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 reversible stage of tumor promotion, which follows the stage of initiation and precedes that of progression in multistage carcinogenesis, is a unique example of reversible toxicity in biological systems. In order to study the molecular mechanisms involved in the action of promoting agents during this stage, the regulation of the expression of genes for two enzymes of glutathione metabolism, gamma-glutamyl transpeptidase (GGT) and the placental isozyme of glutathione S-transferase (GST-P), was studied under several different conditions of promotion during multistage hepatocarcinogenesis in the rat. Promotion by phenobarbital caused an increased expression of both of these genes in altered hepatic focal lesions, although this was somewhat more variable in the case of the GGT gene. C.I. Solvent Yellow 14, an industrial dye, served as an effective promoting agent. Feeding this dye resulted in a dramatic increase in the expression of GST-P, but not that of GGT in altered hepatic foci. Factors in crude, cereal-based diets inhibited the stage of promotion by diethylnitrosamine, but enhanced promotion by phenobarbital in a synergistic manner. In contrast, at least one purified diet had the converse effect during this stage. The mRNA levels of GST-P were uniformly elevated dramatically in reversible nodules and neoplasms of rat liver that had been induced by diethylnitrosamine and phenobarbital promotion. In contrast, the level of GGT mRNA was somewhat variable, with an occasional neoplasm exhibiting almost a background level of expression of this gene. Therefore, the altered regulation of multiple genes in hepatocytes during the stage of promotion can vary with the promoting agent itself; this process may be related to the heterogeneous gene expression seen in hepatic neoplasms. A possible role for specific DNA sequences in the 5' flanking regions of such genes is considered. In addition, a cDNA clone to the mRNA of human liver GGT was isolated and sequenced. The homology of the coding sequence of the human liver GGT mRNA to that of rat kidney GGT mRNA was striking.
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PMID:Regulation of the expression of some genes for enzymes of glutathione metabolism in hepatotoxicity and hepatocarcinogenesis. 256 99

Recent results from our laboratory and others have suggested a possible physiological functional role(s) for leukotrienes in gastric mucosa. In the present study 3H-LTC4 binds to washed rabbit gastric mucosal membranes at 4 degrees C with a Kd of 5 nM and a Bmax of 31.3 pmol/mg protein. Leukotrienes D4, E4, B4, oxidized glutathione (GSSG), cysteine, and mercaptoethanol were unable to displace 3H-LTC4 at 1 microM concentrations, while GSH inhibited binding with a Ki of 47 nM. Differential centrifugation of the membrane preparation to remove mitochondria resulted in Ki values for LTC4 and GSH of 14 and 23 nM, respectively. The similar binding affinities and competitive receptor binding kinetics for GSH and LTC4, the low affinity for other leukotrienes, and a Ki of 7 microM for hematin, a substrate for glutathione S-transferase, suggest that 3H-LTC4 binds to a GSH site which does not discriminate between LTC4 and GSH. Membranes fractionated to remove mitochondria were assayed for glutathione peroxidase, gamma-glutamyltranspeptidase, and glutathione S-transferase as possible binding sites for LTC4. We were unable to detect enzyme activity for any of the three enzymes. The binding of LTC4 in gastric mucosa differs from other tissues with respect to the high affinity for GSH, and thus becomes an appropriate tissue in which to investigate the relationships between LTC4 and GSH.
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PMID:An LTC4 binding site in gastric mucosa is shared with glutathione. 257 Apr 44

1. Glutathione (G-SH) concentration, gamma-glutamyltranspeptidase and glutathione S-transferase activities were studied in several strains of T. cruzi epimastigotes. GSH varied from 1.04 mM for the LQ strain to 0.61 mM for the Tulahuen strain. 2. Cultures of the LQ strain presented more resistance to drugs than those of the Tulahuen. It was necessary a concentration of nifurtimox 4 times higher and one of benznidazole 10 times higher in order to inhibit approximately to 50% the growth of LQ strain cultures when compared with the Tulahuen strain. 3. Buthionine sulfoximine decreased the concentration of glutathione to about 50% in the LQ and Tulahuen strains and potentiated the toxicity of nifurtimox and benznidazole in T. cruzi epimastigote cultures. These results suggest that glutathione is an important factor in the resistance of T. cruzi to nifurtimox and benznidazole.
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PMID:Role of glutathione in the susceptibility of Trypanosoma cruzi to drugs. 257 49

