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)

Liver and muscle amino acid enzyme activities and plasma proteins, urea, amino acids, glucose, lactate, 3-hydroxybutyrate and acetoacetate concentrations were studied in growing rats undergoing adaptation to high-fat, high-energy diet and glucose gavage. Liver and muscle were used for the estimation of alanine transaminase (GPT, EC 2.6.1.1.), adenylate deaminase (AMD, EC 3.5.4.6.), glutamine synthetase (GST, EC 6.3.1.2) and serine dehydratase (SDH, EC 4.2.1.13) activities, the latter only in liver samples. The most important modifications produced in muscle enzyme activities by glucose gavage were observed in rats fed a cafeteria diet. Glucose gavage affects liver enzyme activities in the same sense than cafeteria diet. Energy plasma components were affected in opposite way by glucose gavage according to diet administered.
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PMID:Changes induced in amino acid-enzymes of developing rats by a high-energy diet and glucose gavage. 768 82

The early cellular events in liver carcinogenesis were studied in Fischer-344 male rats that either were fed 200 ppm 2-acetylaminofluorene (AAF) for up to 10 wk or were fed the carcinogen for 8 wk followed by maintenance for an additional 24 wk. By 1 wk of exposure, AAF caused a reduction in the number of glutamine synthetase (GS)-positive centrilobular hepatocytes, an increase in DNA synthesizing hepatocytes in the central areas of the hepatic lobules, and a shift from multinucleated to mononucleated hepatocytes, although overt hepatocellular necrosis was not evident. By 3 wk, altered hepatocellular foci characterized by deficiencies in iron storage (IS-) and collagen production and by expression of gamma-glutamyl transferase (GGT+) and placental-type glutathione transferase (PGT+) activity appeared. Single PGT+ cells were also found. During continued exposure, foci increased in number, size, and total area with the increases escalating between 8 and 10 wk of exposure. Cessation of AAF exposure at 8 wk resulted in a slight decrease in the number of foci after a further 6 wk of maintenance, but with continued maintenance for another 6 and 12 wk, the number again increased. IS- characterized the majority of foci during carcinogen administration, whereas after cessation of exposure, GGT+ and PGT+ foci predominated. None of the foci were positive for GS. After AAF exposure for 10 wk, a few neoplasms developed and greater numbers occurred after maintenance for a further 24 wk of rats exposed for 8 wk. We conclude the following: (a) the low dose of AAF caused subtle alterations in function and proliferation of normal hepatocytes and converted hepatocytes into focus cells; (b) reduction of the GS+ area is a sensitive indicator of cytotoxicity of AAF; (c) the development of some foci at an early stage depends on a promoting action of AAF, which ceased when the carcinogen was withdrawn, allowing some foci to undergo reversion; (d) a strong linkage exists in expression of IS-, GGT+, and PGT+ in foci; (e) the carcinogenic process accelerates in the absence of any indication of increased cytotoxicity by AAF; and (f) under the conditions of this study, no GS+ foci, adenomas, and carcinomas were found, indicating that no carcinogen-induced expression of GS occurred in these lesions and that GS expression is not linked to other phenotypic abnormalities.
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PMID:Sequential functional and morphological alterations during hepatocarcinogenesis induced in rats by feeding of a low dose of 2-acetylaminofluorene. 773 79

