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)

Our previous studies suggested that both COMT and GST genotypes might modify individual breast cancer risk. Here, we extended the studies to examine the potential combined effect of these genotypes in susceptibility to breast cancer. Our study population consisted of 483 Finnish breast cancer cases and 482 population control subjects. The odds ratios (ORs) and (95%) confidence intervals (CIs) were calculated by unconditional logistic regression adjusting for known or suspected confounding factors. No significant increase in the overall breast cancer risk was seen for any combinations of the studied genotypes. However, a substantially increased risk of breast cancer was seen for women who had used hormone replacement therapy (HRT) and simultaneously carried the COMT-L allele containing genotypes and either the GSTP1 Ile/Ile genotype (OR 4.10, 95% CI 1.24-13.6) or the GSTT1 null genotype (OR 4.19, 95% CI 1.30-13.5). These associations appeared to be mainly attributable to long-term users of HRT; the respective ORs were 7.00 (95% CI 1.21-40.6) and 8.36 (95% CI 1.44-49.0) among the users of HRT of more than 30 months. In addition, the combination of COMT-L allele containing genotypes with the GSTM1 null genotype posed a remarkably increased risk (OR 9.10, 95% CI 1.84-45.0) of breast cancer in this study group. These results suggest that the use of HRT could substantially increase the risk of breast cancer among women with specific combinations of the at-risk genotypes of COMT and GST genes.
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PMID:Combined COMT and GST genotypes and hormone replacement therapy associated breast cancer risk. 1177 66

Environmental factors, especially the diet, play a prominent role in the epidemic of prostate cancer (PCA), in the United States. Many candidate dietary components have been proposed to influence human prostatic carcinogenesis, including fat, calories, fruits and vegetables, anti-oxidants, and various micronutrients, but the specific roles dietary agents play in promoting or preventing PCA remain controversial. We have collected evidence to suggest that GSTP1, the gene encoding the pi-class glutathione S-transferase (GST), may serve a "caretaker" function for prostatic cells. Although GSTP1 can be detected in normal prostatic epithelium, in almost all PCA cases, PCA cells fail to express GSTP1 polypeptides, and lack of GSTP1 expression most often appears to be the result of somatic "CpG island" DNA methylation changes. Loss of GSTP1 function also appears to be characteristic of prostatic epithelial neoplasia (PIN) lesions, thought to represent PCA precursors. We have recently learned that a new candidate early PCA precursor lesion, proliferative inflammatory atrophy (PIA), characterized by proliferating prostatic cells juxtaposed to inflammatory cells, contains epithelial cells that express high levels of GSTP1. These findings have formed the basis for a new model of prostatic carcinogenesis, in which prostatic cells in PIA lesions, subjected to a barrage of inflammatory oxidants, induce GSTP1 expression as a defense against oxidative genome damage. When cells with defective GSTP1 genes appear amongst the PIA cells, such cells become vulnerable to oxidants and electrophiles that inflict genome damage that tends to promote neoplastic transformation to PIN and PCA cells. Subsequently, PIN and PCA cells with defective GSTPI genes remain vulnerable to similar stresses tending to promote malignant progression. This new model for prostatic carcinogenesis has implications for the design of new prostate cancer prevention strategies. Rational prevention approaches might include: (i) restoration of GSTPI expression via treatment with inhibitors of CpG methylation, (ii) compensation for inadequate GSTPI activity via treatment with inducers of general GST activity, and (iii) abrogation of genome-damaging stresses via avoidance of exogenous carcinogens and/or reduction of endogenous carcinogenic (particularly oxidant) stresses.
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PMID:Preneoplastic prostate lesions: an opportunity for prostate cancer prevention. 1179 33

