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)

Using the Solt-Farber hepatocarcinogenesis model, a large population of preneoplastic and neoplastic nodules were induced in male Fischer 344 rats. Total cellular polypeptides from normal liver and individual preneoplastic and neoplastic nodules were analyzed for both qualitative and quantitative changes using computer assisted high resolution two-dimensional electrophoresis. Approximately 800-1000 cytosolic and 1200-1400 membrane associated polypeptides were readily separated and detected using an ultrasensitive silver stain. The polypeptide patterns were remarkably similar for each tissue and only four qualitative polypeptide differences were noted. One cytosolic polypeptide, 6.8/57 (designated pl/Mr X 10(-3), and three membrane associated polypeptides, 6.25/41, 6.75/24, and 6.05/21, were expressed in both preneoplastic and neoplastic nodules but not in normal liver. No qualitative polypeptide differences were detected among the individual preneoplastic or individual neoplastic nodules or between preneoplastic and neoplastic nodules. Numerous quantitative changes in both known markers for hepatocarcinogenesis and in as yet unidentified polypeptides were noted. In particular, the Ya subunit of glutathione S-transferase B, the Yb subunit of glutathione S-transferase A, as well as the three isoelectric point variants of the Yp subunit of glutathione S-transferase P were increased 2-, 4-, and 7-fold, respectively, in preneoplastic and neoplastic nodules. Whereas DT-diaphorase was increased 2-3-fold in hyperplastic nodules as compared to normal liver, no differences in the expression of albumin were noted. Although no differences were observed in the expression of aldehyde dehydrogenase in preneoplastic and neoplastic nodules, polypeptide b (6.9/54) was shifted slightly toward the basic region in normal liver. alpha-Fetoprotein was not detected in either preneoplastic or neoplastic nodules. In addition to these changes in known markers, comparison of 500-800 cytosolic and 750-1000 membrane associated polypeptides showed that roughly 4-10% of the polypeptides were undergoing quantitative changes of at least 4-fold during these stages of hepatocarcinogenesis. Thirty (10 cytosolic and 20 membrane) polypeptides were significantly down-regulated while 22 (7 cytosolic and 15 membrane) polypeptides were up-regulated in both preneoplastic and neoplastic nodules. In all cases the direction and magnitude of change were the same in both preneoplastic and neoplastic nodules with the exception of three polypeptides.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Sequential analysis of chemically induced hepatoma development in rats by two dimensional electrophoresis. 394 Feb 6

We previously reported that LEC rats, which show a spontaneous occurrence of liver injury and hepatocellular carcinoma (HCC), are highly susceptible to chemical carcinogens such as diethylnitrosamine (DEN). Since abnormal copper accumulation in the liver of LEC rats was found to be a cause of liver injury, it is necessary to elucidate whether the carcinogen susceptibility of LEC rats is related to the accumulation of copper in the liver. In this study we have examined the relationship between the susceptibility of FI [LEC x LEA or LEC x Fischer 344 (F344)] and FI backcross rats to DEN and hepatic copper concentration, as copper accumulation has been demonstrated to be inherited as an autosomal recessive trait. The groups of F1 and F1 backcross rats were given a single intraperitoneal injection of DEN (20 mg/kg wt) and subjected to a modified Solt-Farber protocol for assaying glutathione S-transferase placental form (GST-P)-positive foci. The hepatic copper concentration was examined by atomic absorption. Although no F1 rats showed a high copper concentration in the liver, the numbers of foci were as high as those in LEC rats which accumulate copper. Backcross rats separated into high and low copper concentration groups at an almost 1:1 ratio, but there was no significant difference in the mean numbers of foci between these two groups. The results clearly indicate that the high susceptibility of LEC rats to DEN is genetically independent of copper accumulation in the liver. A possible dominant inheritance of this high carcinogen susceptibility was suggested. Biochemical measurement of cytochromes P450 and b5 in the liver of F1 rats indicated that alterations in drug metabolizing enzymes may be partially responsible for the high carcinogen susceptibility of LEC rats.
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PMID:The high hepatocarcinogen susceptibility of LEC rats is genetically independent of abnormal copper accumulation in the liver. 769 3

