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)

The mRNA levels of three phosphoseryl/phosphothreonyl protein phosphatases, PP1, PP2A and PP2C, in rat liver have been determined by Northern blot analysis in various stages of rat chemical hepatocarcinogenesis using a Solt-Farber model. Five weeks after administration of diethylnitrosamine, the mRNA levels of PP1 alpha, PP2A and PP2C were elevated 8, 29 and 11 times, respectively, as compared to those of the control livers. However, in primary hepatoma induced according to the Solt-Farber model, the mRNA levels of all three protein phosphatases were dramatically decreased to normal levels or even to much lower levels, whereas the mRNA level of glutathione S-transferase placental form, a tumor marker protein, was greatly elevated as compared with that of the control livers. In a poorly differentiated hepatoma AH13, a line of rat ascites hepatoma, the mRNA level of PP1 alpha was 5.6 times higher than that of the control livers, whereas the mRNA lever of PP2C was almost the same as that of the control livers and the level of PP2A mRNA was distinctly lower than that of the control livers. These data appear to suggest some involvement of protein phosphatases in hepatocarcinogenesis.
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PMID:mRNA levels of catalytic subunits of protein phosphatases 1, 2A, and 2C in hepatocarcinogenesis. 131 79

Three factors involved in the Solt and Farber model of rat liver carcinogenesis were studied alone and in various combinations: diethylnitrosamine (DEN) initiating dose, 2-acetylaminofluorene (2-AAF) feeding and partial hepatectomy. The administration of DEN alone (200 mg/kg) was able to switch on glutathione-S-transferase, placental type (GST-P) expression 3 weeks later at a low level (85 U/micrograms protein) which was stable for 10 weeks in the absence of histopathological lesions. During the same time, gamma-glutamyl transpeptidase (GGT) activity presented 2 waves of increase. The feeding of 0.03% 2-AAF for 2 weeks appeared as a determinant factor in the expression of GST-P protein as well as GGT induction (15- and 7-fold versus DEN alone, respectively). The addition of partial hepatectomy enhanced again GST-P expression (1.5-fold) and GGT induction (2-fold). However, GST-P foci increased in size, not in number while GGT foci increased both in size and in number. These data indicated that 2-AAF was a crucial component of the selection procedure since partial hepatectomy alone, with or without DEN initiation was inefficient in promoting GST-P expression. Therefore, 2-AAF would be able to promote the growth of GST-P-positive cells initiated by DEN, a mechanism likely responsible for its tumor-promoting effect.
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PMID:Role of diethylnitrosamine, 2-acetylaminofluorene and partial hepatectomy in the expression of glutathione-S-transferase-P and gamma-glutamyltranspeptidase in the early steps of rat liver carcinogenesis. 135 47

Increased expression of multidrug-resistance (mdr) gene transcripts and of the encoded protein, P-glycoprotein, is found in many types of tumors. The biological significance of mdr overexpression during the stepwise process of neoplastic development, however, is not well understood. To assess the possible significance of mdr overexpression in carcinogenesis, we examined the cellular distributions of both mdr gene transcripts and P-glycoprotein during hepatocarcinogenesis induced in rats by the Solt-Farber protocol and then compared them to the distributions of the placental form of glutathione S-transferase (GST-P), a known marker of preneoplastic and neoplastic lesions in the liver. In situ hybridization and immunohistochemical techniques were employed. Neither mdr transcripts nor P-glycoprotein was expressed in oval cells that appeared early in the carcinogenic process. GST-P was strongly expressed in the early focal lesions, whereas the levels of mdr transcripts and P-glycoprotein expressed were low and heterogeneous. Expression of mdr transcripts and P-glycoprotein was increased and became more uniform in hyperplastic nodules and carcinomas, although considerable heterogeneity of expression was still found, particularly at the nodular stage. These data suggest that increased expression of mdr is associated with later stages of neoplastic development in the liver. Furthermore, that no chemical treatment of the animals was employed when the expression of mdr was increasing in the preneoplastic and neoplastic lesions suggests that the enhanced mdr expression is intrinsic to the carcinogenic process.
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PMID:Cellular pattern of multidrug-resistance gene expression during chemical hepatocarcinogenesis in the rat. 135 97