This study measured the effect of precise doses of 2-acetylaminofluorene (AAF) in inducing DNA damage, functional changes and neoplastic conversion in rat liver. Groups of male F344 rats at 9 weeks of age were exposed to cumulative doses of 0.5 or 2.0 mmol AAF per kg body weight given by gavage daily 5 days per week over an 8-week period and maintained with no further exposure for up to 8 weeks. Administration of AAF resulted in the formation of N-deoxyguanosin-(8-yl)-2-aminofluorene in liver DNA in relationship to dose. In centrilobular hepatocytes the zone of glutamine synthetase-expressing cells was reduced by exposure. By 8 weeks, but not at 4 weeks, the higher of the two doses of AAF provoked an increase in cell proliferation measured by immunohistochemical incorporation of bromodeoxyuridine. Altered hepatocellular foci expressing the placental form of glutathione transferase were induced by the high dose of AAF at 4 weeks, but not at the low dose. At 8 weeks the incidence of foci at the high dose was 79 times that induced by the low dose. These foci were highly proliferative. In animals exposed to AAF for 8 weeks and maintained for 4 weeks with no exposure, DNA adducts decreased by 80% and cell proliferation subsided by 80%, although the glutamine synthetase zone remained diminished. After discontinuation of AAF, the number of foci diminished by 50% and their proliferation subsided by 80% at 4 weeks, indicating a phenotypic reversion of many foci. With this protocol of administration of precise doses of AAF, we have established non-linearity of effects and a lack of correlation between DNA adduct formation and induction of cellular lesions. We suggest that doses in the range of those reported can be used to study the contribution of epigenetic and genotoxic effects in carcinogenesis and to study threshold events.
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PMID:Dose response effects of 2-acetylaminofluorene on DNA damage, cytotoxicity, cell proliferation and neoplastic conversion in rat liver. 840 92

The influence of gonadectomy on the effects of 2-acetylaminofluorene (AAF) in the livers of rats was studied. Groups of male and female F344 rats at 9 weeks of age were given AAF by daily gavage 5 days per week for 4 or 8 weeks for total cumulative doses of 1.0 or 2.0 mmol/kg body wt. AAF was administered either with no pretreatment or beginning 4 weeks after gonadectomy, which was performed at 5 weeks of age. In male rats AAF induced a large number of placental glutathione S-transferase foci in livers by 8 weeks, while in female rats the number was about 10% of that in males. Orchidectomy decreased the AAF induction of foci in male rats by 60%, whereas ovariectomy had no effect in female rats. Similarly, orchidectomy decreased DNA adduct levels approximately 85% in male rats given AAF by gavage for 4 weeks. In ovariectomized female rats at 4 and 8 weeks hepatic DNA adduct levels were somewhat elevated (< 50%) as compared to intact controls. The zone of glutamine synthetase-positive hepatocytes around the central vein was reduced by AAF exposure of male, but not female, rats. Male rats displayed a larger zone than females and the zone in males was reduced to the level of females by orchidectomy. Orchidectomy also diminished the effect of AAF on glutamine synthetase-positive cells. Thus, the induction of neoplastic conversion by AAF in rat liver, the extent of DNA adduct formation and the reduction of the glutamine synthetase-positive zone of hepatocytes were greater in males than females and were dependent upon the hormonal status of males.
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PMID:Inhibition by gonadectomy of effects of 2-acetylaminofluorene in livers of male, but not female rats. 840 94

The exposure-responses for several effects of limited exposures to diethylnitrosamine (DEN) in the livers of male Fischer 344 rats were measured and phenobarbital promotion was used to enhance expression of initiation of carcinogenesis. Five doses ranging from a cumulative total of 0.5 to 4 mmol DEN per kg body weight were given as weekly i.p. injections for 10 weeks. This was followed by 4 weeks recovery, after which the groups were maintained on either a basal diet or 0.05% phenobarbital (PB) to promote liver tumor development. All doses of DEN produced ethylation in liver DNA, which increased with dose. Indicative of toxicity, the centrilobular zone of glutamine synthetase-positive hepatocytes was reduced in relationship to exposure up to a cumulative exposure of 3 mmol/kg. The two lower exposures to DEN produced no increase in cell proliferation, whereas higher exposures resulted in marked increases, approximately 4-fold between 1.0 and 2.0 mmol/kg cumulative. At the end of the recovery period (14 weeks), hepatocellular altered foci (HAF), which expressed the placental form of glutathione S-transferase, were induced by all exposures, with an increase of approximately 4-fold between the exposures of 1.0 and 2.0 mmol/kg being the greatest. In rats maintained on basal diet or PB for 24 weeks after exposure, HAF increased further and with exposures of 2.0 mmol/kg and above, all rats developed hepatocellular carcinomas. With 1.0 mmol/kg, no liver tumor occurred in 12 rats without promotion, whereas in those given PB, two adenomas and two carcinomas were present in 12 rats. At the lowest exposure of 0.5 mmol/ kg, no tumor occurred in rats on basal diet, although HAF increased approximately 7-fold. With PB promotion, only one adenoma developed in 12 rats and HAF increased another 2-fold. Thus, the findings document non-linearity for some of the effects of DEN and a near no-effect level for initiation of promotable liver neoplasms at the lowest exposure in spite of a substantial induction of HAF.
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PMID:Diethylnitrosamine exposure-responses for DNA damage, centrilobular cytotoxicity, cell proliferation and carcinogenesis in rat liver exhibit some non-linearities. 889 97