Since the expression of glutathione S-transferase P-form (GST-P) has been suggested from in vitro studies to be partly regulated by the oncogene product, c-Jun and c-Fos, their distributions were compared in normal rat tissues and preneoplastic hepatic lesions induced by the Solt-Farber protocol. Immunohistochemically demonstrated GST-P protein was positively correlated with expression of both c-Jun and c-Fos in the epidermis of the skin and the smooth muscle of adult lung and with either c-Jun or c-Fos respectively in the bile ducts and bronchial epithelium. However, GST-P expression was also observed in proximal and distal straight segments of the kidney and other tissues negative for c-Jun and c-Fos and both c-Jun and c-Fos were present in the renal proximal and distal convoluted tubules, where GST-P was lacking. Thus, the localization of GST-P was in some cases clearly separable from those of c-Jun or c-Fos. GST-P was found to be focally expressed from an early stage of hepatocarcinogenesis, when c-Jun was not detectable. At later stages, this oncogene product was stained in 35.7% of GST-P-positive foci, with a clear relation to the degree of GST-P staining. Since GST-P is not always accompanied by appreciable c-Jun or c-Fos, these oncogene products are apparently not prerequisites for its expression. However, c-Jun may be partly responsible for maintaining high levels of GST-P in hepatic foci at later stages of hepatocarcinogenesis.
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PMID:Lack of correlated expression between the glutathione S-transferase P-form and the oncogene products c-Jun and c-Fos in rat tissues and preneoplastic hepatic foci. 769 15

Serial magnetic resonance imaging (MRI) was used to evaluate the influences of dietary deoxycholic acid (DCA) on the rate of progression of chemically induced hepatocellular neoplasms in rats. Male Fischer-344 rats with established persistent hepatocellular nodules generated by the Solt-Farber protocol were exposed to dietary DCA (0.3%) between 6 and 12 mo of age. Growth of nodules and carcinomas in vivo was measured by morphometric quantification of tumor images obtained every 6 wk. The final stages of neoplastic progression were determined by terminal histopathological examination and by expression and functional evaluation of glutathione S-transferase (GST) isoenzyme phenotypes. Dietary DCA increased the number of hepatocellular neoplasms per rat, accelerated the rate of growth of persistent nodules, and increased the histological progression of liver tumors. Expression of immunoreactive GST subunits Yf, Ya, and Yb1 was induced in early persistent nodules, a pattern that was maintained throughout the study in both basal diet and DCA-fed groups. However, 5% of early nodules and about 75% of advanced neoplasms were partially or completely deficient in GST Yb2 expression in both groups. DCA did not alter the cytosolic activity for the GST substrates 1-chloro-2,4-dinitrobenzene (CDNB) or trans-4-phenyl-3-buten-2-one (tPBO) in tumors or surrounding liver. However, in both groups, CDNB activity was increased in the tumors relative to the surrounding nonneoplastic tissue, whereas activity for tPBO, a substrate more specific for the Yb2 subunit, was reduced in the tumors. All advanced neoplasms were similarly more resistant than surrounding liver to DNA-binding metabolites of aflatoxin B1 or benzo[a]pyrene. These data demonstrate that DCA can increase the progression of established hepatocellular nodules to larger, more advanced neoplasms but does not preferentially select for a specific GST phenotype. Preferential loss of constitutively expressed GST Yb2 in both basal diet and DCA-fed groups may be an important aspect of progression from resistant nodules to advanced cancers in this model. These studies also demonstrate that serial MRI is a useful tool for measuring the rates of enlargement and patterns of growth in established hepatocellular neoplasms.
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PMID:Influences of dietary deoxycholic acid on progression of hepatocellular neoplasms and expression of glutathione S-transferases in rats. 773 75

Butylated hydroxytoluene (BHT) is a synthetic, food-use, phenolic antioxidant. It has previously been demonstrated to be operationally non-genotoxic and, in addition, failed to induce biologically significant increases in cellular proliferation in the liver, urinary bladder and thyroid gland on feeding to young adult Wistar rats. Nevertheless, it has been reported to enhance the yield of liver tumors when fed to rats or mice that developed an appreciable background incidence of these tumors without treatment. In order to resolve this situation, cell proliferation in response to BHT treatment was studied in enzyme-altered foci (EAF) induced in male Fischer 344 rats using the Solt-Farber procedure. It was demonstrated that feeding 0.5% dietary BHT for 30 days after the induction of EAF led to a 20- to 30-fold increase in the gamma-glutamyltranspeptidase-positive areas in both DEN- and saline-initiated rat livers, but to no major effects in glutathione S-transferase placental form (GSTP)-positive foci. Cell proliferation rates within EAF and surrounding normal liver were measured using different histological techniques. Nuclear labeling with [3H]thymidine and proliferating cell nuclear antigen (PCNA) over the total hepatocyte population indicated that BHT approximately doubled nuclear labeling in rats initiated with DEN. PCNA labeling in GSTP-positive foci was not affected by BHT. In GSTP-positive foci, evaluation of nucleolar organizer regions (AgNOR), which reflect cell proliferative in addition to transcriptional activity of ribosomal RNA, was achieved using a novel double staining technique. BHT diet did not affect the number of AgNOR per nucleus or the percentage AgNOR area/nucleus. Nevertheless, both PCNA labeling and the AgNOR area per nucleus were significantly greater in GSTP-positive foci compared with non-focal regions in rats fed either BHT or control diets. These results are discussed in the light of further experimental work required to determine the relevance of these data to possible human risk assessment for BHT.
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PMID:The effect of butylated hydroxytoluene on the growth of enzyme-altered foci in male Fischer 344 rat liver tissue. 776 67