The early cellular and molecular changes in the Solt-Farber model of hepatocarcinogenesis with and without initiation was studied by using histochemical, immunohistochemical, and in situ hybridization techniques. Increased cellularity was observed in the periductal space in both models 32 to 56 h after partial hepatectomy. These periductal cells and Ito cells were the only cells that became labeled with tritiated thymidine in the uninitiated liver model. Forty-five to 60% of the labeled periductal cells were positive for gamma-glutamyltranspeptidase. From the periductal area the cells that were positive for antibody raised against oval cells (OV-6) infiltrated into liver parenchyma and were followed by desmin-positive Ito cells. The number of Ito cells in the uninitiated model 6 days after partial hepatectomy was 3.5 times higher in the area occupied by oval cells than elsewhere in the liver. The first alpha-fetoprotein (AFP)-positive cells appeared either as individual cells or as pseudoductal formations 32 or 56 h after partial hepatectomy at the periphery of the periductal space in both initiated and uninitiated animals. A combination of in situ and immunohistochemistry revealed that the OV-6-positive cells were AFP positive, whereas desmin-positive cells were AFP negative. Glutathione S-transferase P (GST-P) transcripts could be found mainly in OV-6-positive oval cells. Bile duct cells were positive for GST-P and negative for transforming growth factor beta 1, whereas cells in the periductal space were positive for both of these transcripts. The GST-P-positive early preneoplastic lesions showed a similar distribution pattern as that of oval cells; the preexisting hepatocytes became trapped between small basophilic hepatocytes that showed either irregular or pseudoalveolar arrangement. This raises the question as to whether cells which are stem cell-like are among the target cells in the Solt-Farber model of hepatocarcinogenesis. Proliferation of transforming growth factor beta 1-producing, desmin-positive cells (Ito cells) and multipotent oval cells in a close proximity to each other indicates an intricate relationship between Ito cells and oval cells in liver that warrants further investigation.
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PMID:Cellular and molecular changes in the early stages of chemical hepatocarcinogenesis in the rat. 169 60

We have developed a simple method to measure gap-junctional intercellular communication (GJIC), by means of microinjection/dye transfer assay, in liver slices freshly removed from the rat. Using this method and immunostaining of connexin 32 (cx32), the major liver gap junction protein, we studied sequential changes of GJIC during chemical hepatocarcinogenesis in male Fischer-344 rats under a modified Solt-Farber protocol (3 weeks 4 day exposure regimen). Four weeks after commencement of the protocol, there was a substantial decrease in GJIC in the liver parenchyma, which was free from focal lesions. The decrease in GJIC persisted up to at least the 15th week of treatment, while a decrease in the number of immunoreactive cx32 spots was evident only at 4 weeks of post-protocol commencement. Most enzyme-altered (GST-P-positive) focal lesions showed markedly lower GJIC and a significantly lower number of cx32-positive spots than surrounding hepatocytes. Most GST-P-positive foci showed a selective lack of GJIC with surrounding heptocytes. Hepatocellular carcinomas arising 1 year after the carcinogenic regimen had significantly reduced communicational capacity accompanied by a large decrease in cx32 expression. These results suggest that a progressive decrease in homologous as well as heterologous GJIC in preneoplastic lesions occurs during rat hepatocarcinogenesis, and that preneoplastic lesions with the most prominent disorders in GJIC may be more likely to develop into carcinomas.
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PMID:Sequential changes of gap-junctional intercellular communications during multistage rat liver carcinogenesis: direct measurement of communication in vivo. 189 31

Phenobarbital (PB) is an effective growth stimulator of hepatic hyperplastic nodules developed with diethylnitrosamine and 2-acetylaminofluorene plus partial hepatectomy (the Solt-Farber model), but it does not apparently stimulate the growth of preneoplastic lesions produced with aflatoxin B1 (AFB). Some studies have suggested a correlation between the induction of specific cytochrome P450 enzymes and the tumor promoting effects produced by repeated treatment with PB. To examine this hypothesis further, hepatic hyperplastic nodules were produced with AFB (10 ip doses of AFB, 150 micrograms/kg/day, followed by partial hepatectomy) or by a modified Solt-Farber protocol (DEN/AAF), and the effects of PB on nodule growth and expression of cytochrome(s) P450 2B1 and/or P450 2B2 (P450 2B1/2) were determined. Both treatment protocols (without PB) produced multiple, large nodules within 10-17 weeks of carcinogen administration. These nodules stained intensely for glutathione S-transferase p (GST-p; GST7-7) and gamma-glutamyl transpeptidase (GGT) and weakly for P450 2B1/2. Pentoxyphenoxazone dealkylation activity was decreased to less than 50% of the surrounding tissue levels in both types of nodules. PB treatment of animals with DEN/AAF-induced nodules greatly increased P450 2B1/2 expression in surrounding tissues, whereas most, but not all, nodules were not inducible. Pentoxyphenoxazone dealkylation was increased 31- to 35-fold in surrounding tissue, but it was increased only 2-fold in pooled nodular tissue, relative to untreated control liver. In contrast to the DEN/AAF group, immunohistochemical staining and pentoxyphenoxazone dealkylation in the AFB group demonstrated that P450 2B1/2 was equally inducible in nodular and surrounding tissues. Short-term treatment (5 days) with PB produced a 2-fold increase in the number and total area of GGT-positive nodules in the DEN/AAF group, but it had no significant effect on the number, size distribution, or total area of GGT-positive nodules in the AFB group. All large GGT-positive nodules in the DEN/AAF group were nonresponsive to induction of P450 2B1/2, whereas all of the GGT-positive nodules which were responsive to P450 2B1/2 induction by PB in this group were relatively small. The size and area of AFB-induced GGT-positive nodules was not affected by PB treatment, and P450 2B1/2 in all of these nodules was inducible by PB. Although a causal, inverse relationship between the responsiveness of nodules to PB induction of P450 2B1/2 and their reaction to PB growth stimulation cannot be firmly established, these data are consistent with such a hypothesis.
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PMID:Differential regulation of cytochrome(s) P450 2B1/2 by phenobarbital in hepatic hyperplastic nodules induced by aflatoxin B1 or diethylnitrosamine plus 2-acetylaminofluorene in male F344 rats. 194 30

