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)

Recently there has been a shift in the prevailing paradigm regarding the dose dependence of carcinogen action with increasing acceptance of hormesis phenomenon, although underlying mechanisms remain to be established. To ascertain whether alpha-benzene hexachloride (alpha-BHC) might act by hormesis, rats were initiated with diethylnitrosamine and then alpha-BHC ranging from 0.01 to 500 ppm was administered in the diet for 10 weeks. The highest concentration of alpha-BHC significantly increased the number and area of glutathione S-transferase placental form (GST-P) positive foci, preneoplastic lesions in the liver, but its low dose, 0.05 ppm, caused significant reduction, showing a J-shape dose-response curve. The proliferating cell nuclear antigen positive index for GST-P positive foci in the low dose-treated group was significantly reduced. The dose response curves of CYP450 content, NADPH-P450 reductase activity and 8-hydroxydeoxyguanosine formation revealed the same pattern as GST-P positive foci data. The response curves of CYP2B1 and 3A2 in their activities, protein and mRNA expression showed a threshold but CYP2C11 activity exhibited an inverted J-shape. These results might suggest the possibility of hormesis of alpha-BHC at early stages of rat hepatocarcinogenesis. The possible mechanism involves induction of detoxifying enzymes at low dose, influencing free radical production and oxidative stress, and consequently pathological change in the liver.
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PMID:Alpha-benzene hexachloride exerts hormesis in preneoplastic lesion formation of rat hepatocarcinogenesis with the possible role for hepatic detoxifying enzymes. 1624 85

Cessation of long-term alcohol exposure is reported to enhance rat hepatocarcinogenesis. The purpose of the present study was to assess this possibility using glutathione-S transferase placental form (GST-P) positive foci as end point lesions. All rats were treated with a single i.p. injection of diethylnitrosamine (DEN) (200 mg/kg body weight) and then given a MF pellet diet for 2 weeks. Thereafter, the animals were maintained on: alcohol liquid diet in which 36% of total calories were provided by alcohol (5% Al diet) for 6 weeks (group 1); control liquid diet (C diet) for 6 weeks (group 2); 5% Al diet for 6 weeks and subsequently C diet for 4 weeks (group 3); 5% Al diet for 10 weeks (group 4); or C diet for 10 weeks (group 5). All rats were subjected to two thirds partial hepatectomy at 3 weeks after DEN injection. The number and area of GST-P positive foci per cm2 of liver tissue were slightly increased in group 1 compared to the group 2 and significantly elevated in the group 4 compared to group 5. However, numbers in group 3 were significantly lower in group 4 and similar to the group 5 values. PCNA positive cells in the GST-P positive foci in the group 1 and group 4 were significantly increased as compared with respective controls (groups 2 and 5, respectively), while indices in the group 3 were again similar to values for group 5. Cessation of short-term alcohol administration thus had no promoting effects on development of GST-P foci, suggesting that the duration of alcohol treatment may be important. The results also imply the existence of a cumulative exposure time or dose threshold for alcohol if promoting effects of cessation are to be seen on rat hepatocarcinogenesis.
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PMID:Effects of cessation of alcohol exposure on rat hepatocarcinogenesis. 1662 29

Mice primed by feeding griseofulvin or diethyl 1,4-dihydro 1,4,6-trimethyl 3,5-pyridine decarboxylate for 5 months followed by drug withdrawal for 1 month (drug-primed mice) were given thioacetamide intraperitoneally, and the livers were subsequently studied at intervals up to 7 days. The hepatocellular proliferative response was measured by immunostaining for proliferative cell nuclear antigen. Necrosis was followed by measuring ALT. Mallory bodies were identified by immunoperoxidase stains for ubiquitin and cytokeratin. Preneoplastic foci were localized using immunofluorescence stain for glutathione S-transferase (GST mu) and histochemical stain for gamma glutamyl transpeptidase (GGT). The results showed that the preneoplastic foci selectively proliferated and expanded and formed nodules as indicated by quantitation of nuclei stained positive for proliferating cell nuclear antigen after thioacetamide treatment. Data support the hypothesis that the preneoplastic foci consisted of clones of hepatocytes which preferentially express GST mu, GGT and Mallory bodies. These preneoplastic cells selectively proliferate in response to the promoter effects of necrosis-induced liver cell regeneration ("chemical partial hepatectomy").
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PMID:Preneoplastic liver cell foci expansion induced by thioacetamide toxicity in drug-primed mice. 1672 98

