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)

Female F344/N rats were given 70% partial hepatectomies and intubated with diethyl-nitrosamine (DEN, 10 mg/kg) 24 hours later. They were fed a cereal-based diet, NIH-07 (NIH) + 0.05% phenobarbital (PB) for 6 months, at which time NIH + PB was withdrawn and the rats were ovariectomized (OV) or sham-operated (SH). Groups of 7-10 rats were fed a semipurified diet (AIN-76) for 1 or 2 months after withdrawal of NIH + PB, or NIH + PB for 2 months, or AIN-76 diet for 1 month and subsequently NIH + PB for 1 month. Placental glutathione S-transferase (PGST)- and gamma-glutamyltransferase (GGT)-positive (+) altered hepatic foci (AHF) were analysed by quantitative stereology. Ovariectomy stimulated growth of AHF after withdrawal and reintroduction of NIH + PB. AHF, especially PGST+ AHF, continued to regress throughout the PB withdrawal period in rats fed AIN-76 diet. In most studies of chemical hepatocarcinogenesis, females have been shown to develop a greater volume of AHF than males. In our study, however, ovariectomy stimulated the growth of AHF after withdrawal and reintroduction of PB. Because AHF occurring spontaneously in male rats develop more rapidly than in female rats, the greater rate of growth of AHF in OV female rats may reflect a similar mechanism.
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PMID:Ovariectomy promotes the growth of altered hepatic foci after withdrawal and reintroduction of phenobarbital during hepatocarcinogenesis in rats. 136 Nov 60

The present report describes a study of the hepatocarcinogenic potential of a second large assay series of 94 compounds carried out using the rapid bioassay system (DEN-PH model) developed in this laboratory and based on the two-step concept of hepatocarcinogenesis. Male F344 rats were initially given a single dose of diethylnitrosamine (DEN, 200 mg/kg body weight ip) and, starting 2 wk later, were treated with test compounds for 6 wk and then killed, all rats being subjected to a two-thirds partial hepatectomy at wk 3. Carcinogenic potential was scored by comparing the numbers (no./cm2) and areas (mm2/cm2) of induced glutathione S-transferase placental form (GST-P) positive foci in the livers of groups of about 15 rats with those of corresponding control groups given DEN alone. Positive was scored for a significant increase (P < 0.05) in quantitative values of GST-P positive foci, negative for no change or a decrease. Results for the 94 compounds were also compared with previously published data from Salmonella/microsome (Ames) tests and long-term carcinogenicity studies in rats and mice. Of the known liver carcinogens, 14 out of 14 (100%) mutagenic (Ames test) compounds and 10 out of 12 (83%) non-mutagenic compounds gave positive results in our DEN-PH system (mean 92%). Two hepatocarcinogenic peroxisome proliferators did not enhance the development of GST-P positive foci. Carcinogens other than hepatocarcinogens gave fewer positive results (five out of 17, 29%). One of the 13 compounds reported as non-carcinogenic, malathion, gave positive results in the DEN-PH assay, suggesting that this compound is a weak hepatocarcinogen or tumour promoter for hepatocarcinogenesis based on the two-stage hypothesis for carcinogenesis. The present study also provided information regarding the inhibitory potential of nine compounds. The practical usefulness and benefits of the DEN-PH protocol for the rapid screening of carcinogenic agents are discussed.
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PMID:Liver medium-term bioassay in rats for screening of carcinogens and modifying factors in hepatocarcinogenesis. 147 91