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.
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PMID:Immunofluorescent analysis of gamma-glutamyl transpeptidase and glutathione-S-transferase-P during the initial phase of experimental hepatocarcinogenesis. 196 86

The initiation sensitivity of the liver of the LEC (Long-Evans with a cinnamon-like coat color) rat, a new mutant strain with a high incidence of spontaneous liver tumors, was studied by treatment with low doses of diethylnitrosamine (DEN) coupled with modified Solt and Farber's selection. LEC and control LEA (Long-Evans with an agouti coat color) rats received i.p. injections of 10 mg/kg of DEN, then selected by feeding with a diet containing 0.02% 2-acetylaminofluorene (AAF) for 7 days combined with partial hepatectomy (PH). The numbers of placental glutathione S-transferase (GST-P)-positive foci in the livers of LEC rats were 10 times higher than those in LEA rats. These results suggested a high sensitivity of the LEC rat liver to the carcinogenic effect of DEN. The association between initiation sensitivity and spontaneous liver-tumor development and the possible usefulness of the LEC rat for in vivo short-term tests of hepatocarcinogens are discussed.
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PMID:High sensitivity of the LEC rat liver to the carcinogenic effect of diethylnitrosamine. 219 Jun 88

Comparison of binding of specific antibodies to glucose-6-phosphate dehydrogenase (G6PD), gamma-glutamyl transpeptidase (GT), ornithine decarboxylase (ODC) and the glutathione S-transferase B and P forms (GST-B, P) was made in putative pre-neoplastic lesions during their induction and subsequent development using the Solt-Farber model. The earliest focal hepatocellular lesions were evident as single, or small groups of GST-P-positive hepatocytes in tissue taken at partial hepatectomy 3 weeks after initial application of diethylnitrosamine (DEN). With the onset of proliferation and increase in size the majority of the lesions expressed elevated levels of all of the enzyme proteins investigated with a correlation between strength of binding and morphology being apparent. While [3H]thymidine incorporation was limited during the period of acetylaminofluorene administration, to the hepatocytes demonstrating altered enzyme phenotype no direct link between proliferation rate within individual foci and level of G6PD expression could be discerned. Similarly, the elevated level of labelling characteristic of persisting nodular lesions at later stages also did not correlate with degree of G6PD alteration in individual cells. The results indicate that while changed enzyme phenotype appears as an ordered pattern suggestive of physiological adaptive nature, the degree of alteration is not directly related to proliferation kinetics under the rapid induction conditions characteristic of the Solt-Farber model.
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PMID:Immunohistochemically demonstrated glucose-6-phosphate dehydrogenase, gamma-glutamyl transpeptidase, ornithine decarboxylase and glutathione S-transferase enzymes: absence of direct correlation with cell proliferation in rat liver putative pre-neoplastic lesions. 287 98

Female F344/N rats dosed with diethylnitrosamine (DEN) 24 h after partial hepatectomy were treated with the promoting agents, phenobarbital (PB) or 3,4,7,8-tetrachlorodibenzo-p-dioxin (TCDD), or the peroxisome proliferating agent, WY 14,643, for 6 months. Another group was subjected to the Solt-Farber protocol. Altered hepatic foci (AHF) were analyzed by quantitative stereology from frozen serial sections stained for gamma-glutamyl transferase (GGT), canalicular adenosine triphosphatase (ATPase), glucose-6-phosphatase (G6Pase) and the placental isozyme of glutathione S-transferase (PGST). PGST scored more foci in all groups than GGT and ATPase. PGST marked greater focal volume than GGT or ATPase, and PGST marked focal volume equal to or greater than G6Pase in rats treated with PB, TCDD or the Solt-Farber protocol. However, after treatment with WY 14,643, GGT and PGST marked much less focal volume than ATPase or G6Pase, and PGST scored fewer foci than G6Pase. Numerical estimations of foci scored by those markers on the basis of area of the entire tissue section (per cm2) were relatively different from those values determined by quantitative stereology. While these results confirm earlier studies, they demonstrate the importance of quantitative stereologic analysis of AHF during multistage hepatocarcinogenesis.
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PMID:Quantitative stereological evaluation of four histochemical markers of altered foci in multistage hepatocarcinogenesis in the rat. 288 1


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