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)

Potential synergism between 5 or 10 carcinogenic heterocyclic amines (Trp-P-1, Trp-P-2, Glu-P-1, Glu-P-2, IQ, MeIQ, MeIQx, MeA alpha C, A alpha C and PhIP) acting at low doses was examined in a medium-term liver bioassay system for carcinogens. Immunohistochemically-demonstrated glutathione S-transferase placental form (GST-P) positive foci were assessed as the endpoint marker lesions. Male F344 rats were initially given diethylnitrosamine (DEN, 200mg/kg, ip) and beginning 2 weeks later received heterocyclic amines individually or in combination for 6 weeks. All animals were subjected to partial hepatectomy at week 3 and killed at week 8. A clear dose response relationship was observed for all heterocyclic amines, except for the nonhepatocarcinogen PhIP, with the dose used in earlier carcinogenicity assays and 1/5, 1/10, 1/25 and 1/100 of these levels. Carcinogenicity could be predicted for all compounds at the highest dose or lower dose levels except for PhIP. With combined administration of 5 or 10 chemicals, foci induction significantly exceeded the sums of 5 or 10 individual data for the 1/5, 1/10 and 1/25 dose levels, but not for the 1/100 case. The findings are of particular significance since several heterocyclic amines and other carcinogenic agents might be simultaneously generated during cooking, although each at very low concentration.
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PMID:Enhancement of rat liver cell foci development by combined treatment with heterocyclic amines at low doses. 884 16

Potential synergism between four N-nitroso compounds (nitrosomorpholine, nitrosodimethylamine, nitrosodiethanolamine, nitroso-oxazolidine) in rat liver carcinogenesis was examined in the medium-term bioassay. Male F344 rats were initially given diethylnitrosamine (DEN, 200 mg/kg, ip) and beginning 2 weeks later received test chemicals for 6 weeks individually at a full or 1/4 dose of that proven to be carcinogenic individually or in combination. All animals were subjected to partial hepatectomy at week 3 and killed at week 8. Induction of immunohistochemically-demonstrated glutathione S-transferase placental form (GST-P) positive foci was evaluated. The numbers and size of GST-P positive foci were significantly higher than the control levels by the treatment with each nitrosamine at full (1/1) and one quarter doses (1/4), excepting nitrosodiethanolamine and by combination of the four chemicals at 1/4 and 1/16. Because the dose-response curves were considered non-linear for most nitrosamines, synergistic effects were not apparent for the 1/4 mixture. Interestingly, however, the values for rats treated with these four chemicals in combination at the 1/4 dose level were almost the same as the average of four individual treatments at the full dose, and those for the 1/16 dose mixture were almost the same as the average of 1/4 individual treatment groups. These results indicate that these nitrosamines worked additively, rather than synergistically, in rat liver carcinogenesis.
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PMID:Effects of low dose mixtures of four N-nitroso compounds on hepatic foci development in the rat. 884 82

Although it is known that doublets of hepatocytes GST-P+ are produced during the first week after initiation with DEN, the activity levels of the enzyme are not known in the initial stages of the process, neither is its behavior through an initiation-promotion scheme. We consider the latter issues important in order to obtain information of the initiation step and its relation with GST-P.DEN was applied as initiator in a single dose on day 0 to F344 rats (200 mg/kg) and as promoter 2-AAF in 20 mg/kg doses on days 7, 8 and 9 of the scheme. Partial hepatectomy was performed on day 10, and daily during the 28 days in which the experiment lasted. The GST-P activity was determined in postmicrosomal supernatants of respective livers (by immunoadsorption) as well as their histological section (by immunohistochemistry). In both cases antibody anti-GST-pi produced in our laboratory was employed. The results obtained show GST-P appearance on day 5 of the scheme in rats treated with carcinogens. The activity of the enzyme increased slowly reaching its maximum on day 18, together with the appearance of GST-P+ preneoplastic nodules. Our results suggest that GST-P could display an additional function to those previously known, in cellular differentiation this could explain the very frequent expression of this enzyme in preneoplastic as well as in neoplastic cells.
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PMID:Follow-up of GST-P during hepatocarcinogenesis with DEN-2AAF in F344 rats. 884 44

Four pesticides were examined for hepatopromoting activity using a medium-term bioassay based upon induction of glutathione S-transferase placental form (GST-P) positive foci in the rat liver. Male F344 rats were initially injected with diethylnitrosamine (DEN; 200 mg/kg body weight) intraperitoneally and 2 weeks later were treated with O-ethyl O-4-nitrophenyl phenylphosphonothioate (EPN; 75 and 150 ppm), diazinon (500 and 1,000 ppm), phenthoate (500 and 1,000 ppm), or iprobenfos (500 and 1,000 ppm) in the diet for 6 weeks and then killed, all rats being subjected to partial hepatectomy at week 3. All of the pesticides gave negative results, the numbers and areas of GST-P positive foci not exceeding the control values for animals given DEN alone. Indeed, a significant reduction of foci development was seen for EPN (75 ppm). These findings provide experimental evidence that the presently examined four pesticides do not have hepatocarcinogenic potential in rats.
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PMID:Lack of promoting activity of four pesticides on induction of preneoplastic liver cell foci in rats. 886 80