In order to elucidate whether T-2 toxin (T-2) and nivalenol (NIV), the naturally occurring trichothecene mycotoxins in food and feed, are carcinogenic or possess an ability to modulate aflatoxin B1 (AFB1)-induced hepatocarcinogenicity, a medium-term liver bioassay was carried out. F344 male rats were given a single i.p. injection of diethylnitrosamine (DEN, 200 mg/kg), and then fed the test trichothecenes in diet (2 and 5 p.p.m. T-2 or 6 p.p.m. NIV) for 6 weeks beginning 2 weeks after the injection. Some control groups received DEN alone. For synergism between AFB1 and the trichothecenes, DEN-initiated rats as above were given a single i.p. injection of AFB1 (0.5 mg/kg) 2 weeks later and were fed a NIV-containing diet (6 p.p.m.) for 6 weeks. The other control group received the vehicle alone. Control rats not initiated with DEN were also treated with AFB1, NIV or T-2 alone as above. All rats were subjected to a two-thirds partial hepatectomy (PH) at week 3 and killed at week 8, and liver sections were analyzed by glutathione S-transferase placental form (GST-P) expression. In rats that did not receive DEN, AFB1 alone enhanced both the numbers and areas of GST-P-positive foci as reported earlier, while NIV or T-2 alone induced no marked changes. In rats initiated with DEN, AFB1 caused a marked expression of GST-P, and thus the hepatocarcinogenicity of AFB1 was reconfirmed. The expression of GST-P foci in rats fed T-2 or NIV was found to be at background level, indicating that the hepatocarcinogenicity was not predicted for the trichothecene mycotoxins such as T-2 and NIV by this medium-term bioassay system. In the group initiated by DEN followed by AFB1, on the other hand, an elevation of both the numbers and areas of GST-P-positive foci was observed by the subsequent feeding of rats with NIV, and this elevation was statistically significant from the sum totals of individual data of AFB1 or NIV alone. From this evidence, it is predicted that NIV causes an enhancing effect on AFB1-induced hepatocarcinogenesis.
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PMID:Enhancement of GST-P-positive liver cell foci development by nivalenol, a trichothecene mycotoxin. 158 91

Praziquantel, the widely used anti-helminthic agent, was investigated for hepatocarcinogenesis-promoting potential using a medium-term liver bioassay system for carcinogens. F344 male rats were given a single intraperitoneal injection of diethylnitrosamine (DEN, 200 mg/kg) and then starting 2 weeks later, received praziquantel in the diet at concentrations of 1.5 or 0.5%, or intragastrically at a dose of 1,500 mg/kg once a week for 6 weeks. Control groups received DEN or praziquantel alone. All rats were subjected to two-thirds partial hepatectomy at week 3 and killed at week 8. Development of glutathione S-transferase placental form-positive foci in the liver was significantly increased in terms of both number and area with the 1.5% dose, while only area was affected by the 0.5% dose. The results thus indicate that praziquantel at high dose has promoting potential in rat hepatocytic tumorigenesis.
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PMID:Promotion of rat hepatocarcinogenesis by praziquantel. 168 46

Effects of age on the induction of glutathione S-transferase placental form (GST-P)-positive hepatic foci in rats were examined using a medium-term liver bioassay system (for carcinogens). F344 male rats aged 6, 26 and 46 weeks were initially given a single intraperitoneal injection of diethylnitrosamine (DEN, 200 mg/kg) and, beginning 2 weeks later, received 0.02% 2-acetylaminofluorene (2-AAF), 0.05% phenobarbital (PB) or 1.3% acetaminophen (AAP) in the diet for 6 weeks. All animals were subjected to two-thirds hepatectomy 3 weeks after the DEN injection and were killed at week 8. Quantitative analysis of GST-P-positive foci revealed significantly (P less than 0.001) increased induction over control levels in terms of both numbers and areas for 2-AAF at all ages (6, 26 and 46 weeks), but especially in the 6-week-old case. In the PB- and AAP-treated groups, the respective enhancing and inhibitory influences were most pronounced in the animals aged 6 weeks, and were less marked in older rats. Thus, the response of F344 rats to the modifying effects of chemicals was age-dependent, the conclusion being drawn that young rats are more susceptible and therefore more appropriate for assessment of carcinogenic, promoting and inhibitory effects of chemicals.
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PMID:Age-dependent induction of preneoplastic liver cell foci by 2-acetylaminofluorene, phenobarbital and acetaminophen in F344 rats initially treated with diethylnitrosamine. 190 51

Dose-dependent modifying effects of quinacrine on induction of preneoplastic liver cell foci were investigated in male F344 rats. Six week old animals were injected i.p. with N-nitrosodiethylamine (DEN) at a dose of 200 mg/kg, and starting 2 weeks later, rats were given quinacrine at dietary levels of 20, 100 and 500 p.p.m. for 6 weeks. Groups without either DEN or quinacrine treatment were used as controls. At week 3 following DEN administration, all animals were subjected to two-thirds partial hepatectomy, and after killing the animals at week 8, development of preneoplastic liver cell foci was investigated using the glutathione S-transferase placental form (GST-P) as a marker. The numbers and unit areas of GST-P-positive foci per cm2 were significantly increased in the DEN/quinacrine (500 p.p.m.) group as compared to DEN-alone group values. An increase in number was also evident in the 100 p.p.m. but not the 20 p.p.m. treated group, no lesions being induced by quinacrine alone (500 p.p.m.). Electron microscopic study confirmed that quinacrine dose-dependently induces lipidosis in hepatocytes, i.e. markedly myeloid lamellar cytoplasmic inclusion bodies were observed. The results thus demonstrated that quinacrine treatment enhances GST-P-positive liver cell foci development in a dose-dependent way, this effect presumably being related to the induction of lipidosis.
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PMID:Dose-dependent enhancing effects of quinacrine on induction of preneoplastic glutathione S-transferase placental form positive liver cell foci in male F344 rats. 193 72