Critical parameters in the quantitation of altered hepatic foci (AHF) developing during multistage hepatocarcinogenesis in the rat include: 1) the enumeration of AHF induced by test agents as well as those AHF occurring spontaneously in livers of untreated animals; 2) the volume percentage or fraction of the liver occupied by all AHF as a reflection of the total number of altered cells within the liver and the degree of tumor promotion which has occurred; and 3) the phenotype of individual AHF as determined by multiple markers with serial sections. These parameters, especially the number of AHF, should be corrected by the presence of spontaneous AHF which increase with the age of the animal, more so in males than females. While accurate estimation of the background level of spontaneous AHF can be important in demonstrating that a carcinogenic agent does not possess the ability to increase the numbers of AHF above the background level, a better method to distinguish the effectiveness and relative potencies of agents as initiators or promoters is reviewed. The relative effectiveness of four different markers--gamma-glutamyltranspeptidase (GGT), a placental form of glutathione S-transferase (GST), canalicular ATPase, and glucose 6-phosphatase (G6Pase)--was described for the chemicals C.I. Solvent Yellow 14 and chlorendic acid as promoting agents in males and females. C.I. Solvent Yellow 14 is a more effective promoting agent in females than males, and AHF exhibit extremely low numbers scored by GGT. On the other hand, the numbers of AHF present in livers of male rats promoted by this agent are more than twice those seen in livers of female animals, possibly owing to the effectiveness of this agent as an initiator in the male but not the female. Very few AHF, especially in the male, are scored by GGT during chlorendic acid promotion. The distribution of phenotypes with these markers also differs in the spontaneous AHF appearing in the livers of animals fed 0.05% phenobarbital on either a crude NIH-07 or AIN-76 purified diet. Such studies emphasize the extreme dependence of the promoting stage of hepatocarcinogenesis on environmental factors of sex, diet, and the molecular nature of the promoting agent itself. The hallmark of the final stage of progression in the development of hepatocellular carcinomas is aneuploidy, which may be reflected by phenotypic heterogeneity within individual AHF, termed foci-in-foci. The implications of such quantitative analyses during hepatocarcinogenesis induced by specific agents in relation to the specific action of the agent at one or more of the stages of hepatocarcinogenesis are discussed.
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PMID:Critical parameters in the quantitation of the stages of initiation, promotion, and progression in one model of hepatocarcinogenesis in the rat. 269 39

The gene expression of liver major gap junction (GJ) protein was studied in rats systemically administered phenobarbital, a rat liver tumor promoter. Using a GJ protein cDNA and northern blot analysis, the level of GJ protein mRNA in liver was observed to be markedly reduced at 4 and 11 wk of phenobarbital exposure (0.1% in drinking water). However, the level of GJ protein mRNA was not altered in kidney at 11 wk of exposure. In liver, phenobarbital did not induce expression of the neoplasm-associated marker genes glutathione S-transferase (placental form) and gamma-glutamyltranspeptidase, while in kidney the observed expression of these genes was not changed. These in vivo results indicate that phenobarbital reduces GJ protein gene expression specifically in rat liver without altering expression of genes often altered during liver carcinogenesis, and they support assigning a role for the impairment of gap junctional intercellular communication in phenobarbital-mediated liver tumor promotion.
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PMID:Phenobarbital specifically reduces gap junction protein mRNA level in rat liver. 285 4

Immunohistochemical staining using anti-rat glutathione S-transferase placental form (GST-P) rabbit antibody and enzyme histochemical staining for gamma-glutamyltranspeptidase (gamma-GT) were investigated in putative preneoplastic lesions and adenocarcinomas in the pancreas of Syrian golden hamsters treated with N-nitrosobis(2-hydroxypropyl)amine (BHP). Areas with ductular proliferation, ductal hyperplasia, and intraductal carcinoma were strongly positive for GST-P binding and negative for gamma-GT. Cystic adenoma, microcarcinoma, and carcinomas were constantly positively stained by GST-P and partially positive for gamma-GT. GST-P appears to be useful as a positive marker for putative preneoplastic lesions in pancreatic carcinogenesis. Since normal acinar cells are strongly positive for gamma-GT, the findings might suggest that acinar cells contribute to the development of cystic adenoma, microcarcinoma, and carcinomas.
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PMID:Comparative histochemical investigation of the glutathione S-transferase placental form and gamma-glutamyltranspeptidase during N-nitrosobis(2-hydroxypropyl)amine-induced pancreatic carcinogenesis in hamsters. 287 Aug 24

4-Monomethylaminoantipyrine (MAA)-induced increase of hepatic drug metabolizing enzymes was suppressed by SKF 525-A. This may be due to the partial binding of SKF 525-A to a portion of cytochrome P-450. On the other hand, glutathione S-transferase and gamma-glutamyltranspeptidase (gamma-GTP) activities of rat liver were both induced by repeated administration of MAA in combination with SKF 525-A. In addition, under the same condition, glutathione level in rat liver was significantly decreased.
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PMID:Effects of co-administration of monomethylaminoantipyrine with diethylaminoethyl 2,2-diphenylvalerate (SKF 525-A) on gamma-glutamyltranspeptidase, glutathione S-transferase and hepatic drug metabolizing enzyme activities in rats. 287 6

