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)

To obtain information on the effects of nongenotoxic carcinogens at low doses for human cancer risk assessment, the carcinogenic potential of the organochlorine insecticide, 1,1-bis(p-chlorophenyl)-2,2,2-trichloroethane (DDT), in the liver was assessed in F344 rats. In experiment 1, 240 male animals, 21 days old, were administered 0, 0.5, 1.0, 2.0, 5.0, 20, 100 and 500 ppm DDT in the diet for 16 weeks. Experiment 2 was conducted to elucidate the carcinogenic potential of DDT at lower levels using 180 rats given doses of 0, 0.005, 0.01, 0.1, 0.2 and 0.5 ppm. The livers of all animals were immunohistochemically examined for expression of glutathione S-transferase placental form (GST-P), putative preneoplastic lesions. Quantitative values for GST-P-positive foci in the liver were increased dose-dependently in rats given 20 ppm DDT and above with statistical significance as compared with the concurrent control value. In contrast, doses of 0.005 and 0.01 ppm were associated with a tendency for decrease below the control value, although not significantly. Western blotting analysis show that cytochrome P-450 3A2 (CYP3A2) protein expression tended to decrease at 0.005 and 0.01 ppm, a good correlation being observed with the change in the number of GST-P-positive foci. These findings suggest that a DDT hepatocarcinogenicity may show nonlinear response, that is, hormetic response at low doses. Furthermore, since CYP3A2 protein expression appears to be important for the effects of phenobarbital and the alpha-isomer of benzene hexachloride, mRNAs for IL-1 receptor type 1 (IL-1R1) and TNF-alpha receptor type 1 (TNFR1) whose ligands have roles not only in downregulating CYP3A2 expression but also in inducing antiproliferative effect or apoptosis in hepatocyte were examined. Increase was observed at low doses of DDT. Oxidative stress in liver DNA, assessed in terms of 8-hydroxydeoxyguanosine as a marker, was also decreased. These findings suggest that the possible hormetic effect that was observed in our detailed low-dose study of DDT carcinogenesis, although not statistically significant, may be linked to levels of oxidative stress and proinflammatory cytokines.
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PMID:Detailed low-dose study of 1,1-bis(p-chlorophenyl)-2,2,2- trichloroethane carcinogenesis suggests the possibility of a hormetic effect. 1194 1

Effects of lemon grass extract (LGE) on hepatocarcinogenesis were examined in male Fischer 344 rats, administered diethylnitrosamine (DEN) at three weekly intraperitoneal doses of 100 mg/kg body weight and partially hepatectomized at the end of week 5. LGE was given at dietary concentrations of 0, 0.2, 0.6 or 1.8% from the end of week 4 for 10 weeks. All rats were sacrificed at the end of week 14. LGE reduced the number of putatively preneoplastic, glutathione S-transferase placental form-positive lesions and the level of oxidative hepatocyte nuclear DNA injury, as assessed in terms of 8-hydroxydeoxyguanosine production. In contrast, LGE did not affect the size of the preneoplastic lesions, hepatocyte proliferative activity, activities of phase II enzymes or hepatocyte extra-nuclear oxidative injury. These results suggest inhibitory effects of LGE on the early phase hepatocarcinogenesis in rats after initiation with DEN.
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PMID:Inhibitory effects of lemon grass (Cymbopogon citratus, Stapf) extract on the early phase of hepatocarcinogenesis after initiation with diethylnitrosamine in male Fischer 344 rats. 1204 9

