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 effects of dietary administration of ethoxyquin (EQ) on aflatoxin B1 (AFB1) metabolism, DNA adduct formation and removal, and hepatic tumorigenesis were examined in male Fischer rats. Rats were fed a semipurified diet containing 0.4% EQ for 1 wk, gavaged with 250 micrograms of AFB1 per kg 5 times a wk during the next 2 wk, and, finally, restored to the control diet 1 wk after cessation of dosing. At 4 mo, focal areas of hepatocellular alteration were identified and quantitated by staining sections of liver for gamma-glutamyl transpeptidase. Treatment with EQ reduced by greater than 95% both area and volume of liver occupied by gamma-glutamyl transpeptidase-positive foci. Utilizing the same multiple dosing protocol, patterns of covalent modifications of DNA by AFB1 were determined. EQ produced a dramatic reduction in the binding of AFB1 to hepatic DNA: 18-fold initially and 3-fold at the end of the dosing period. Although binding was detectable at 3 and 4 mo postdosing, no effect of EQ was observed, suggesting that these persistent adducts are not of primary relevance to AFB1 carcinogenesis. Analysis of nucleic acid bases by high-performance liquid chromatography revealed no qualitative differences in adduct species between treatment groups. The inhibitory effect of EQ on AFB1 binding to DNA and tumorigenesis appears related to induction of detoxication enzymes. Rats fed 0.4% EQ for 7 days showed a 5-fold increase in hepatic cytosolic glutathione S-transferase (GST)-specific activities. Multiple molecular forms of GST were induced, and concomitant elevations in messenger RNA levels coding for the synthesis of GST subunits were observed. Correspondingly, biliary elimination of AFB1-glutathione conjugate was increased 4.5-fold in animals on the EQ diet during the first 2 h following p.o. administration of 250 micrograms of AFB1 per kg. Thus, induction by EQ of enzymes important to AFB1 detoxication, such as GST, can lead to enhanced carcinogen elimination, as well as reductions of AFB1-DNA adduct formation and subsequent expression of preneoplastic lesions, and, ultimately, neoplasia.
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PMID:Modulation of aflatoxin metabolism, aflatoxin-N7-guanine formation, and hepatic tumorigenesis in rats fed ethoxyquin: role of induction of glutathione S-transferases. 287 84

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

The natural occurrence of gamma-glutamyl-glutathione (gamma-glutamyl-gamma-glutamylcysteinylglycine) in bile was established by analytical and chromatographic studies on the isolated and chemically synthesized materials. Evidence that it is formed in kidney was obtained. The origin of gamma-glutamyl-glutathione was explored through studies on the interaction of glutathione with gamma-glutamyl transpeptidase. When purified gamma-glutamyl transpeptidase was incubated with various concentrations (4 microM-50 mM) of glutathione, the initial rates of formation of gamma-glutamyl-glutathione were substantial at all concentrations of glutathione studied and were greater than the rates of formation of glutamate at physiological levels of glutathione (1-10 mM). The findings indicate that gamma-glutamyl transpeptidase catalyzes transpeptidation in vivo. That gamma-glutamyl-glutathione is formed in vivo and that it is a significant product of the reaction between glutathione and gamma-glutamyl transpeptidase under physiological conditions suggest that this polyanionic tetrapeptide may have a physiological role. gamma-Glutamyl-glutathione is not a substrate of glutathione reductase or of glutathione S-transferase, but it is a substrate of gamma-glutamyl-cyclotransferase. That gamma-glutamyl-glutathione has an additional negative charge as compared to glutathione suggests that it may be more effective than glutathione in forming complexes with certain metal ions and other cations.
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PMID:Gamma-glutamyl-glutathione. Natural occurrence and enzymology. 287 99

