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)

Overexpression of detoxication enzymes is associated with the development of drug-resistant, preneoplastic nodules in the carcinogen-treated rat liver. The most consistent marker of preneoplasia in many experimental models is increased expression of the pi-class glutathione S-transferase (GST) YfYf. We have confirmed by immunostaining that the pi-class GST is overexpressed in aflatoxin B1-induced preneoplastic nodules and liver tumours in rats. However, pi-class GST YfYf has low activity against aflatoxin B1-8,9-epoxide, and most activity against this cytotoxic and genotoxic metabolite is associated with the alpha-class GSTs YaYa, YaYc and YcYc. We have demonstrated that there is also a consistent increase in the alpha-class GSTs in this model. It seems likely that the overexpression of the Ya and Yc subunits, rather than increased levels of the pi-class GST YfYf, is responsible for the acquisition of a drug-resistant phenotype in rat liver preneoplastic nodules and tumours induced by aflatoxin B1.
Carcinogenesis 1990 Jun
PMID:Glutathione S-transferase localization in aflatoxin B1-treated rat livers. 211 61

Two principal pathways of metabolism of the carcinogenic compound 1,2-dichloroethane (DCE) have been proposed. One is a mixed function oxidase dependent pathway requiring oxygen and NADPH. The other pathway depends on the presence of glutathione (GSH) and glutathione transferase (GST). The aim of this study was to investigate the role of the latter pathway for the in vivo mutagenicity of DCE in the somatic wing spot test in Drosophila melanogaster. DCE caused a dose-dependent increase of wing spots. In order to investigate the role of cellular GSH for the mutagenicity, the level of GSH was decreased by 24 h pretreatment with buthionine sulfoximine (BSO), an efficient inhibitor of GSH synthesis. This pretreatment decreased the GSH level to approximately 6% as compared to the control. The pretreatment also resulted in a significant decrease of the mutagenicity of DCE. Treatment of the larvae with phenobarbiturate (PB) resulted in approximately 200% induction of cytosolic GST, and a corresponding increase in the DCE mutagenicity. These results indicate that the important pathway in vivo for the mutagenicity of DCE is dependent on GSH and GST. A similar experimental protocol was used to study interactions between aflatoxin B1 (AFB) and GSH and GST. No effect of the treatment with BSO on the mutagenicity of AFB was observed, while pretreatment with PB caused a decrease of the mutagenicity of AFB.
Carcinogenesis 1990 Aug
PMID:The importance of glutathione and glutathione transferase for somatic mutations in Drosophila melanogaster induced in vivo by 1,2-dichloroethane. 211 3

The level of quinone oxidoreductases (microsomal and cytosolic DT-diaphorase, NADPH-cytochrome P450 reductase and NADH-cytochrome b5 reductase), superoxide dismutase and glutathione-related enzymatic activities in diethylstilbestrol (DES)-induced carcinogenesis in kidney from Syrian golden hamsters are presented. Animals that exhibited two different stages of DES-induced carcinogenesis in kidney--pre- and neoplastic lesions and tumorous lesions (after 6 and 8 months of continuous exposure to DES respectively)--were studied in comparison to kidneys from control animals. A dramatic decrease in microsomal and cytosolic DT-diaphorase activities (13.6 and 37.8% of controls), as well as in glutathione disulphide reductase (39.5%), and less marked in superoxide dismutase (45.6%), NADH cytochrome b5 reductase (61.9%) glutathione transferase (GST) towards 1-chloro-2,4-dinitrobenzene (CDNB) (66.2%) and glutathione peroxidase (GSH-Px) (80%) activities, were observed in kidneys with pre- and neoplastic lesions. NADPH-cytochrome P450 reductase and GST activity towards 4-hydroxy-2,3-trans-nonenal (4-HNE) showed no statistically significant variation at this stage of carcinogenesis. In kidney from animals with tumorous lesions, all the enzymatic activities mentioned above decreased, except for superoxide dismutase, which was increased to 186% of the control activity. GST activity towards 4-HNE again showed no statistically significant variation. These results suggest that if one-electron reduction of diethylstilbestrol-4',4''-quinone (DESQ) occurs, it may play a very important role in the development of DES carcinogenesis (pre- and neoplastic lesions), since at this stage of carcinogenesis the primary defense mechanisms against the oxygen free radicals generated in this way, i.e. SOD activity, is reduced to less than a half of control values. Both cytosolic and microsomal DT-diaphorase activities are unable at this stage of carcinogenesis to promote effectively the two-electron reduction of DESQ, which would avoid the initial formation of superoxide anion. The consequences of these decreases may be an increased steady-state concentration of superoxide anion and hydrogen peroxide, which in the presence of iron might lead to lipid peroxidation. GST activity towards 4-HNE could be responsible for the possible higher steady-state concentration of this lipid peroxidation product during DES treatment. The induction of DT-diaphorase and its protective role in the prevention of the development of pre- and neoplastic lesions in kidney from Syrian golden hamster during DES treatment is also discussed.
Carcinogenesis 1990 Oct
PMID:The levels of quinone reductases, superoxide dismutase and glutathione-related enzymatic activities in diethylstilbestrol-induced carcinogenesis in the kidney of male Syrian golden hamsters. 211 5

