of Saccharomyces cerevisiae after 4 [cyclophosphamide], 24 [benzo(a)pyrene,2-naphthylamine, dimethylnitrosamine] or 48 [diethylstilbestrol], h of exposure in the presence of 3 x 10(6) cells/flask. The degree of conservation and the inducibility of representative oxidative and postoxidative reactions in the novel epithelial cell lines C2.8 and C6, together with their ability to activate a wide spectrum of procarcinogens, offers a means to study the potential of chemicals for inducing DNA damage in short-term genotoxicity testing. In addition the cells may be suitable for analyzing the metabolic disposition of compounds and the multistage process of carcinogenesis.
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PMID:Expression and inducibility of drug-metabolizing enzymes in novel murine liver epithelial cell lines and their ability to activate procarcinogens. 198 92

Ten paired samples of primary human colorectal carcinoma and adjacent non-neoplastic mucosa were analysed for total glutathione S-transferase (GST) activities as determined by 1-chloro-2,4-dinitrobenzene assays. These tissues were also investigated for the expression of acidic (pi), basic (alpha) and neutral (mu) GSTs using Western blotting procedures and immunohistochemical staining. For each of the paired samples examined the total GST activity was higher in tumour than in adjacent non-neoplastic mucosa. Western blotting, using an antibody against acidic GST also showed strong immunoreactivity in all the samples with more intense reactions in tumour compared to mucosa in nine out of the ten paired samples. Low levels of basic GST were also expressed in all samples of tumour and mucosa. Neutral GST was not detectable in two samples of tumour and corresponding mucosa, but low levels of expression were demonstrated in the remaining eight. Immunohistochemical staining for acidic GST showed a dark brown reaction in all tumour cells; in non-neoplastic mucosa there was positive immunoreactivity for epithelial cells situated deep within the crypts and a negative reaction for surface epithelial cells. Immunohistochemical staining for basic GST was negative except for one sample of tumour and two of mucosa. Neutral GST was expressed only in two samples of tumour and two samples of mucosa. We therefore conclude that there is enhanced expression of GSTs, acidic GST being the predominant form, in tumour compared to normal mucosa, in keeping with a role for GSTs in colonic carcinogenesis and acquired or innate drug resistance.
Carcinogenesis 1991 Jan
PMID:Enhanced expression of glutathione S-transferases in colorectal carcinoma compared to non-neoplastic mucosa. 198 73

Chenodeoxycholic acid (CDC), a dihydroxylated primary bile acid, was evaluated for promotional activity in the liver of rats using a two-stage initiation-promotion model. CDC is a primary bile acid that can attain high concentrations in serum and liver during induced or naturally occurring hepatocellular disorders. Female Sprague-Dawley rats were injected once (i.p.) with diethylnitrosamine (DEN, 150 mg/kg) or sterile physiologic saline (SAL, 0.85% NaCl). Two weeks later, rats in each group were placed into one of two subgroups and fed either NIH-31 mash (Control) or NIH-31 mash containing 0.5% CDC for a 10 week period. At the end of the feeding period, blood and liver samples were collected for determination of bile acid profiles and quantitation of hepatocellular foci respectively. Serum samples were analyzed for concentrations of individual bile acids using a HPLC method that utilizes a post-column enzymatic reaction and fluorescence detection. Liver slices from the left hepatic lobe were stained for foci positive for placental glutathione S-transferase. In serum, significant increases occurred in concentrations of all forms of CDC and were accompanied by mild, insignificant increases in lithocholic acid. Decreased serum concentrations occurred in all forms of cholic and deoxycholic acids. Analysis of liver sections revealed that rats treated with DEN-CDC had significant increases in numbers and volume of foci compared to those treated with DEN-Control. For rats in groups DEN-CDC and DEN-Control, the numbers of foci per square centimeter were 32 and 12; per cubic centimeter, 2221 and 937; and the per cent volume of foci, 1.487 and 0.385 respectively. In this study, CDC was a promoter of hepatocellular foci. Because concentrations of CDC in liver and serum increase in a variety of hepatobiliary disorders, the possibility that increases in endogenous concentrations can enhance the formation of hepatocellular foci is being explored.
Carcinogenesis 1991 Jan
PMID:Promotion of hepatocellular foci in female rats by chenodeoxycholic acid. 198 83

A mouse monoclonal antibody and a rabbit polyclonal antibody prepared against the placental form of the enzyme glutathione S-transferase (GST-pi) were used to immunohistochemically stain normal and neoplastic human uterine cervical tissues from 88 cases. Of 65 cases of preneoplastic squamous lesions and invasive carcinomas of the cervix, 94% stained with the monoclonal antibody and 100% with the polyclonal antibody. In the 23 benign tissues, staining of ectocervical squamous epithelium was generally not observed; however, areas of reserve-cell hyperplasia, immature squamous metaplasia and adjacent endocervical cells did show staining (68% with the monoclonal antibody and 95% with the polyclonal antibody). Many of the positive tissue types showed a variety of staining patterns and intensities. These findings do not support the concept that GST-pi staining can be used to distinguish preneoplastic lesions of the cervix from benign reactive or proliferative processes. These results are of interest in the investigation of cervical carcinogenesis since GST-pi may be involved in an early stage of neoplastic transformation of the cervical epithelium. The correlation of these findings with the results of human papillomavirus testing and DNA content analysis should be of interest in determining the relationship of this enzyme to cervical neoplasia.
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PMID:Immunohistochemical localization of glutathione S-transferase in preneoplastic and neoplastic lesions of the human uterine cervix. 152 39

Cyclosporine, a powerful immunosuppressant, has been used successfully for organ transplantation. Its efficacy on liver transplants of patients with primary hepatic tumors remains controversial because of a high rate of recurrence of the original tumors in the transplanted livers. In this study, we experimentally tested whether cyclosporine exerts any effects on the growth of carcinogen-initiated liver cells using the short-term assays of rat liver carcinogenesis. Dietary cyclosporine, which maintained sufficient levels of blood cyclosporine and suppressed host immune functions, enhanced the development of the glutathione S-transferase, placental form-positive hepatocyte foci in the liver of male F-344 rats treated with a single weekly dose of diethylnitrosamine (75 mg/kg) for 3 wk. Dietary cyclosporine also accelerated the growth of preformed glutathione S-transferase, placental form-positive foci induced by a single dose of diethylnitrosamine (250 mg/kg) followed by the promoting regimen of a choline-deficient diet. It is possible that the enhancement of the size of hepatocyte foci by cyclosporine could be due to stimulation of growth or inhibition of regression. The mechanisms by which cyclosporine modifies the growth of preneoplastic lesions in the liver are not yet fully understood. Possible involvement of immunologically relevant cells in the liver, Kupffer cells and pit cells in the process is suggested.
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PMID:Cyclosporine enhances the growth of carcinogen-induced enzyme-altered foci in rat liver. 199 40


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