Reduced glutathione (GSH) and activities of several glutathione-related enzymes were measured in two 9L rat brain tumor cell lines with differing sensitivities to both 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and nitrogen mustard. GSH, measured by a specific high-performance liquid chromatographic method, was found to be approximately twice as high in 9L cells sensitive to BCNU but resistant to nitrogen mustard. The nitrogen mustard resistant cell line was also found to have 2.5-fold more bulk glutathione transferase activity and approximately 3-fold more gamma-glutamyl transpeptidase activity. Glutathione reductase activity, protein thiol, and total protein content were similar in the two cell lines. Pretreatment of 9L cells with 50 microM buthionine sulfoximine for 24 h to deplete GSH only slightly potentiated BCNU cytotoxicity in a clonogenic assay whereas that of nitrogen mustard was markedly potentiated in both cell lines. Similarly, buthionine sulfoximine pretreatment had little effect on the induction of sister chromatid exchanges by BCNU, but significantly increased the number of sister chromatid exchanges induced by nitrogen mustard in both cell lines. Depleting GSH also had no significant effect on the cytotoxicity of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea and 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea to 9L cells. Pretreatment of 9L cells with 1 mM GSH significantly protected against nitrogen mustard cytotoxicity. Moreover, nitrogen mustard incubated with GSH and glutathione transferase was 4-fold less cytotoxic than nitrogen mustard incubated with GSH alone. Incubation of BCNU with GSH alone or with glutathione transferase had no effect on BCNU cytotoxicity. These results indicate that elevated GSH and glutathione transferase activity is one mechanism of cellular resistance to nitrogen mustard in the 9L cell line, but it does not correlate with resistance to BCNU or other clinically important nitrosoureas.
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PMID:Glutathione and related enzymes in rat brain tumor cell resistance to 1,3-bis(2-chloroethyl)-1-nitrosourea and nitrogen mustard. 288 34

Glutathione peroxidases, glutathione transferase, glutathione reductase and gamma-glutamyl transpeptidase activities were analyzed in human thyroid tissues obtained from 17 patients undergoing resectional surgery because of a malignancy. It was deduced, from measurements of glutathione peroxidase activity with both H202 and cumene hydroperoxide, that thyroid contains only the selenium enzyme. The absence of selenium independent glutathione peroxidase activity in thyroid was confirmed with gel filtration experiments. An interindividual variation of about 28-fold was found measuring glutathione transferase activity with 1-chloro-2,4-dinitrobenzene. Subjecting a fraction of human thyroid cytosols partially purified by G-100 Sephadex column to isoelectricfocusing run, a single peak of glutathione transferase activity centered at pH 4.6 was obtained. An adequate level of glutathione reductase and gamma-glutamyl transpeptidase activities was also found in all specimens investigated.
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PMID:Glutathione metabolizing enzyme activities in human thyroid. 288 74

Our laboratory has developed an in vivo short-term screening test for hepatocarcinogens based on quantitation of gamma-glutamyl transpeptidase (gamma-GT) positive foci. However, gamma-GT positive hepatocytes appear in periportal areas under a variety of circumstances apparently unrelated to hepatocarcinogenesis. Glutathione S-transferase placental type (GST-P), which is hardly detectable in normal rat liver, was recently demonstrated as a new marker protein for preneoplastic liver foci. In experiment I, rats were initially given a single dose (200 mg/kg) of diethylnitrosamine intraperitoneally and 2 weeks later were treated with test compounds for 6 weeks. All rats were subjected to partial hepatectomy at week 3. The long-term development of preneoplastic lesions was followed in rats for 50 weeks. The immunohistochemical investigation of GST-P binding and the histochemical demonstration of gamma-GT in serial sections revealed that almost all gamma-GT foci were GST-P positive, but 5-10% of GST-P foci could not be detected by gamma-GT staining. From week 8, many gamma-GT foci partially lost gamma-GT activity. However, no comparable disappearance of GST-P was evident in the lesions. All hepatocellular carcinomas (HC) found at week 50 consisted of GST-P positive HC cells. In contrast, 37.9% (11/29) of HC were negative for gamma-GT. In experiment II (in vivo short-term screening test for hepatocarcinogens), rats were treated in the same manner as for experiment I and killed at week 8. Fifty-eight chemicals were investigated for their potential to modify GST-P positive foci development.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Placental glutathione S-transferase (GST-P) as a new marker for hepatocarcinogenesis: in vivo short-term screening for hepatocarcinogens. 288 19

Biochemical phenotypes such as the forms of enzyme proteins alter during the promotion and progression stages in chemical hepatocarcinogenesis. Many enzymes or isoenzymes have been identified as markers of (pre) neoplastic hepatic tissues and used for analysis of the carcinogenic process. The levels of hepatic isoenzymes decrease and those of prototypic or fetal isozymes increase during the progression of hepatocarcinogenesis. Some drug-metabolizing enzymes are also very variable at the promotion stage in rat chemical carcinogenesis; Phase I enzymes such as cytochrome P-450 decrease and Phase II (iso)-enzymes such as UDP-glucuronyl-transferase, glutathione S-transferase (GST) and gamma-glutamyl transpeptidase (gamma-GTP) increase. A new neutral GST form with pI 7.0 (GST-P) has been identified by us as one of the best markers for rat chemical hepatocarcinogenesis. GST-P is a homodimer consisting of a subunit (Mr 26,000, more accurately 23,307, and pI 6.7), the smallest among rat GST subunits, and differs immunochemically from any other GST form. It is present in very low levels in normal rat liver and is not inducible by most drugs including carcinogens without the appearance of preneoplastic hepatocyte nodules (HN) but it is increased by several ten-fold in HN-bearing liver and hepatomas induced by different carcinogens. Immunohistochemically, it is localized in HN and very early and small GST-positive foci are detectable using anti-GST-P antibody. (Pre) neoplastic hepatic lesions induced by nongenotoxic carcinogens such as hypolipidemic peroxisome-proliferating agents do not express GST-P as well as gamma-GTP.
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PMID:[Enzyme alterations during chemical hepatocarcinogenesis]. 288 6