The effects of inhibitors of poly(ADP-ribose)polymerase, 3-aminobenzamide (ABA), luminol and 3-methoxybenzamide (MBA) on the rat liver tumor promotion activity of phenobarbital (PB) were assessed. Fischer 344 male rats were initiated with N-nitrosodiethylamine (200 mg/kg) and placed on either basal diet, diet containing 0.05% PB, diet containing various doses of the inhibitors alone or diet containing 0.05% PB plus various doses of inhibitors for 10 weeks, and then killed. Quantitation of the development of glutathione S-transferase placental form-positive foci revealed that ABA at doses of 2 and 1.5, but not 1%, significantly inhibited the PB promotion activity. Luminol dose-dependently reduced PB promotion at doses of 3 and 6% but exerted no effects at the 1 and 2% levels. MBA also demonstrated a dose-dependent inhibitory influence at doses of 1 and 2%. The results are thus strongly suggestive of an involvement of poly ADP-ribosylation in the mechanisms underlying liver tumor promotion by PB.
Carcinogenesis 1990 Oct
PMID:Possible involvement of poly ADP-ribosylation in phenobarbital promotion of rat hepatocarcinogenesis. 211 7

The conjugation capacity of 4-nitroquinoline 1-oxide (4-NQO) with GSH by a number of human, rat, mouse and bacteria glutathione transferases (GSTs) was investigated. Pi and mu classes GSTs exhibited maximum conjugation capacity. Alpha class glutathione transferases as well as bacteria glutathione transferases were found to be unable to conjugate GSH to 4-NQO. The Km values as well as the catalytic efficiency (Kcat/Km) for most of the GSTs investigated were also determined. Mouse liver GST MIII (class mu) was the most efficient of the various isoenzymes tested. Its Kcat/Km value was 162 times higher than that of mouse liver GST MI (class alpha). The relatively high catalytic efficiency exhibited by GST-alpha (class pi) is prevalently due to its low affinity for 4-NQO.
Carcinogenesis 1990 Dec
PMID:Differential activity of human, rat, mouse and bacteria glutathione transferase isoenzymes towards 4-nitroquinoline 1-oxide. 212 54

The glutathione S-transferases (GSTs) have been implicated in carcinogenesis and tumour drug-therapy resistance. In this study GST pi was the predominant isoenzyme in the fetal human kidney. It was present in differentiated epithelial structures but never in the primitive mesenchyme. By contrast most cases of Wilms' tumours showed GST pi in both epithelial structures and undifferentiated blastema. The level of expression, as assessed by immunostaining, was no more than moderate, and was generally higher in differentiated elements. In only one case was GST alpha found in Wilms' tumour. This study had demonstrated a difference between fetal kidney and Wilms' tumour blastema in terms of GST expression.
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PMID:Glutathione S-transferase expression in fetal kidney and Wilms' tumour. 216 34

Free radicals are found to be involved in both initiation and promotion of multistage carcinogenesis. These highly reactive compounds can act as initiators and/or promoters, cause DNA damage, activate procarcinogens, and alter the cellular antioxidant defense system. Antioxidants, the free radical scavengers, however, are shown to be anticarcinogens. They function as the inhibitors at both initiation and promotion/transformation stage of carcinogenesis and protect cells against oxidative damage. Altered antioxidant enzymes were observed during carcinogenesis or in tumors. When compared to their appropriate normal cell counterparts, tumor cells are always low in manganese superoxide dismutase activity, usually low in copper and zinc superoxide dismutase activity and almost always low in catalase activity. Glutathione peroxidase and glutathione reductase activities are highly variable. In contrast, glutathione S-transferase 7-7 is increased in many tumor cells and in chemically induced preneoplastic rat hepatocyte nodules. Increased glucose-6-phosphate dehydrogenase activity is also found in many tumors. Comprehensive data on free radicals, antioxidant enzymes, and carcinogenesis are reviewed. The role of antioxidant enzymes in carcinogenesis is discussed.
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PMID:Free radicals, antioxidant enzymes, and carcinogenesis. 219 55