We investigated promotion potential of ethanol after initiation of hepatocarcinogenesis in male, 21-day-old, F344 rats by exposure to 10 ppm 2-amino-3, 8-dimethylimidazo[4,5-f]quinoxaline pellet diet for 8 weeks. The rats in group 1 were then fed on liquid control diet for 16 weeks, group 2 receiving the same diet containing 5% ethanol for 8 weeks followed by 8 weeks on the control diet, while group 3 animals were given 5% ethanol containing liquid diet for the entire16 weeks. On sacrifice at the end of week 24, glutathione S-transferase placental form positive foci, putative preneoplastic lesions in the liver, cell proliferation as indicated by proliferating cell nuclear antigen immunohistochemical staining and levels of 8-hydroxydeoxyguanosine, a marker of oxidative DNA damage, were significantly increased in the liver of group 3 along with non significant alteration of 8-oxoguanine DNA glycosylase mRNA expression. Lack of persistent increase of above parameters was found in transient ethanol exposure group. These results suggest that chronic consumption of ethanol promotes hepatocarcinogenesis by increasing oxidative stress and cell proliferation. It is also evident that abstinence of ethanol during the second stage stops its persistent promotion effect.
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PMID:Enhancing risk of ethanol on MeIQx-induced rat hepatocarcinogenesis is accompanied with increased levels of cellular proliferation and oxidative stress. 1263 51

Our recent research indicated that phenobarbital (PB) may inhibit the development of N-diethylnitrosamine (DEN)-initiated pre-neoplastic lesions at low doses in a rat liver medium-term bioassay (Ito test), while high doses exhibit promoting activity. This raises the question of whether treatment with low doses of PB might reduce cancer risk. For clarification, male 6-week-old F344 rats were treated with PB at doses of 0, 2, 15 and 500 p.p.m. in the diet for 10 or 33 weeks after initiation of hepatocarcinogenesis with DEN. In a second, short-term experiment, animals were given PB at doses of 2, 4, 15, 60 and 500 p.p.m. for 8 days. Formation of glutathione S-transferase placental form (GST-P) positive foci and liver tumors was inhibited at 2 p.p.m. Generation of oxidative DNA damage marker, 8-hydroxy-2'-deoxyguanosine (8-OHdG), cellular proliferation within the areas of GST-P positive foci and apoptosis in background liver parenchyma were suppressed. Suppression of 8-OHdG formation by PB at low dose might be related to the enhanced mRNA expression of 8-OHdG repair enzyme, oxoguanine glycosylase 1 (Ogg1). Moreover, as detected by cDNA microarray analysis, PB treatment at low dose enhanced mRNA expression of glutamic acid decarboxylase (GAD65), an enzyme involved in the synthesis of gamma-aminobutyric acid (GABA), and suppressed MAP kinase p38 and other intracellular kinases gene expression. On the contrary, when PB was applied at a high dose, GST-P positive foci numbers and areas, tumor multiplicity, hydroxyl radicals and 8-OHdG levels were greatly elevated with the increase in CYP2B1/2 and CYP3A2 mRNA, protein, activity and gene expression of GST, nuclear tyrosine phosphatase, NADPH- cytochrome P-450 reductase and guanine nucleotide binding protein G(O) alpha subunit. These results indicate that PB exhibits hormetic effect on rat hepatocarcinogenesis initiated with DEN by differentially altering cell proliferation, apoptosis and oxidative DNA damage at high and low doses.
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PMID:Phenobarbital at low dose exerts hormesis in rat hepatocarcinogenesis by reducing oxidative DNA damage, altering cell proliferation, apoptosis and gene expression. 1280 26