Previous studies have demonstrated that short-term treatment with a peroxisome proliferator (PP) decreased the size and number of genotoxic carcinogen-induced hepatic hyperplastic lesions identified by gamma-glutamyl transpeptidase (GGT) or glutathione S-transferase P1-1 (rGSTP1-1) staining. However, longer-term PP treatment of animals bearing similar hepatic hyperplastic lesions produced an increase in both the size and number of liver tumors. To characterize the hepatic hyperplastic lesions which are inhibited or promoted by PP, a unique double labeling technique was developed to determine the relative rate of cell division (e.g., DNA synthesis) in rGSTP1-1-positive nodules before and after ciprofibrate (Cip) treatment. rGSTP1-1-positive nodules were induced with the Solt-Farber resistance protocol (diethylnitrosamine-2-acetylaminofluorene partial hepatectomy). Eleven weeks after diethylnitrosamine initiation, 3 groups of rats were maintained on a control chow diet or switched to a powdered chow diet containing 0.025% Cip or 0.05% phenobarbital (PB) for the last 8 days of the experiment. A minipump implanted in the abdominal cavity released [methyl-3H]thymidine continuously for 72 h and was then removed prior to CIp or PB treatment. A second minipump was then implanted which released bromodeoxyuridine to the abdominal cavity 5 days after the start of Cip or PB administration and lasted for 72 h until the termination of the experiment. Both the [methyl-3H]thymidine and bromodeoxyuridine labeling indices (LIs) were determined in the same group of cells within individual rGSTP1-1-positive nodules in the right posterior lobes of livers. PB treatment increased both the average number of persistent GGT-positive nodules and the ratio of persistent GGT-positive to rGSTP1-1-positive nodules/cm2. In contrast, Cip treatment greatly decreased the average number and area of persistent GGT-positive nodules, as well as the ratio between persistent GGT-positive and rGSTP1-1-positive nodules/cm2. Cip treatment also resulted in a 40% decrease in the average LI in the rGSTP1-1-positive nodules. In some rGSTP1-1-positive nodules, the LI was decreased from > 40% prior to Cip treatment to < 5% afterward, suggesting that Cip treatment interrupted progression in these nodules. Such drastic changes in the LI before and after treatments were not observed in either PB- or vehicle-treated (control) animals. A number of small nodules with a high bromodeoxyuridine LI but with no or very few [methyl-3H]thymidine-labeled nuclei and negative GGT and rGSTP1-1 staining were detected only in the Cip group.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Inhibition of cell proliferation by ciprofibrate in glutathione S-transferase P1-1-positive rat hepatic hyperplastic nodules. 790 93

We followed the expression of several glutathione S-transferase subunits in altered foci, liver neoplasms and metastases produced in male Fischer 344 rats by a modified Solt-Farber protocol, to determine whether components of the resistant phenotype are lost during neoplastic progression. At 6 mo after initiation, altered foci and persistent nodules displayed increased immunohistochemical expression of glutathione S-transferase subunits Yf (pi-class), Ya (alpha-class) and Yb1 (mu-class) in comparison with normal or surrounding liver tissue. However, although most altered foci exhibited little change in glutathione S-transferase Yb2 (mu-class) subunit expression, 5% of Yf-positive foci and nodules were partially or completely deficient in Yb2 expression. At 12 and 18 mo after initiation, most grossly visible hepatocellular tumors retained induced expression of glutathione S-transferase subunits Yf, Ya and Yb1, but 63% of the carcinomas, 88% of the primary metastatic carcinomas and 94% of the pulmonary metastases were deficient in Yb2 expression. These differences in glutathione S-transferase subunit expression were confirmed by quantitative analysis by reverse-phase HPLC of S-hexylglutathione affinity-purified glutathione S-transferases from advanced tumors. Cytosolic glutathione S-transferase activity for trans-4-phenyl-3-buten-2-one in advanced tumors ranged from 42% to 66% of the activity in matched surrounding liver, whereas glutathione S-transferase activities for 1-chloro-2,4-dinitrobenzene were increased by 140% to 161%. These studies demonstrate that progression of hepatocellular carcinomas in the resistant hepatocyte model of carcinogenesis in which several glutathione S-transferase subunits are induced is associated with the loss of a major constitutive mu-class hepatic glutathione S-transferase. Although the mechanism and role of the reduction or loss of glutathione S-transferase Yb2 during malignant progression are unknown, we propose that loss of glutathione S-transferase Yb2 in some preneoplastic populations of hepatocytes might be conducive to further DNA damage by presently unknown environmental or endogenous compounds that are normally detoxified preferentially by glutathione S-transferase isoenzymes containing this subunit.
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PMID:Reduced expression of glutathione S-transferase Yb2 during progression of chemically induced hepatocellular carcinomas in Fischer 344 rats. 802 Aug 84