We had previously shown in a human feeding study that ingestion of tomato and carrot juices decreases DNA breaks and oxidized pyrimidine bases in peripheral lymphocytes and enhances expression of glutathione S-transferase (GST) in a subpopulation of the volunteers. The aim of this study was to determine how the major carotenoids of these juices (beta-carotene or lycopene) could contribute to the observed antigenotoxicity. Physiological concentrations (2 microM) of water-soluble beta-carotene and lycopene were incubated for 18-24 h with lymphocytes and then treated with bleomycin or H(2)O(2). Strand breaks, oxidized DNA bases, and persistence of damage (DNA repair) were measured by single-cell microgelelectrophoresis. GST-protein (GSTP1) was determined using an immunoassay and by measuring enzyme activity. HPLC analysis showed that beta-carotene was taken up by the cells after 24 h, and this was associated with a reduction of bleomycin-induced damage (29.11 +/- 1.86% tail intensity without versus 21.54 +/- 2.36% with beta-carotene). Lycopene was ineffective. The carotenoids did not modulate repair of bleomycin- and H(2)O(2)-induced damage and did not alter levels of oxidized pyrimidine bases nor GST expression. The results indicate that beta-carotene can enter the cell and protect against strand breaks but not against oxidized DNA bases. Therefore, beta-carotene accounts for only part of the protection observed in vivo with carotenoid-rich vegetable juices.
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PMID:beta-Carotene reduces bleomycin-induced genetic damage in human lymphocytes. 1188 38

We observed previously that polymorphisms in glutathione S-transferase (GST) genes modified allergic responses to diisocyanate exposure. Here, we extended the study to examine the possible role of N-acetyltransferase (NAT) genotypes in the development of diisocyanate-induced ill effects, both separately and in combination with the previously examined GSTM1, GSTM3, GSTP1 and GSTT1 genotypes. The study population comprised 182 diisocyanate-exposed workers, 109 of whom were diagnosed with diisocyanate-induced asthma and 73 of whom had no symptoms of asthma. The diisocyanates to which the workers had been exposed to were diphenylmethane diisocyanate (MDI), hexamethylene diisocyanate (HDI) and toluene diisocyanate (TDI). The NAT2 genotype did not have any significant effect on the risk of developing asthma, but the putative slow acetylator NAT1 genotypes posed a 2.54-fold risk of diisocyanate-induced asthma (95% confidence interval [CI] 1.32 to 4.91). The effect of the NAT1 genotype was especially marked for workers exposed to TDI, among whom the NAT1 slow acetylator genotypes posed a 7.77-fold risk of asthma (95% CI 1.18 to 51.6). Statistically significant increases in asthma risk were also observed among the whole study population for the concurrent presence of the GSTM1 null genotype and either NAT1 (odds ratio [OR] 4.53, 95% CI 1.76 to 11.6) or NAT2 (OR 3.12, 95% CI 1.11 to 8.78) slow acetylator genotypes, and of NAT1 and NAT2 slow acetylator genotypes (OR 4.20, 95% CI 1.51 to 11.6). The results suggest for the first time that in addition to GSTs, the NATs play an important role in inception of asthmatic reactions related to occupational exposure to diisocyanates.
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PMID:N-Acetyltransferase genotypes as modifiers of diisocyanate exposure-associated asthma risk. 1192 38

During the pathogenesis of human hepatocellular carcinoma (HCC), the CpG island encompassing the pi-class glutathione S-transferase gene (GSTP1) becomes hypermethylated. Repression of transcription accompanying CpG island hypermethylation has been proposed to be mediated by methyl-CpG binding domain (MBD) proteins. We report here that inhibition of transcription from hypermethylated GSTP1 promoters in Hep3B HCC cells, which fail to express GSTP1 mRNA or GSTP1 polypeptides, appears to be mediated by MBD2. Treatment of Hep3B cells with 5-azadeoxycytidine (5-aza-dC), a methyltransferase inhibitor, activated GSTP1 expression, whereas treatment with trichostatin A, a histone deacetylase inhibitor, had little effect. To more precisely assess the contribution of the pattern of GSTP1 CpG island methylation on GSTP1 mRNA expression, Hep3B cells were treated for 72 h with 5-aza-dC and then subjected to limiting dilution cloning. Bisulfite sequencing was used to map the methylation patterns of the GSTP1 promoter region in GSTP1-expressing and -non-expressing clones. In the clone that expressed GSTP1 mRNA determined by Northern blot analysis and quantitative reverse transcriptase (RT)-PCR, widespread demethylation of at least one GSTP1 allele was evident. Chromatin immunoprecipitation experiments revealed the presence of MBD2, but not Sp1, at the GSTP1 promoter in Hep3B cells. In contrast, Sp1 was detected at the GSTP1 promoter in a GSTP1-expressing Hep3B 5-aza-dC subclone. To test whether MBD2 might be responsible for the inhibition of GSTP1 transcription from hypermethylated GSTP1 promoters, siRNAs were used to reduce MBD2 polypeptide levels in Hep3B cells. SssI-catalyzed methylation of GSTP1 promoter sequences resulted in diminished luciferase reporter activity after transfection into Hep3B cells. However, when hypermethylated GSTP1 promoter sequences were transfected into Hep3B cells that had been treated with siRNA-targeting MBD2 mRNA, no repression of luciferase reporter expression was evident. These findings implicate MBD2 in the repression of GSTP1 expression associated with GSTP1 CpG island hypermethylation in HCC cells.
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PMID:Methyl-CpG binding domain protein 2 represses transcription from hypermethylated pi-class glutathione S-transferase gene promoters in hepatocellular carcinoma cells. 1196 Sep 94