The distributions of a gap junctional protein, connexin 32 (cx 32), and proliferating cell nuclear antigen (PCNA) were examined immunohistochemically in glutathione S-transferase placental form (GST-P)-negative foci, induced in rat liver by initiation with diethylnitrosamine (DEN, 200 mg/kg) followed by promotion with clofibrate (1% in diet) in an in vivo medium-term assay system for hepatocarcinogenesis. The results were compared to those in GST-P-positive foci induced by DEN alone. The treatment with clofibrate caused the appearance of GST-P-negative foci, increased in size as compared to GST-P-positive foci in the same liver or induced by the DEN alone. The proportion of PCNA-positive hepatocytes in GST-P-negative foci was significantly higher than in the surrounding parenchyma, indicating increased cell proliferation. The numbers of cx 32-positive spots per hepatocyte in GST-P-negative foci were clearly decreased, reaching 65.4% at week 20 and 51.8% at week 30 of values for surrounding normal hepatocytes. In GST-P-positive foci induced by DEN, only a slight decrease (80%) was observed at week 8. These findings show that a positive association between the sustained inhibition of gap junctional intercellular communication and increased cell proliferation of GST-P-negative foci in Fischer-344 male rats induced with DEN and promoted with clofibrate.
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PMID:Immunohistochemical demonstration of the gap junctional protein connexin 32 and proliferating cell nuclear antigen in glutathione S-transferase placental form-negative lesions of rat liver induced by diethylnitrosamine and clofibrate. 899 95

The potent mutagen, 5-fluoroquinoline (5-FQ), and non-mutagenic 3-fluoroquinoline (3-FQ) were tested for hepatocarcinogenicity using a medium-term assay system employing quinoline, a moderately mutagenic hepatocarcinogen, as a reference. F344 male rats were given a single i.p. injection of a submanifestational dose of diethylnitrosamine (DEN, 200 mg/kg). Then, quinoline, 3-FQ, or 5-FQ at two doses (0.1%, and 0.05%) was added to their diet for a period of 6 weeks, starting from 2 weeks after the DEN injection. Control groups were administered DEN alone. All rats were subjected to a partial (two-thirds) hepatectomy at the end of week 3 and sacrificed at the end of week 8. The number and areas of GST-P (placental glutathione S-transferase)-positive foci induced in the liver increased significantly as a result of treatment with 0.1% quinoline, and this increase was dramatic with 5-FQ at both doses, whereas no increases were noted with 3-FQ at either dose. Thus, the results of the medium-term carcinogenicity assay predicted that quinoline, a hepatocarcinogen, would be deprived of carcinogenicity by fluorine atom substitution at position 3, and would conversely be endowed with a higher carcinogenic capacity by substitution at position 5. A semi-quantitative relationship was demonstrated between carcinogenic and mutagenic potencies.
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PMID:Modification of the carcinogenic potency of quinoline, a hepatocarcinogen, by fluorine atom substitution: evaluation of carcinogenicity by a medium-term assay. 901 4

To bridge the gap between long-term carcinogenicity tests and short-term screening assays, a medium-term liver bioassay system for rapid detection of carcinogenic agents using male F344 rats has been developed. The system is fundamentally based on the two-stage hypothesis of carcinogenesis: initiation with diethylnitrosamine (200 mg/kg, ip) is followed by test chemical administration during the second stage in combination with 2/3 partial hepatectomy. It requires only 8 weeks for the animal treatment and a further few weeks for quantitative analysis of immunohistochemically-demonstrated glutathione S-transferase placental form positive hepatic foci. A total of 277 chemicals have already been analyzed in this laboratory and the efficacy of the system for hepatocarcinogens has thereby been well established. This bioassay is particularly useful for dose-response and chemical mixture studies usually requiring large-scale experiments and also for evaluation of chemopreventive agents. Furthermore, medium-term multi-organ bioassay system, using 5 different chemical carcinogens (DEN, MNU, BBN, DMH and DHPN) has also been established for rapid detection of not only hepatocarcinogens, but also other carcinogens.
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PMID:Initiation-promotion model for assessment of carcinogenicity: medium-term liver bioassay in rats for rapid detection of carcinogenic agents. 903 59