Glutathione transferase P (GST-P; glutathione transferase, EC 2.5.1.18) is known to be specifically expressed at high levels in precancerous lesions and in hepatocellular carcinomas from a very early phase of chemically induced hepatocarcinogenesis in the rat. The almost invariable occurrence of this phenotype in these lesions strongly suggests a mechanism by which GST-P gene is activated together with a crucial transforming gene of liver cells. To distinguish the two alternative possibilities--either the GST-P gene is coactivated with a closely located transforming gene by a cis mechanism or it is activated in trans by a common trans-acting factor--we carried out carcinogenesis experiments using transgenic rats harboring the bacterial chloramphenicol acetyltransferase reporter gene ligated to the upstream regulatory sequence of the GST-P gene. In each of three independent lines tested, liver foci and nodules produced by chemical carcinogens (Solt-Farber procedure) were found to express high levels of chloramphenicol acetyltransferase activity, indicating clearly that the GST-P gene is activated by a trans mechanism during hepatocarcinogenesis.
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PMID:Trans-activation of glutathione transferase P gene during chemical hepatocarcinogenesis of the rat. 844 29

While glutathione S-transferase P form (GST-P), a reliable marker for preneoplastic lesions induced by mutagenic hepatocarcinogens, is generally not expressed in rat liver foci, hyperplastic nodules and hepatomas induced by peroxisome proliferators (PPs), such lesions can be detected due to their peroxisomal enzyme-negative nature. For comparative purposes we examined the inducibility of enoyl CoA hydratase (ECH), a key peroxisomal enzyme, in rat hepatic preneoplastic lesions induced by mutagenic carcinogens. Clofibrate (CF) was therefore administered for 2 or 4 weeks following performance of the Solt-Farber protocol using diethylnitrosamine and 2-acetylaminofluorene. Immunohistochemical examination revealed no or only very weak expression of ECH within the induced foci in clear contrast to the strong staining of surrounding parenchyma. ECH expression was thus diametrically opposed to that of GST-P which was found only in foci. Although ECH was completely lacking in GST-P-strongly positive foci, it was expressed in GST-P-negative hepatocytes inside some foci otherwise positive for GST-P. CF administration resulted in a significant decrease in the numbers and areas of foci exhibiting strongly positive or positive GST-P staining; this being reflected in a lowering of GST-P protein levels. Furthermore, in primary cultured rat hepatocytes, clofibric acid as well as dexamethasone suppressed the expression of both GST-P and the oncogene, c-jun. These results taken together suggest that possible interaction of the PP receptor with JUN might be involved in loss of ECH expression in GST-P-strongly positive foci.
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PMID:Lack of peroxisomal enzyme inducibility in rat hepatic preneoplastic lesions induced by mutagenic carcinogens: contrasted expression of glutathione S-transferase P form and enoyl CoA hydratase. 845 14

Glutathione S-transferase P-form (GST-P) mRNA levels and distribution were sequentially analyzed by in situ hybridization histochemistry (ISH) in rat livers during and after induction of preneoplastic foci and nodules in the Solt-Farber model. Dot blot analysis showed GST-P transcripts in the liver to be elevated coincidental with the development of GST-P-positive lesions. GST-P ISH indicated that the majority of early foci and some of the resultant lesions showed uniformly high levels of GST-P mRNA. However, the majority of foci and nodules after completion of the selection regimen exhibited a progressive loss of staining for GST-P mRNA. Similar results were obtained for gamma-glutamyltransferase (GGT) transcripts, indicating that phenotypic reversion is controlled by factors operating at the level of gene expression in both cases. Expression of GST-P mRNA was high in all hepatocellular carcinoma samples, whereas the levels of GGT transcripts varied considerably, so that the two enzymes showed a degree of independence in their regulation. The present data for transcription suggest that GST-P is a stable marker of preneoplastic and neoplastic cells, not only at the protein but also at the mRNA level, throughout hepatocarcinogenesis in the rat. The reason why transcription of GST-P mRNA is switched off as part of the reversion to a normal organization remains to be elucidated.
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PMID:Reduction of glutathione S-transferase P-form mRNA expression in remodeling nodules in rat liver revealed by in situ hybridization. 906 55


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