Phthalates are widely used as a plasticizer and cause a peroxisome proliferation. Peroxisome proliferators (PPs), such as di-2-ethylhexyl phthalate (DEHP) and clofibrate (CF) are known to have a hepatocarcinogenic potential in rodents. It has been proposed that these PPs may cause hepatocellular cancer by an oxidative damage-mediated mechanism(s). The primary purpose of this study is to find whether there is a difference between the oxidative damage by hepatocarcinogenic PPs (DEHP and CF) and the oxidative damage by weak PPs [di-n-butyl phthalate (DBP) and n-butylbenzyl phthalate (BBP)]. The second purpose is to investigate if phthalates can affect the phase I/phase II enzymes, and if the effect of PPs on metabolizing enzymes correlates with peroxisome proliferation or not. After rats were treated with PPs (DEHP, DBP and BBP; 50, 200, 1000 mg/kg, CF; 100 mg/kg, p.o., for 14 days), the activities of metabolizing enzymes and peroxisomal enzymes were investigated, and the oxidative damage was measured using 8-hydroxydeoxyguanosine (8-OHdG) in the DNA and malonedialdehyde (MDA) in the livers. These four PPs significantly increased the relative liver weights, palmitoyl-CoA oxidation and activity of carnitine acetyltransferase. DEHP was found to be the most potent PP among three phthalates. A dramatic and dose-dependent increase in hepatic MDA levels was observed in CF (100 mg/kg), DEHP (>or=50 mg/kg), DBP and BBP (>or=200 mg/kg) groups. However, the 8-OHdG in hepatic DNA was increased only in DEHP (1000 mg/kg) and CF groups. Activities of cytochrome p4501A1, 1A2, 3A4, UDP-glucuronosyl transferase and glutathione S-transferase were decreased overall by PPs, but there is no correlation between the inhibitory effect on metabolizing enzymes and the peroxisome proliferation. These results indicate that 8-OHdG positively correlates with carcinogenic potential of PPs, but other factors as well as peroxisomal H(2)O(2) could be involved in the generation of 8-OHdG and the carcinogenesis of PPs. The present findings also demonstrate that the effect of PPs on xenobiotic metabolizing enzymes may be independent of the peroxisome proliferation and the oxidative stress. Thus it is possible that the PPs affect the hepatic toxification/detoxification capacity even in humans.
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PMID:Comparison of oxidative stress and changes of xenobiotic metabolizing enzymes induced by phthalates in rats. 1463 Jan 34

The studies using an immunohistological technique revealed that overexpression of oxidative stress-related substance such as HNE was observed in the liver of primary biliary cirrhosis patients. These data suggested that oxidative stress participated in the pathogenesis of primary biliary cirrhosis. Therefore we analyzed serum oxdative stress marker (8-OHdG) and anti oxidative substances (Mn-SOD and TRX) to evaluate their clinical significance. In addition we analyzed the genotype of anti oxidative substance GST that has been reported to relate susceptibility of autoimmune disease. Serum levels of 8-OHdG, Mn-SOD and TRX in PBC patients were significantly higher than those of healthy subjects (P<0.001). Though there was no relation between serum level of 8-OHdG and clinical data, positive correlation between serum level of Mn-SOD, TRX and serum level of ALP, IgM was observed. Positive correlation was also observed between serum level of Mn-SOD and TRX. Serum levels of Mn-SOD of patients who responded to UDCA therapy were significantly higher than those of patients who did not response to therapy (P<0.01). Although genotypic difference of GSTM1 and GSTT1 by peripheral blood mononuclear cells did not relate to susceptibility of PBC, serum titer of AMA of GSTM1 null and GSTT1 null patients were significantly higher than those of GSTM1 positive and/or GSTT1 positive patients (P< 0.05). These findings suggest that serum oxidative stress-related markers may reflect the extent of liver damage of PBC, and may relate to the efficacy of UDCA therapy on PBC. It also made clear that genotype of GST related to the titer of AMA.
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PMID:[Significance of serum oxidative stress related markers and genotype of GST gene in the pathogeneses of primary biliary cirrhosis]. 1555 21

Previously we reported a tendency for reduction of the development of glutathione-S-transferase placental form (GST-P) positive foci, recognized as preneoplastic changes in rat liver, by a low dose of 1,1-bis(p-chlorophenyl)-2,2,2-trichloroethane (DDT), which belongs to the same group of hepatic cytochrome P-450 inducers as phenobarbital and is itself a non-genotoxic hepatocarcinogen. In order to clarify the biological significance of this phenomenon, we investigated the reproducibility and changes in other parameters using an initiation-promotion model in which male F344 rats were treated with DDT at doses of 0, 0.005, 0.5, 500 ppm in the diet for 11 or 43 weeks after initiation of hepatocarcinogenesis with N-diethylnitrosamine (DEN). When 500 ppm DDT was applied, the formation of GST-P positive foci and tumor were markedly elevated. In contrast, induction of GST-P positive foci and liver tumors tended to be inhibited at a dose of 0.005 ppm, correlating with protein levels of cytochrome P450 2B1 and 3A2 (CYP2B1 and 3A2) and generation of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage. mRNA levels for 8-oxoguanine glycosylase 1 (OGG1), an 8-OHdG repair enzyme, connexin 32 (Cx32), a major component of Gap junctions, and hepatic nuclear factor 1alpha (HNF-1alpha), a Cx32 regulator, were inversely correlated with GST-P positive foci and tumor formation. These results indicate that low dose DDT may indeed exhibit inhibitory effects on chemically initiated-rat hepatocarcinogenicity, in contrast to the promotion observed with high doses, and that this is related to changes in metabolizing enzymes, cell communication, and DNA damage and its repair.
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PMID:Low dose DDT inhibition of hepatocarcinogenesis initiated by diethylnitrosamine in male rats: possible mechanisms. 1588 32