Liver lipid peroxidation, nonheme iron, antioxidants, and protein oxidation were investigated in experimental alcohol-induced liver disease in the rat. Wistar male rats were intragastrically and continuously infused for 4 weeks with a high-fat diet plus an ethanol or an isocaloric amount of dextrose, maintaining a high blood alcohol level (200-300 mg%). This model induced fatty liver, spotty necrosis, and focal inflammation. This pathology was associated with an enhanced lipid peroxidation and a decrease in the major antioxidant factors. Hepatic alpha-tocopherol and glutathione concentrations were significantly decreased in ethanol-fed rats. Glutathione peroxidase (GPx) was also decreased, whereas glutathione S-transferase (GST) was unaffected. The nonheme iron level was significantly decreased. Protein oxidation was assessed through three parameters: protein thiols, protein carbonyl groups, and the activity of glutamine synthetase (GS), a centrilobular enzyme particularly susceptible to free-radical-mediated damage. Ethanol-fed rats had decreased protein thiol concentrations and reduced GS activity, together with increased protein carbonyls. A significant correlation between GS activity and the pathological score was observed. This study confirms the ethanol-related increase in lipid peroxidation and shows that ethanol impairs the hepatic antioxidant potential. Furthermore, evidence of oxidative protein damage is given, including decreased activity of a key enzyme of ammonia metabolism. These protein disturbances may contribute to the pathogenesis of the observed liver damage.
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PMID:Effect of chronic ethanol feeding on lipid peroxidation and protein oxidation in relation to liver pathology. 902 46

Phenobarbital elicits pleiotropic effects in the liver, including induction of enzymes involved in xenobiotic metabolism. The spectrum of this response was analyzed by differential display of a large population (approximately 7500) of mRNAs in chicken embryo liver treated in vivo with phenobarbital. We identified 29 cDNA fragments that reproducibly and significantly changed in intensity after a 48-hr in ovo treatment. Eighteen of these (62%) were increased, whereas 11 (38%) were decreased. Twenty strongly regulated cDNA fragments were subcloned and further analyzed. Nucleotide sequence analysis revealed three types of genes: (a) those previously described to be regulated by phenobarbital, including CYP2H1, glutathione S-transferase, and uridine diphosphate-glucuronosyltransferase; (b) genes reported herein for the first time to be regulated by phenobarbital, including fibrinogen beta-chain and gamma-chain, retinal glutamine synthetase, apolipoprotein B, two gene products with homologies to elongation factor 1delta and complement factor H, respectively, and (c) several novel genes with hitherto unknown functions. If these data are extrapolated to the entire population of mRNAs of a liver cell, phenobarbital seems to significantly modulate the expression of more than 50 different genes. Our results also demonstrate that a large fraction of genes is negatively regulated by drug treatment.
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PMID:Extent and character of phenobarbital-mediated changes in gene expression in the liver. 905 89