Phenobarbital (PB) is an effective growth stimulator of hepatic hyperplastic nodules developed with diethylnitrosamine and 2-acetylaminofluorene plus partial hepatectomy (the Solt-Farber model), but it does not apparently stimulate the growth of preneoplastic lesions produced with aflatoxin B1 (AFB). Some studies have suggested a correlation between the induction of specific cytochrome P450 enzymes and the tumor promoting effects produced by repeated treatment with PB. To examine this hypothesis further, hepatic hyperplastic nodules were produced with AFB (10 ip doses of AFB, 150 micrograms/kg/day, followed by partial hepatectomy) or by a modified Solt-Farber protocol (DEN/AAF), and the effects of PB on nodule growth and expression of cytochrome(s) P450 2B1 and/or P450 2B2 (P450 2B1/2) were determined. Both treatment protocols (without PB) produced multiple, large nodules within 10-17 weeks of carcinogen administration. These nodules stained intensely for glutathione S-transferase p (GST-p; GST7-7) and gamma-glutamyl transpeptidase (GGT) and weakly for P450 2B1/2. Pentoxyphenoxazone dealkylation activity was decreased to less than 50% of the surrounding tissue levels in both types of nodules. PB treatment of animals with DEN/AAF-induced nodules greatly increased P450 2B1/2 expression in surrounding tissues, whereas most, but not all, nodules were not inducible. Pentoxyphenoxazone dealkylation was increased 31- to 35-fold in surrounding tissue, but it was increased only 2-fold in pooled nodular tissue, relative to untreated control liver. In contrast to the DEN/AAF group, immunohistochemical staining and pentoxyphenoxazone dealkylation in the AFB group demonstrated that P450 2B1/2 was equally inducible in nodular and surrounding tissues. Short-term treatment (5 days) with PB produced a 2-fold increase in the number and total area of GGT-positive nodules in the DEN/AAF group, but it had no significant effect on the number, size distribution, or total area of GGT-positive nodules in the AFB group. All large GGT-positive nodules in the DEN/AAF group were nonresponsive to induction of P450 2B1/2, whereas all of the GGT-positive nodules which were responsive to P450 2B1/2 induction by PB in this group were relatively small. The size and area of AFB-induced GGT-positive nodules was not affected by PB treatment, and P450 2B1/2 in all of these nodules was inducible by PB. Although a causal, inverse relationship between the responsiveness of nodules to PB induction of P450 2B1/2 and their reaction to PB growth stimulation cannot be firmly established, these data are consistent with such a hypothesis.
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PMID:Differential regulation of cytochrome(s) P450 2B1/2 by phenobarbital in hepatic hyperplastic nodules induced by aflatoxin B1 or diethylnitrosamine plus 2-acetylaminofluorene in male F344 rats. 194 30

Chenodeoxycholic acid (CDC), a dihydroxylated primary bile acid, was evaluated for promotional activity in the liver of rats using a two-stage initiation-promotion model. CDC is a primary bile acid that can attain high concentrations in serum and liver during induced or naturally occurring hepatocellular disorders. Female Sprague-Dawley rats were injected once (i.p.) with diethylnitrosamine (DEN, 150 mg/kg) or sterile physiologic saline (SAL, 0.85% NaCl). Two weeks later, rats in each group were placed into one of two subgroups and fed either NIH-31 mash (Control) or NIH-31 mash containing 0.5% CDC for a 10 week period. At the end of the feeding period, blood and liver samples were collected for determination of bile acid profiles and quantitation of hepatocellular foci respectively. Serum samples were analyzed for concentrations of individual bile acids using a HPLC method that utilizes a post-column enzymatic reaction and fluorescence detection. Liver slices from the left hepatic lobe were stained for foci positive for placental glutathione S-transferase. In serum, significant increases occurred in concentrations of all forms of CDC and were accompanied by mild, insignificant increases in lithocholic acid. Decreased serum concentrations occurred in all forms of cholic and deoxycholic acids. Analysis of liver sections revealed that rats treated with DEN-CDC had significant increases in numbers and volume of foci compared to those treated with DEN-Control. For rats in groups DEN-CDC and DEN-Control, the numbers of foci per square centimeter were 32 and 12; per cubic centimeter, 2221 and 937; and the per cent volume of foci, 1.487 and 0.385 respectively. In this study, CDC was a promoter of hepatocellular foci. Because concentrations of CDC in liver and serum increase in a variety of hepatobiliary disorders, the possibility that increases in endogenous concentrations can enhance the formation of hepatocellular foci is being explored.
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PMID:Promotion of hepatocellular foci in female rats by chenodeoxycholic acid. 198 83