Expression of TGF-alpha during promotion of neoplastic development from GST-P-positive foci in rat chemical hepatocarcinogenesis was investigated. One-hundred male F344 rats were given a single intraperitoneal injection of DEN (200 mg/kg bodyweight) and subjected to two-thirds partial hepatectomy at week 3. Commencing 2 weeks from the start, PB at doses of 0 or 500 p.p.m. was fed to the rats for 46 weeks. Groups of 10 rats were killed at weeks 4, 8, 16, 32, 48 and their livers were immunohistochemically examined for expression of GST-P and TGF-alpha. TGF-alpha-positive foci and single positive cells were observed from week 4, partially overlapping with GST-P-positive foci but being much fewer. Numbers of TGF-alpha-positive lesions did not increase from weeks 4-48, but their areas showed increment at weeks 32 and 48, especially with PB administration. Almost all of the tumors observed at weeks 16, 32 and 48 were positive for TGF-alpha (98%). In addition, epidermal growth factor receptor overexpression was observed in most TGF-alpha-positive lesions (foci and tumors). The proliferating cell nuclear antigen labeling index in double positive foci for GST-P and TGF-alpha was significantly higher than that in TGF-alpha-negative foci. In conclusion, TGF-alpha may be closely related with promotion from altered foci to neoplasms in rat hepatocarcinogenesis. Our data suggest that double positive foci for GST-P and TGF-alpha in the early stages of rat hepatocarcinogenesis may develop into tumors with promotion.
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PMID:Possible tumor development from double positive foci for TGF-alpha and GST-P observed in early stages on rat hepatocarcinogenesis. 1673 25

The base excision repair carried out by the bacterial MutY DNA glycosylase and eukaryotic MutY homolog (MYH) is responsible for removing adenines misincorporated into DNA opposite 7,8-dihydro-8-oxo-guanines (8-oxoG), thereby preventing G:C to T:A mutations. MutY and MYH can also remove adenines from A/G and A/C and can remove guanines from G/8-oxoG mismatches at reduced rates. Biallelic germline mutations in the human MYH gene predispose individuals to multiple colorectal adenomas and carcinoma. Four functional assays are usually employed to characterize the MutY and MYH. Gel mobility shift or fluorescence anisotropy assays measures DNA-binding affinity and the apparent dissociation constants. Glycosylase assay determines the catalytic parameters of the enzyme. By using a trapping assay in the presence of sodium borohydride, the protein-DNA covalent intermediate can be identified. The in vivo activity of MutY or MYH can be measured by complementation in Escherichia coli mutY mutants or fission yeast Schizosaccharomyces pombe MYH knockout cells. MutY and MYH interacting proteins can be analyzed by the glutathione S-transferase pull-down assay, Far-western, and coimmunoprecipitation. The in vitro and in vivo activities of MYH can be modulated by several proteins, including mismatch recognition enzymes MSH2/MSH6, proliferating cell nuclear antigen, and apurinic/apyrimidinic endonuclease.
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PMID:Isolation and analyses of MutY homologs (MYH). 1679 63

The replication clamp PCNA and its loader RFC (Replication Factor C) are central factors required for processive replication and coordinated DNA repair. Recently, several additional related clamp loaders have been identified. These alternative clamp loaders contain the small Rfc2-5 subunits of RFC, but replace the large Rfc1 subunit by a pathway-specific alternative large subunit, Rad24 for the DNA damage checkpoint, Ctf18 for the establishment of sister chromatid cohesion, and Elg1 for a general function in chromosome stability. In order to define biochemical functions for these loaders, the loaders were overproduced in yeast and purified at a milligram scale. To aid in purification, the large subunit of each clamp loader was fused to a GST-tag that, after purification could be easily removed by a rhinoviral protease. This methodology yielded all clamp loaders in high yield and with high enzymatic activity. The yeast 9-1-1 checkpoint clamp, consisting of Rad17, Mec3, and Ddc1, was overproduced and purified in a similar manner.
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PMID:Overproduction and purification of RFC-related clamp loaders and PCNA-related clamps from Saccharomyces cerevisiae. 1679 92

We previously reported that oxidative stress and renal tubular damage occur in chronic hyperoxaluric rats. However, the in vivo responses of renal epithelial cells after vitamin E administration and their correlations with calcium oxalate (CaOx) crystal formation have not been evaluated. Male Wistar rats received 0.75% ethylene glycol (EG) for 7, 21, or 42 days to induce CaOx deposition (EG group). Another group of EG-treated rats received 200 mg kg(-1) of vitamin E intraperitoneally (EG+E group) to evaluate its effect on hyperoxaluria. Urinary electrolytes and biochemistry and levels of lipid peroxides and enzymes were examined, together with serum vitamin E levels. Levels of the tubular markers, alpha and mu glutathione S-transferase, proliferating cell nuclear antigen (PCNA), osteopontinin (OPN), and Tamm-Horsfall protein (THP) were also measured, and TUNEL staining was performed to examine the viability of the tubular epithelium. There were no significant differences between the two age-matched controls either untreated or given vitamin E. Compared to untreated controls, tubular cell death was increased at all time points in EG rats with a gradual increase in CaOx crystals, whereas the number of PCNA-positive cells was only significantly increased on day 21. In EG+E rats, tubular cell death was decreased compared to the EG group, and cell proliferation was seen at all time points, while CaOx crystal deposition was decreased, but hyperoxaluria, urinary lipid peroxides, and enzymuria were unaffected. Vitamin E supplement prevented the loss of OPN and THP in renal tissues by EG and the reduction in their levels in the urine. The beneficial effect of vitamin E in reducing CaOx accumulation is due to attenuation of tubular cell death and enhancement of the defensive roles of OPN and THP.
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PMID:Vitamin E attenuates crystal formation in rat kidneys: roles of renal tubular cell death and crystallization inhibitors. 1680 40