The dose responses for several effects of low-level limited exposures to 2-acetylaminofluorene (AAF) in the livers of male Fischer 344 rats were measured and a subsequent phenobarbital tumor promotion regimen was used to manifest initiation of carcinogenesis. Three doses over a 10-fold range yielding cumulative total exposures of 0.126, 0.42, and 1.26 mmol AAF/kg body weight were achieved by daily intragastric instillation for up to 12 weeks with interim terminations. This was followed by 24 weeks administration of 500 ppm phenobarbital (PB) in the diet to promote liver tumor development. At 12 weeks at the end of AAF administration, all exposures produced adducts in liver DNA, measured by 32P postlabeling, and the level of adducts increased with exposure, except that the high exposure did not produce a dose proportional increase. Measurement of arylsulfotransferase activity, a key enzyme in the metabolic activation of AAF, revealed that in livers from the high exposure animals, the enzyme was inhibited. To assess for toxicity, the centrilobular zone of glutamine synthetase-positive hepatocytes was quantified immunohistochemically at 12 weeks. The area of the zone was reduced in the high exposure group and there was a trend to reduction in relationship to exposure. The two lower exposures to AAF produced no increase in cell proliferation, whereas the high exposure resulted in a marked increase, about 8-fold over controls. Initiation was assessed by induction of hepatocellular altered foci (HAF) that expressed the placental form of glutathione S-transferase. AAF induced HAF in the high exposure group, 9-fold at 8 weeks and 170-fold at 12 weeks compared to controls. In rats maintained on PB for 24 weeks after exposure, the multiplicity of HAF increased in controls and comparably in the low and mid exposure groups, but remained at the about the same high level in the high exposure group. The high exposure produced a substantial incidence of benign neoplasms by 12 weeks, and with promotion by 36 weeks, all rats developed hepatocellular neoplasia. In the mid exposure group, only one adenoma occurred at 36 weeks in 17 rats, while in the low exposure group, no liver tumor occurred in 23 rats. Thus, these findings document nonlinearities for some of the effects of AAF, with supralinear effects at the high exposure for cell proliferation and induction of HAF, and a no-observed-effect level for induction of promotable liver neoplasms at the lowest cumulative exposure of 0.126 mmol/kg, in spite of the formation of DNA adducts. We conclude that the effects of this DNA-reactive hepatocarcinogen leading to initiation exhibit nonlinearities and possible thresholds.
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PMID:Nonlinearities in 2-acetylaminofluorene exposure responses for genotoxic and epigenetic effects leading to initiation of carcinogenesis in rat liver. 984 22

The activities of the enzymes related to glutathione synthesis, degradation, and functions as well as reactive oxygen scavenging enzymes were analyzed in different brain regions, such as cerebral hemisphere, cerebellum, brainstem, thalamus, and hypothalamus after 1 and 3 mo of streptozotocin-induced diabetes in rats. Parallel studies were also made in age-matched control rats and insulin-treated diabetic rats. The content of glutathione (GSH) and its synthesizing enzyme gamma-glutamylcystein synthetase and also superoxide dismutase (SOD) and catalase activities (reactive oxygen scavenging enzymes) were significantly decreased from almost all the brain regions studied. However, glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST), gamma-glutamyl transpeptidase (gamma-GTP), and glutamine synthetase (GS) activities were increased in the diabetic rat brain. Insulin treatment to the diabetic rats resulted in partial to full recovery in these enzymes activities. The present results emphasize the potentially serious alterations of brain free radical scavenger system in uncontrolled Type I diabetes.
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PMID:Alterations in free radical scavenger system profile of type I diabetic rat brain. 1034 79

A Fasciola hepatica cDNA clone of 779 bp was isolated from an adult worm cDNA expression library by immunological screening using a rabbit serum against the excretory-secretory antigens. The nucleotide sequence of the cDNA revealed the presence of an open reading frame of 582 bp which encoded a 194-amino-acid-residue polypeptide (M(r) 21,723 Da) showing a high degree of homology to thioredoxin peroxidases. This putative antioxidant protein gene was expressed in Escherichia coli as a GST fusion protein. The recombinant fusion protein showed in vitro antioxidant properties and protected rabbit muscle enolase and E. coli glutamine synthetase from inactivation by nonenzymatic Fe(3+)/O(2)/DTT or Fe(3+)/O(2)/ascorbate metal-catalyzed oxidation systems.
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PMID:Fasciola hepatica: heterologous expression and functional characterization of a thioredoxin peroxidase. 1086 19


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