Potential synergism between five heterocyclic amines at low doses was evaluated in a medium-term liver bioassay system for carcinogens. F344 male rats were given a single i.p. injection of diethylnitrosamine (DEN, 200 mg/kg) and then received test compound(s) in their diet for 6 weeks beginning 2 weeks later. Control groups received DEN or test compound(s) alone. All rats were subjected to two-thirds partial hepatectomy at week 3 and killed at week 8. Compounds tested and reported positive were 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1, 150 p.p.m.), 2-aminodipyrido[1,2-a:3',2'-d]imidazole (Glu-P-2, 500 p.p.m), 2-amino-3-methylimidazo[4,5-f]quinoline (MeIQ, 300 p.p.m.), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx, 400 p.p.m.). Groups were given each chemical at the carcinogenic dose, or 1/5 or 1/25 of this. Other groups received the five chemicals in combination, each at the 1/5 or 1/25 levels. Enhancing activity was assessed by quantitative analysis of glutathione S-transferase placental form (GST-P) positive foci, the numbers being significantly increased with all chemicals at the highest dose. Trp-P-1, IQ and MeIQ also exerted positive influence even at the 1/5 dose level. Similar results were obtained regarding areas of foci at the highest dose levels, with the exception of Glu-P-2. An increase was also observed for MeIQ at the 1/5 dose. Additive or synergistic effects between the chemicals were evident in the groups given the five chemicals together at both the 1/5 and 1/25 dose levels, development of GST-P positive foic being increased over the sum totals of individual data for the 1/5 or 1/25 dose groups. Thus, carcinogenicity was predicted for all five heterocyclic amines tested in dose-dependent manner in the present system of 8 weeks duration, synergistic effects being apparent especially at the low dose level.
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PMID:Enhancement of GST-P positive liver cell foci development by combined treatment of rats with five heterocyclic amines at low doses. 202 39

Dose-dependent development of pre-neoplastic liver cell foci induced by 2-acetylaminofluorene (2-AAF) was investigated in relation to cell-proliferative activity. Male F344 rats were initially given a single i.p. injection of diethylnitrosamine (DEN, 200 mg/kg) and starting 2 weeks later received diets containing 2-AAF at dose levels of 150, 100, 60, 45, 35 or 30 p.p.m., 500 p.p.m. phenobarbital (PB) or basal diet as a control for 6 weeks. Two-thirds partial hepatectomy (PH) was performed at week 3. The rats were sequentially killed from weeks 0 to 16 and liver sections were analysed by double staining for both BrdU incorporation and glutathione S-transferase placental form (GST-P) expression. 2-AAF increased numbers and areas of GST-P positive (GST-P+) foci in a dose-dependent manner, especially after PH. Proliferation of hepatocytes, as indicated by BrdU labelling indices (LI), was higher in GST-P+ foci than in surrounding hepatocytes in all 2-AAF-treated groups, even after cessation of carcinogen administration. Proliferative response of hepatocytes to PH was delayed in rats treated with the highest dose of 2-AAF in both foci and in surrounding areas possibly due to the 2-AAF toxicity. In the PB treated group, the results were similar to those for the lower dose 2-AAF-treated groups. It is concluded that the development of GST-P+ foci and cell proliferation in GST-P+ foci are directly related to 2-AAF treatment in a dose-dependent manner and the present assay system is reliable for detection of carcinogenicity of chemicals even at low doses.
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PMID:Dose-dependent effects of 2-acetylaminofluorene on hepatic foci development and cell proliferation in rats. 204 5


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