The modification potential of indole-3-carbinol (I3C), a naturally occurring compound found in cruciferous vegetables, on neoplastic development was assessed using a rat medium-term multiorgan carcinogenesis model. One-hundred male Sprague-Dawley (SD) rats were randomly divided into three groups and sequentially treated with diethylnitrosamine (DEN; 100 mg/kg b.w., a single i.p.), N-methyl-N-nitrosourea (MNU; 20 mg/kg b.w., four times i.p., at days 5, 8, 11 and 14), and dihydroxy-di-N-propyl-nitrosamine (DHPN; 0.1% in the drinking water during weeks 1 and 3) (DMD treatment; groups 1 and 2) or the vehicles alone (group 3) in the first 3-week initiation period. Animals of groups 1 and 3 were then given diet containing 0.25% I3C from week 4 until week 24, followed by a return to basal diet for 28 weeks, and subgroups were killed at weeks 24 and 52. I3C caused significant increases in both number (no./cm2) and area (mm2/cm2) of glutathione S-transferase placental form (GST-P)-positive liver cell foci assessed at week 24 of the experiment (P<0.01, 0.001). The incidence of hepatocellular adenomas in the DMD and I3C group at week 52 showed a tendency for elevation as compared to the DMD alone group, but this was not statistically significant. The thyroid gland tumour incidences in the DMD and I3C groups were significantly increased compared with the DMD alone group values at week 52 (P<0.01). In conclusion, I3C enhanced liver and thyroid gland neoplastic development when given during the promotion stage in the present rat medium-term multiorgan carcinogenesis model.
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PMID:Enhancement by indole-3-carbinol of liver and thyroid gland neoplastic development in a rat medium-term multiorgan carcinogenesis model. 905 32

Diethylnitrosamine (DEN) was administered to rats as a single dose, which is known not to give rise to liver tumours without subsequent promotion. Iron dextran (Fe/Dex) was then administered parenterally to the animals, to induce iron overload. At 3 and 6 months after the final Fe/Dex treatments, livers were examined quantitatively for the numbers of the placental form of glutathione-S-transferase (GST-P) expressing foci, the area occupied by these foci and their size distribution. The results demonstrate that iron not only increased the number of foci after DEN initiation in the rat liver, but that the area occupied by these lesions increased significantly between 3 and 6 months after initiation. There is no evidence that iron increased the number of GST-P expressing foci present in rats not exposed to DEN. This indicates that iron did not act as an initiator in this rodent model of liver cancer. The increase in the area of the liver occupied by the foci in iron and DEN treated rats was due to an increase in the size of the foci, as well as to an increase in the number of foci. This is the first demonstration that iron can act as a promoter of DEN initiated hepatocytes. It also demonstrates that fibrogenesis is not an absolute requirement for the promotion, by iron, of liver foci in the rat, and that this could also be the case for iron overload in man. Iron may also act as a promoter of already initiated hepatocytes in the development of human liver cancer, as it does in the rat.
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PMID:Iron promotes DEN initiated GST-P foci in rat liver. 906 62

Effects of simultaneous administration of five or 10 heterocyclic amines (HCAs) at low dose levels on rat liver carcinogenesis were investigated using a medium-term bioassay protocol. Male F344 rats were initially given diethylnitrosamine (DEN, 200 mg/kg, ip) and received HCAs starting 2 wk later for 6 wk. All animals were subjected to two-third partial hepatectomy at wk 3 and were killed at wk 8. Five carcinogenic HCAs in the first two experiments: 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole, 2-aminodipyrido[1,2-alpha: 3',2'-d]imidazole, 2-amino-3-methylimidazo-[4,5-f]quinoxaline, 2-amino-3,4-dimethylimidazo[4,5-f]quinoline, 2-amino-3,8-dimethylimidazo-[4,5-f]quinoxaline in experiment 1 and 3-amino-1-methyl-5H-pyrido[4,3-b]indole, 2-amino-6-methyl-dipyrido[1,2-alpha: 3',2'-d]imidazole,2-amino-3-methyl- 9H-pyrido-[2,3-b]indole, 2-amino-9H-pyrido[2,3-b]indole, and 2-amino-1-methyl-6-phenylimidazo[4,5- b]pyridine in experiment 2] were administered together or individually in the diet at levels of 1/1, 1/5 or 1/25 carcinogenic doses, and all 10 chemicals were given at 1/10 or 1/100 levels in experiment 3. Induction of preneoplastic glutathione S-transferase placental from (GST-P) positive foci was increased in some combination groups over the sums of effects for the individual groups at the same doses (apparent synergism). This was most obvious in the group given all 10 chemicals at the 1/10 dose levels. However, it was of interest that the values in the combined groups were generally very close to the averages of five or 10 individual results for the corresponding higher dose groups, indicating isoadditivity of HCA effects. True (strict) synergism, however, was expected for the results of groups including PhlP and Trp-P-2 in combination, since they are non-hepatocarcinogenic but induce the key metabolic enzyme for HCAs (CYP1A2).
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PMID:Enhancement of hepatocarcinogenesis by combined administration of food-derived heterocyclic amines at low doses in the rat. 911 21


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