Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.5.1.18 (glutathione S-transferase)
 22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Groups of 8 6-w-old female Sprague-Dawley rats were initiated with 30 mg diethylnitrosamine (DEN)/kg. Control and initiated groups were fed a semipurified diet or diets supplemented with Fusarium proliferatum-contaminated corn to contain 20 or 50 mg fumonisin B1 (FB1)/kg. Histochemical staining for gamma-glutamyltransferase (GGT) and immunochemical staining for placental glutathione S-transferase (PGST), markers of altered hepatic foci (AHF), were performed on serial frozen hepatic sections. Gamma-glutamyltransferase -(+) AHF were not found in any group. Dosing with DEN significantly increased the number of PGST-(+) hepatocytes compared to the uninitiated groups. Groups fed F proliferatum-containing diets also had a significantly increased number of PGST-(+) AHF compared with those fed no F proliferatum. The volume percentage of liver occupied by PGST-(+) foci was significantly greater in the groups treated with DEN or F proliferatum. The number of PGST-(+) AHF/liver in the groups given DEN was also significantly greater than in the uninitiated groups. Fusarium proliferatum exposure also significantly increased the number of PGST-(+) AHF/liver. Feeding F proliferatum containing 20 mg FB1/kg promoted the development of DEN-initiated AHF in rats. Placental glutathione S-transferase was a more useful marker than GGT in detecting AHF produced by small amounts of F proliferatum mycotoxins fed after initiating dosing with DEN.
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PMID:Fusarium proliferatum-fermented corn stimulates development of placental glutathione S-transferase-positive altered hepatic foci in female rats. 770 94

The study was undertaken to study the effects of N-nitrosodimethylamine (NDMA) on the formation of single-strand DNA breaks and gamma-glutamyltransferase-positive knots, the status of the enzymatic systems involved in NDMA metabolism and some other biochemical parameters when rats were on retinol-deficient diets and when they were given excessive vitamin A. The action of retinol on NDMA effects were analyzed by evaluating the activity of glutathione-S-transferase (EC 2.5.1.18), glutathione-reductase (EC 1.2.1.1), aldehyde-dehydrogenase and aldehyde-oxidase (EC 1.2.1.3 and EC 1.2.3.1, respectively), p-450 reductase NADPH cytochrome (EC 1.6.2.4), the demethylase and hydroxylase activities, levels of malonic dialdehyde and the rate of ascorbate-dependent lipid peroxidation, the contents of proteins, phospholipids, cysteine, redox glutathione, glucuronides, sulfates. The level of vitamin A in the animals was found to substantially affect the magnitude of the genotoxic action of NDMA. The supplementary administration of vitamin A reduced the effect of the carcinogen. The mechanism of protective action of retinol was largely explained by the mediated activity of cytochrome-P-450 and glutathione-dependent systems involved in the biotransformation of NDMA. Based on the data available in the literature and their own data, the authors analyzed the effects of retinol on the metabolism of genotoxicants and described possible mechanisms of its antimutagenic and anticarcinogenic action. It is concluded that the effective protection of the body from unfavourable environmental influences may be provided only by supplementary (more than the optimum) intake of vitamin A against the background of a damaging factor.
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PMID:[Vitamin A and enzyme systems of metabolic activation of genotoxic compounds]. 776 15