The modifying effects of fenvalerate and esfenvalerate administration on liver carcinogenesis were investigated in male F344/DuCrj rats initially treated with N-nitrosodiethylamine (DEN). Two weeks after a single dose of DEN (200 mg/kg, intraperitoneally), rats were given fenvalerate at dietary levels of 1500, 500, 150, 50 and 15 parts per million (ppm), esfenvalerate at 500 ppm, or 2-acetylamino-fluorene (2-AAF) at 200 ppm and sodium phenobarbital (PB) at 500 ppm as positive controls for 6 weeks. At week 3 following DEN administration, all animals were subjected to partial hepatectomy. Prominent neurologic signs and moderate retardation of body weight were observed in the groups given 1500 ppm fenvalerate and 500 ppm esfenvalerate, although no adverse effects on survival were evident. While statistically significant increases in relative liver weights were noted in rats given fenvalerate at doses of 1500 or 500 ppm, no toxic hepatocyte lesions were found. Neither fenvalerate nor esfenvalerate significantly increased the numbers or areas of glutathione S-transferase placental form (GST-P) positive liver cell foci observed after DEN initiation, in clear contrast to the positive controls, 2-AAF and PB. The results thus demonstrated that fenvalerate and esfenvalerate are non-toxic for rat hepatocytes and lack modifying potential for liver carcinogenesis in our medium-term bioassay system.
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PMID:Lack of enhancing effects of fenvalerate and esfenvalerate on induction of preneoplastic glutathione S-transferase placental form positive liver cell foci in rats. 220 92

6-Hydroxymethylbenzo[a]pyrene was activated to an electrophilic and mutagenic sulfuric acid ester metabolite by rat and mouse liver sulfotransferase activity. The intrinsic mutagenicity of this reactive ester, 6-sulfooxymethylbenzo[a]pyrene, was inhibited by glutathione and glutathione S-transferase. A single i.p. dose of 2.5 nmol/g body wt of 6-sulfooxymethylbenzo[a]pyrene in infant male B6C3F1 mice induced liver tumors in 35 of 36 mice at 10 months with an average multiplicity of 4.4. A comparable dose of the parent hydrocarbon, 6-hydroxymethylbenzo[a]pyrene, was only a tenth as active. The electrophilic sulfuric acid ester produced high levels of benzylic DNA adducts in the livers of these mice that accounted for about 80% of the total DNA adducts. These results strongly suggest that this sulfuric acid ester is an important ultimate electrophilic and carcinogenic metabolite in carcinogenesis by 6-hydroxymethylbenzo[a]pyrene and possibly even by 6-methylbenzo[a]pyrene and benzo[a]pyrene in mouse liver.
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PMID:The strong hepatocarcinogenicity of the electrophilic and mutagenic metabolite 6-sulfooxymethylbenzo[a]pyrene and its formation of benzylic DNA adducts in the livers of infant male B6C3F1 mice. 222 84

The level of expression of glutathione S-transferases (GSTs) and cytochrome P450s in breast tissue are potentially important determinants in both the susceptibility of this tissue to the mutagenic effects of chemical carcinogens and in the response of breast tumors to chemotherapy. In this study we have investigated the expression of these proteins in 41 tumor and surrounding normal breast tissue samples by measurement of substrate metabolism. Western blot analysis and immunohistochemistry. In addition, we have quantitated the concentration of alpha, mu and pi class GST subunits using radioimmunoassay. All three classes of GST were expressed in breast tissue. The pi and mu class enzymes preponderate. Both the polymorphic mu class GST as well as a further form, present in all individuals, were found in high concentration. The polymorphic mu class GST was expressed in approximately 50% of the samples, which is consistent with the frequency of this polymorphism in the population and therefore does not appear to be a factor in susceptibility to this disease. Interestingly, although levels of the alpha class GST were very low, in two tumor samples extremely high levels of the B1B1 subunit were detected. Immunohistochemical studies showed significant variability in the localization of the pi class of GST between normal epithelial cells, infiltrating plasma cells and tumor cells, and in some samples GST pi appeared to be almost absent from the tumor tissue. No direct, or inverse correlation was found between GST pi concentration determined by radioimmunoassay and estrogen receptor levels. However, when studied by immunohistochemistry estrogen receptor negative tumors did tend to have higher GST pi content. The only cytochrome P450 detectable by Western blot analysis was a member of the P450IIC gene family. This was apparently distinct from the P450IIC proteins expressed in the liver and was detected in normal and tumor tissues to a similar extent.
Carcinogenesis 1990 Dec
PMID:Expression of glutathione S-transferases and cytochrome P450 in normal and tumor breast tissue. 226 68


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