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

To investigate associations among occupational exposure to coke oven emissions (COEs), oxidative stress, cytogenotoxic effects, change in the metabolizing enzyme glutathione S-transferase (GST), and internal levels of polycyclic aromatic hydrocarbons (PAHs) in coke oven workers, we recruited 47 male coke oven workers and 31 male control subjects from a coke oven plant in northern China. We measured the levels of 1-hydroxypyrene (1-OHP) and 8-hydroxy-2 -deoxyguanosine (8-OHdG) in urine, micronucleated binucleated cells (BNMNs) in peripheral blood lymphocyte, and GST in serum. Our results showed that the group exposed to COEs had significantly increased levels of 1-OHP [median 5.7; interquartile range (IQR), 1.4-12.0 micromol/mol creatinine] compared with the control group (3; 0.5-6.4 micromol/mol creatinine). In addition, the median levels (IQR) of 8-OHdG, BNMNs, and GST were markedly increased in the exposed [1.9 (1.4-15.4) micromol/mol creatinine; 6 (2-8) per thousand ; 22.1 (14.9-31.2) U/L, respectively] compared with controls [1.3 (1.0-4.0) micromol/mol creatinine, 2 (0-4) per thousand; and 13.1 (9.5-16.7) U/L, respectively]. These results appeared to be modified by smoking. However, multivariate logistic regression analysis revealed that exposure to COEs had the highest odds ratio among variables analyzed and that smoking was not a significant confounder of the levels of studied biomarkers. Overall, the present findings suggest that COE exposure led to increased internal PAH burden, genetic damage, oxidative stress, and GST activity. The consequences of the changes in these biomarkers, such as risk of cancer, warrant further investigations.
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PMID:Elevated levels of urinary 8-hydroxy-2 -deoxyguanosine, lymphocytic micronuclei, and serum glutathione S-transferase in workers exposed to coke oven emissions. 1667 19

Nonalcoholic steatohepatitis (NASH) may cause fibrosis, cirrhosis, and hepatocellular carcinoma (HCC); however, the exact mechanism of disease progression is not fully understood. Angiogenesis has been shown to play an important role in the progression of chronic liver disease. The aim of this study was to elucidate the role of angiogenesis in the development of liver fibrosis and hepatocarcinogenesis in NASH. Zucker rats, which naturally develop leptin receptor mutations, and their lean littermate rats were fed a choline-deficient, amino acid-defined diet. Both Zucker and littermate rats showed marked steatohepatitis and elevation of oxidative stress markers (e.g., thiobarbital acid reactive substances and 8-hydroxydeoxyguanosine). In sharp contrast, liver fibrosis, glutathione-S-transferase placental form (GST-P)-positive preneoplastic lesions, and HCC developed in littermate rats but not in Zucker rats. Hepatic neovascularization and the expression of vascular endothelial growth factor (VEGF), a potent angiogenic factor, only increased in littermate rats, almost in parallel with fibrogenesis and carcinogenesis. The CD31-immunopositive neovessels were mainly localized either along the fibrotic septa or in the GST-P-positive lesions. Our in vitro study revealed that leptin exerted a proangiogenic activity in the presence of VEGF. In conclusion, these results suggest that leptin-mediated neovascularization coordinated with VEGF plays an important role in the development of liver fibrosis and hepatocarcinogenesis in NASH.
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PMID:Leptin-mediated neovascularization is a prerequisite for progression of nonalcoholic steatohepatitis in rats. 1700 38


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