The present study was performed to assess the roles of hepatocellular oxidative damage to DNA and constituents other than DNA in rat liver carcinogenesis caused by a choline-deficient, L-amino acid-defined (CDAA) diet by examining the effects of the antioxidant N,N'-diphenyl-p-phenylenediamine (DPPD). The parameters used for cellular oxidative damage were the level of 8-hydroxy-guanine (8-OHGua) for DNA and that of 2-thiobarbituric acid-reacting substance (TBARS) for constituents other than DNA. A total of 40 male Fischer 344 rats, 6 weeks old, were fed the CDAA diet for 12 weeks with or without DPPD (0.05, 0.10 or 0.20%) or butylated hydroxytoluene (BHT, 0.25%). In the livers of the rats, the numbers and sizes of glutathione S-transferase (EC 2.5.1.18) placental form (GSTP)- and/or gamma-glutamyltransferase (GGT, EC 2.3.2.2)-positive lesions and levels of 8-OHGua and TBARS were determined. The GSTP-positive lesions of 0.08 mm2 or larger were all stained positively for GGT as well in cross-sectional area, whereas the smaller lesions were generally negative for GGT. DPPD and BHT reduced the size of the GSTP-positive lesions without affecting their total numbers. At the same time, they reduced TBARS generation without affecting 8-OHGua formation in DNA. The present results indicate that oxidative DNA damage (represented by 8-OHGua formation) and damage to constituents other than DNA (represented by TBARS generation) may play different roles in rat liver carcinogenesis caused by the CDAA diet; the former appears to be involved in the induction of phenotypically altered hepatocyte populations while the latter may be related to the growth of such populations.
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PMID:Different roles of 8-hydroxyguanine formation and 2-thiobarbituric acid-reacting substance generation in the early phase of liver carcinogenesis induced by a choline-deficient, L-amino acid-defined diet in rats. 801 8

Biochemical and histochemical studies were conducted in aflatoxin B1-induced liver tumors in adult rainbow trout. Specific activities of the phase I enzymes, ethoxyresorufin-O-deethylase (EROD), microsomal and cytosolic epoxide hydrolase (mEH and cEH), aldehyde dehydrogenase (ALDH) and DT-diaphorase, and the phase II enzymes, gamma-glutamyltransferase (gamma-GT), glutathione transferase (GST) and uridine diphosphoglucuronyl transferase (UDPGT) were measured. Cryostat sections of tumor and surrounding liver from the same cohorts were analyzed immunohistochemically for cytochrome P450IA1 and histochemically for ALDH (benzaldehyde and hexanal), DT-diaphorase, gamma-GT and uridine diphosphoglucuronyl dehydrogenase (UDPGdH). In tumor tissues, the largest biochemical changes were found with benzaldehyde dehydrogenase, where activity increased from undetectable levels to 7.4 nmol/min/mg protein, and gamma-GT, where activity increased 12-fold over controls. Increases in other enzymes ranged from 1.26 to 2.84 times that of control liver, except EROD, which decreased, and cEH and mEH, which were unchanged. Histochemical analyses showed the induction of ALDH, gamma-GT, DT-diaphorase and UDPGdH, and the depression of cytochrome P450IA1 in hepatic neoplasms. In addition, marker enzyme histochemistry of neoplasms revealed heterogeneous populations of hepatocytes and absence of necrotic areas.
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PMID:Biochemical and histochemical properties of hepatic tumors of rainbow trout, Oncorhynchus mykiss. 809 46

Glutathione conjugation has been identified as an important detoxication reaction. However, in recent years several glutathione-dependent bioactivation reactions have been identified. Current knowledge on the mechanisms and the possible biological importance of these reactions are discussed. 1. Dichloromethane is metabolized by glutathione conjugation to formaldehyde via S-(chloromethyl)glutathione. Both compounds are reactive intermediates and may be responsible for the dichloromethane-induced tumorigenesis in sensitive species. 2. Vicinal dihaloalkanes are transformed by glutathione S-transferase-catalyzed reactions to mutagenic and nephrotoxic S-(2-haloethyl)glutathione S-conjugates. Electrophilic episulphonium ions are the ultimate reactive intermediates formed. 3. Several polychlorinated alkenes are bioactivated in a complex, glutathione-dependent pathway. The first step is hepatic glutathione S-conjugate formation followed by cleavage to the corresponding cysteine S-conjugates, and, after translocation to the kidney, metabolism by renal cysteine conjugate beta-lyase. Beta-Lyase-dependent metabolism of halovinyl cysteine S-conjugates yields electrophilic thioketenes, whose covalent binding to cellular macromolecules is responsible for the observed toxicity of the parent compounds. 4. Finally, hepatic glutathione conjugate formation with hydroquinones and aminophenols yields conjugates that are directed to gamma-glutamyltransferase-rich tissues, such as the kidney, where they undergo alkylation or redox cycling reactions, or both, that cause organ-selective damage.
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PMID:Glutathione-dependent bioactivation of xenobiotics. 828 43