Glutathione levels were measured in 30 human lung cancer lines. Lower levels were detected in cell lines derived from small cell lung cancer specimens compared to non-small cell lines (mean 42 vs. 130 nmol mg-1 protein, P = 0.005). However, no difference were detected between cell lines derived from previously untreated patients, compared to those derived from patients who had received chemotherapy. Non-small cell lines were found to have increased activity of 4 detoxification enzymes compared to small cell lines, although these differences did not reach statistical significance: glutathione transferase activity (69 vs. 36 units, P = 0.137), glutathione reductase (139 vs. 82 units, P = 0.05), gamma-glutamyl transpeptidase (9.39 vs. 3.03 units, P = 0.072) and superoxide dismutase (20 vs. 13.6 units, P = 0.137). As the cell lines exhibit a similar chemosensitivity pattern to that observed in clinical practice, these differences in glutathione and detoxification enzyme levels may prove to be important indicators of intrinsic drug resistance often seen in patients with non-small cell lung cancer.
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PMID:Glutathione and related enzyme activity in human lung cancer cell lines. 290 63

Target organ-specific estrogen-induced DNA adducts were previously shown to precede renal carcinogenesis in Syrian hamsters. Because estrogens induced these DNA modifications, but were not part of the adduct structure, free radical activation of endogenous electrophiles was postulated as a mechanism of tumor induction by estrogens. In the present study, the activities of enzymes which detoxify reactive intermediates were studied in liver and kidney of hamsters treated with estradiol for 1, 2, and 4 mo and in untreated controls. These studies were done to detect oxidative stress in the target organ of carcinogenesis. In the estrogen-exposed hamster kidney (1, 2, and 4 mo), activities of glutathione peroxidases I and II were significantly increased. The activity of catalase was decreased compared to those in untreated controls. In livers which are not the target organ of carcinogenesis, treatment of hamsters with estrogen for 1, 2, and 4 mo resulted in changes of activities of glutathione peroxidases I and II and catalase, which were opposite to the pattern found in the kidney. Activities of superoxide dismutase, glutathione reductase, glucose-6-phosphate dehydrogenase, gamma-glutamyl transpeptidase, and glutathione transferase in estradiol-treated hamster liver and kidney did not differ significantly from those in either liver or kidney of untreated age-matched controls. Fluorescent products of lipid peroxidation more than doubled in the kidney, but not in the liver of hamsters treated with estradiol for 1 mo. It is concluded that the increases in glutathione, in the activity of glutathione peroxidase, and in products of lipid peroxidation in the kidneys of hamsters treated chronically with estrogen all point towards elevated levels of oxidative stress.
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PMID:Changes in activities of free radical detoxifying enzymes in kidneys of male Syrian hamsters treated with estradiol. 292 1

The effects of concomitant treatment with dehydroepiandrosterone, an inhibitor of glucose-6-phosphate dehydrogenase (G6PD), diaminopropane (DAP), an inhibitor of ornithine decarboxylase or the microsomal drug detoxifying enzyme inducer butylated hydroxyanisole (BHA) during the induction phase of rat liver nodular lesion development were investigated. Clear reductions in both number and size of foci and nodules as assayed quantitatively with the aid of marker enzymes G6PD, glutathione S-transferase P form or gamma-glutamyl transpeptidase were established for treatment with either DHEA or BHA. DAP in contrast did not exert influence on the number of lesions, but brought about a significant reduction in size. The quantitative data taken together with the finding that increased labelling of tritiated thymidine occurred in extrafocal hepatocyte populations in BHA-treated animals, give direct support to the view that alteration in enzyme phenotype within putative pre-neoplastic lesions plays a central role in their generation with this short-term model. In particular, a physiological adaptive significance of G6PD elevation is suggested.
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PMID:Influence of dehydroepiandrosterone, diaminopropane and butylated hydroxyanisole treatment during the induction phase of rat liver nodular lesions in a short-term system. 294 Nov 78


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