REV1 protein is a eukaryotic member of the Y family of DNA polymerases involved in the tolerance of DNA damage by replicative bypass. The precise role(s) of REV1 in this process is not known. Here we show, by using the yeast two-hybrid assay and the glutathione S-transferase pull-down assay, that mouse REV1 can physically interact with ubiquitin. The association of REV1 with ubiquitin requires the ubiquitin-binding motifs (UBMs) located at the C terminus of REV1. The UBMs also mediate the enhanced association between monoubiquitylated PCNA and REV1. In cells exposed to UV radiation, the association of REV1 with replication foci is dependent on functional UBMs. The UBMs of REV1 are shown to contribute to DNA damage tolerance and damage-induced mutagenesis in vivo.
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PMID:Ubiquitin-binding motifs in REV1 protein are required for its role in the tolerance of DNA damage. 1698 85

To elucidate the roles of the transcription factor NF-E2-related factor (Nrf2) in hepatocarcinogenesis induced by 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), a mutagenic and carcinogenic heterocyclic amine, Nrf2-deficient mice were treated with 300 p.p.m. IQ in their diet for 1, 4 or 52 weeks. In the long-term experiment, the multiplicity and incidence of liver tumors in male and female IQ-treated Nrf2 deficient (-/-) mice were significantly higher than those in their counterpart wild-type (+/+) mice exposed to IQ. In the short-term experiment, although IQ exposure to Nrf2(+/+) mice of both sexes did not modify UDP-glucuronosyltransferase values, glutathione S-transferase values were significantly increased due to IQ treatment, in contrast to no alteration in male and female Nrf2(-/-) mice. Levels of oxidative stress markers such as 8-hydroxydeoxyguanosine and thiobarbituric acid reactive substances in the livers of all treated mice were not changed by IQ treatment. IQ-specific DNA adduct levels were elevated only in female Nrf2(-/-) mice, although the increase was not significant. IQ treatment caused an increase in proliferating cell nuclear antigen labeling indices only in male Nrf2(-/-) mice. The present data clearly show that Nrf2(-/-) mice of both sexes are susceptible to IQ hepatocarcinogenicity, which might result from IQ accumulation due to failure of metabolizing enzyme induction. In addition, inconsistent results concerning IQ-specific adducts and proliferating cell nuclear antigen labeling indices in male and female Nrf2(-/-) mice suggest the existence of different contributions of Nrf2 to IQ hepatocarcinogenesis between mice of the two sexes.
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PMID:Increased susceptibility to hepatocarcinogenicity of Nrf2-deficient mice exposed to 2-amino-3-methylimidazo[4,5-f]quinoline. 1708 68

Monocyclic phenolics (MPs) occur widely in foods, both naturally and as synthetic antioxidant additives. Several have been shown to inhibit the carcinogenicity of a variety of genotoxic carcinogens in various tissues. Hydroquinone (HQ), one of the simplest of the MPs, which occurs naturally as the glucose conjugate arbutin, was studied for its ability, at low dietary levels, to inhibit the initiating effects in the rat liver of the DNA-reactive carcinogen 2-acetylaminofluorene (AAF). Male Fischer 344 rats (F344), 8 weeks old at the start of the study, were allocated to six groups. HQ was fed daily ad libitum in PMI certified diet at either 0.05% (approximately 25 mg/kg bw/d) or 0.2% (approximately 100 mg/kg bw/d) for 13 weeks, starting one week before AAF administration was initiated, and at the same doses to two groups not receiving AAF. AAF was given intragastrically three times a week for 12 weeks at doses of 3mg/kg bw in 0.5% carboxymethyl cellulose (CMC) to a basal diet group and two of the groups receiving HQ in the diet. Vehicle controls were fed basal diet and administered 0.5% CMC intragastrically three times a week. The rats were observed daily and body weights were taken before initial dosing and at weekly intervals thereafter. Body weight gain over time, terminal body weights and absolute (mg) and relative liver weights (relative to body weight) were measured. At the end of the study (13 weeks), DNA adducts ((32)P-postlabeling), cell proliferation (PCNA immunohistochemistry) and preneoplastic hepatocellular altered foci (HAF) (glutathione S-transferase-placental type immuno-histochemistry) were measured. No significant differences were observed in body weight gains or liver weights. AAF produced liver DNA adducts and at the low dose of HQ adduct levels were 90% of that for AAF alone, whereas at the high dose adducts were reduced by 33% (p<0.05). AAF exposure yielded about a 50% increase in hepatocellular proliferation and both HQ doses reduced the AAF-induced increases in proliferation by about 25%. Likewise, the AAF-induced GST-P-positive HAF per cm(2) of liver tissue were decreased by both doses of HQ by about 50%. Thus, under the conditions of this experiment, HQ at both 0.05% and 0.2% in the diet diminished AAF-induced cancer initiating effects in rat liver.
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PMID:Inhibition by dietary hydroquinone of acetylaminofluorene induction of initiation of rat liver carcinogenesis. 1743 18


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