The antioxidant and anticarcinogenic activities of soybean isoflavone extracts were investigated in female F344/rats. Diethylnitrosamine (DEN, 15 mg/kg body wt) as a cancer initiator was injected intraperitoneally into 120 female F344/N rats at 10 days of age, and at weaning, phenobarbital (PB, 500 mg/kg diet) was fed to one-half of the rats. Soybean isoflavones were extracted in acetone-0.1 N HCl and analyzed by high-performance liquid chromatography, and two levels of soybean isoflavones (920 and 1,840 mumol/kg diet) were fed during PB treatment for 3 and 11 months. Control rats were fed diets without PB and with or without isoflavones. The effect of soybean isoflavone extract on hepatic glutathione peroxidase was measured, and development of gamma-glutamyltransferase (GGT)-positive (GGT+) and placental glutathione transferase (PGST)-positive (PGST+) altered hepatic foci (AHF) was analyzed by computerized stereology. Soybean isoflavone extract providing 920 or 1,840 mumol/kg diet normalized total heptic glutathione peroxidase activity, which was suppressed about 17% by PB (p < 0.05), and both doses of isoflavone extract suppressed PB promotion of hepatocarcinogenesis, decreasing the volume occupied by GGT+ and PGST+ AHF (p < 0.05) after three months. After 11 months of PB promotion, isoflavone extract at 920 mumol/kg diet decreased PGST+ AHF compared with the PB-fed group, but neither dose of isoflavone extract suppressed development of GGT+ AHF compared with the group fed PB alone. Furthermore the control group fed isoflavone extract at 1,840 mumol/kg diet showed greater development of GGT+ and PGST+ AHF than the group fed the basal diet alone. Therefore soybean isoflavones may be anticarcinogenic, but their margin of safety is relatively narrow, with a cancer-promoting dose of 1,840 mumol/kg in female F344/N rats initiated with DEN.
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PMID:Soybean isoflavone extract suppresses early but not later promotion of hepatocarcinogenesis by phenobarbital in female rat liver. 861 46

The systemic toxicity of benzothiophene, a sulfur-containing heterocyclic present in petroleum, coal, and their derived products, was studied in male rats following short-term oral exposure. Male Sprague-Dawley rats (130 +/- 20 g) (n = 5 per dose group) were treated with benzothiophene by gavage at dosages of 0, 2, 20 or 200 mg/kg/d for 21 d. In another study, male rats were treated with 0, 100, or 500 ppm benzothiophene via the diet for 28 d. In the gavage study, the 200 mg/kg/d rats showed depressed weight gain, increased relative liver and kidney weights, decreased relative thymus weights, and elevated levels of serum gamma-glutamyltransferase (gamma-GT), hepatic aniline hydroxylase (AH), aminopyrine N-demethylase (APDM), pentoxyresorufin O-dealkylase (PROD), glutathione S-transferase (GST), and UDP-glucuronosyltransferase (UDPGT) activities. A 4.5-fold increase in urine volume on d 14-21 and a transient, 4-fold increase in urinary ascorbic acid on d 1 were also detected. No treatment related changes in urinary N-acetylglucosaminidase (NAGA) activity were observed. Benzothiophene residues were not detected in adipose tissue, liver, and serum of rats in the 200 mg/kg rats, but a small quantity was detected in the urine. In the diet study, animals fed the 500 ppm diet had increased absolute and relative liver weights, elevated AH, APDM, and GST activities, decreased red blood cell count, and minor increases in serum urea nitrogen and glucose. In summary, benzothiophene produced adverse effects in male rats that included increased relative liver and kidney weights and increased urine output. Benzothiophene also caused increases in hepatic drug metabolizing enzyme activities of a phenobarbital type and a transient elevation in urinary ascorbic acid.
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PMID:Effects of benzothiophene on male rats following short-term oral exposure. 901 32