Structurally unrelated peroxisome proliferators induce altered areas (AA), neoplastic nodules (NN), and hepatocellular carcinomas (HCC) in rats and mice. In this study we have examined several AA, NN, and HCC induced by Wy-14,643 and ciprofibrate in rats for gamma-glutamyltranspeptidase (GGT) and the placental form of glutathione S-transferase (GST-P) by histochemical and immunohistochemical procedures, respectively. In Wy-14,643-treated animals 96-100% of NN and HCC was negative for both GGT and GST-P. Eighty-seven % of the AA was negative for both GGT and GST-P, and only 2% was positive for both the marker enzymes. In ciprofibrate-treated animals 52% and 75% of AA were negative for GST-P and GGT, respectively, and 16% was positive for both the enzymes. However, a large majority of NN and HCC (more than 95%) was devoid of both these marker enzymes. Thus these studies clearly indicate that the hepatic lesions induced by peroxisome proliferators display different phenotypic properties as compared to the lesions induced by commonly used classical liver carcinogens. We conclude that GGT and GST-P are not the ideal markers for identifying AA, NN and HCC induced by peroxisome proliferators.
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PMID:Analysis of peroxisome proliferator-induced preneoplastic and neoplastic lesions of rat liver for placental form of glutathione S-transferase and gamma-glutamyltranspeptidase. 287 89

The effect of a low dose of preadministered diethylnitrosamine (DEN) on the induction of enzyme-altered foci in the livers of male full-grown Fischer 344 rats was studied. As a pretreatment, DEN at a dose of 10 mg/kg body wt was injected i.p. At various times after DEN pretreatment a complete initiation, consisting of administration of the same dose of DEN by the same route in rats subjected to partial hepatectomy (PH), was performed, followed by application of selection pressure. Enzyme-altered foci stained with gamma-glutamyltranspeptidase (gamma-GTP) and glutathione S-transferase placental form (GST-P) were then assayed. Decreases in the numbers and areas of foci in the rats which received saline + PH 14 or 28 days after DEN pretreatment were observed in comparison with rats which received saline + PH immediately after DEN. On the other hand, the numbers and areas of foci were not decreased in rats which received the complete initiation, consisting of DEN + PH, at various times after DEN pretreatment when compared with rats which received these at the same time as the DEN pretreatment. This persistent effect of DEN pretreatment on the complete initiation lasted up to 182 days after the time of DEN pretreatment. In this experiment, GST-P was found to be a more sensitive marker for the detection of putative preneoplastic liver-cell foci than gamma-GTP.
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PMID:Persistent effect of a low dose of preadministered diethylnitrosamine on the induction of enzyme-altered foci in rat liver. 288 28

Immunohistochemical staining using anti-rat glutathione S-transferase placental form (GST-P) rabbit antibody and enzyme histochemical staining for gamma-glutamyltranspeptidase (gamma-GT) were investigated in lesions appearing during lung carcinogenesis induced by N-nitrosobis(2-hydroxypropyl)amine (BHP) in rats. Rats were given BHP at a concentration of 2000 p.p.m. in drinking water, and were killed after 12 weeks of BHP intake, after 12 weeks of BHP intake followed by 12 weeks of tap water intake or after 20 weeks of continuous BHP intake. It was found that bronchiolo-alveolar hyperplasias, adenomas, adenocarcinomas, squamous metaplasias and squamous cell carcinomas had been induced by BHP. All of the squamous metaplasias and squamous cell carcinomas were shown to stain with GST-P but not with gamma-GT. On the other hand, the hyperplasias, adenomas and adeno-carcinomas stained with gamma-GT to various degrees and in different areas, but did not stain with GST-P. The incidence of gamma-GT phenotype and the average percentage of gamma-GT-positive areas in hyperplasias and adenomas suggested that adenocarcinomas might develop from hyperplasias and adenomas. These results suggest that GST-P is a marker for squamous lesions while gamma-GT is a marker for adenomatous lesions in rat lung carcinogenesis. Furthermore, squamous metaplasias appear to be preneoplastic lesions of squamous cell carcinomas while gamma-GT-positive hyperplasias or adenomas are preneoplastic lesions of peripheral adenocarcinomas.
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PMID:Comparative histochemical investigation of the glutathione S-transferase placental form and gamma-glutamyltranspeptidase during N-nitrosobis(2-hydroxypropyl)amine-induced lung carcinogenesis in rats. 289 57


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