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

The tumor promoting activity of 2,3,3',4,4',5-hexachlorobiphenyl (PCB 156) was studied in an initiation/promotion bioassay in female Sprague-Dawley rats initiated with N-nitrosodiethylamine after partial hepatectomy. PCB 156 (50, 300, 1500, or 7500 microg/kg body weight/week) was administered by once-weekly subcutaneous injections for 20 weeks. Some high dose animals were left without treatment for an additional 20 weeks to study posttreatment effects. The volume fraction of the liver occupied by glutathione S-transferase P-positive foci was significantly increased to 2.9, 3.3, and 12% at 300, 1500, and 7500 microg/kg body weight/week, respectively, compared to 1.2% in the controls. The volume fraction was 43% in the high dose group 20 weeks after treatment was stopped, probably reflecting the slow body clearance of PCB 156 as indicated by the sustained liver and adipose tissue concentrations. Treatment with PCB 156 following initiation caused decreased body weight gain, thymic atrophy, liver enlargement, induction of hepatic cytochrome P450 1A1/2 (CYP1A1/2) and CYP2B1/2 activities, histopathological effects, and increased activities of aspartate aminotransferase and gamma-glutamyltransferase in plasma. These results show that PCB 156 can enhance the growth of altered foci in rat liver and probably act as a tumor promoter of hepatocarcinogenesis. Based on promotional activity a relative potency of PCB 156 to 2,3,7, 8-tetrachlorodibenzo-p-dioxin of 0.0001-0.001 is proposed.
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PMID:Promotion of enzyme altered foci in female rat 2,3,3',4,4',5-hexachlorobiphenyl. 935 6

Hepatocarcinogenesis initiated with N-nitrosodiethylamine (DEN) and that initiated by feeding of a choline-deficient, L-amino acid-defined (CDAA) diet were compared in transgenic male Wistar rats harboring a rat glutathione S-transferase placental form (GST-P) gene (GST-P-Tg rats) and non-transgenic (N-Tg) rats. Eight-week-old GST-P-Tg and N-Tg rats were administered DEN intraperitoneally at 100 mg/kg body weight, subjected to a selection procedure with 2-acetylaminofluorene and CCl4, and killed at the end of weeks 5 and 12. Other groups were fed the CDAA diet for 12 weeks and killed. Five weeks after the DEN treatment, numbers and sizes of gamma-glutamyltransferase (GGT)- or GST-P-positive lesions and 8-hydroxyguanine (8-OHG) levels in the livers were significantly less in GST-P-Tg rats than in N-Tg rats. The lesion numbers were unchanged between the ends of weeks 5 and 12 in GST-P-Tg rats, but decreased in N-Tg rats. The lesion sizes were increased in GST-P-Tg rats, but unchanged in N-Tg rats. While the proliferating cell nuclear antigen labeling indices (PCNA L.I.) in and surrounding the lesions were decreased, more prominently in GST-P-Tg rats than in N-Tg rats, the 8-OHG levels were also decreased but similarly in both cases. After 12 weeks on the CDAA diet, the lesion incidences, numbers and sizes, 8-OHG levels, PCNA L.I. in and surrounding the lesions, and liver injury were significantly less in GST-P-Tg rats than in N-Tg rats. These results indicate that insertion of a rat GST-P transgene alters the early phase of exogenous and endogenous rat hepatocarcinogenesis, presumably due to enhanced detoxification by GST-P expressed both transiently during the initiation and chronically in the altered hepatocyte populations.
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PMID:Inhibition of early-phase exogenous and endogenous liver carcinogenesis in transgenic rats harboring a rat glutathione S-transferase placental form gene. 991 80


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