Interindividual differences in susceptibility to hematologic malignancies may be mediated in part through polymorphic variability in the bioactivation and detoxification of carcinogens. The glutathione S-transferases (GSTs) have been implicated as susceptibility genes in this context for a number of cancers. The aim of this study was to examine whether polymorphic variation in GSTs confers susceptibility to chronic lymphocytic leukemia (CLL). GSTM1, GSTT1, and GSTP1 genotypes were determined in 138 patients and 280 healthy individuals. The frequency of both GSTM1 and GSTT1 null genotypes and the GSTP1-Ile allele was higher in cases than in controls. There was evidence of a trend in increasing risk with the number of putative "high-risk" alleles of the GST family carried (P =.04). The risk of CLL associated with possession of all 3 "high-risk" genotypes was increased 2.8-fold (OR = 2.8, 95% confidence interval: 1.1-6.9). Our findings suggest that heritable GST status may influence the risk of developing CLL.
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PMID:Relationship between glutathione S-transferase M1, T1, and P1 polymorphisms and chronic lymphocytic leukemia. 1201 Aug 28

The aim of this study was to use DNA adducts levels, detected by 32P-postlabelling, as a biomarker to assess human exposure to polycyclic aromatic hydrocarbons (PAHs) from a coke oven plant and explore the possible association between CYP1A1 MspI, GSTP1, GSTM1 and GSTT1 genotypes, and smoking status on bulky DNA adduct formation. A large amount of inter-individual variation in adduct level was observed among workers with the same job and the same smoking habits. No significant differences were observed in DNA adduct levels between the coke oven workers and control group. Smokers in the control group had significantly higher DNA adducts than the non-smokers in the same group (35.13+/-21.11 versus 11.18+/-8.00, per 10(8) nucleotides, P=0.003). In this group, the correlation between the level of DNA adducts and the cigarettes smoked was strongly significant (r=0.70, P<0.0005), but no correlation was found among the coke oven workers. Among non-smokers there was a significant difference between the control group and the coke oven workers (11.18+/-8.00 versus 24.62+/-15.20, per 10(8) nucleotides, P=0.03). These results suggests that tobacco smoke could behave as a confounding factor for evaluation of DNA adducts arising from occupational exposure. The levels of DNA adducts in smokers not occupationally exposed to PAHs is dependent on the polymorphisms CYP1A1 MspI in the 3' non-coding region (49.04+/-22.18 versus 25.85+/-15.87, per 10(8) nucleotides, P<0.05), but no effect was observed for the GST genotypes studied.
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PMID:Aromatic DNA adduct levels in coke oven workers: correlation with polymorphisms in genes GSTP1, GSTM1, GSTT1 and CYP1A1. 1203 16

During 1991-1993 period a study of detoxifying activity of the fetoplacental barrier and genotyping of the major detoxifying enzymes in it (CYP1A1 Ile462Val, GSTP1 Ile104Val, GSTM1 present/absent) was undertaken in different regions of Ukraine that were radioactively contaminated with summary effective equivalent annual expositional doses (SEEAED approximately 1.7 mSv (Group I) and 0.1-0.4 mSv (Group III), chemically polluted Zaporizzhia, monitored for ambient levels of benzo(a)pyrene (BP) (Group II) and Poltava that was judged as "clean" one (Group IV). Glutathione-S-transferase (GSTase) and glutathionereductase (GSSG-Rase) activities of cytosol and concentration of thiobarbituric acid reacting compounds (TBA-reactants) and reduced low-molecular weight thiols (rLMW thiols) were used as phenotype parameters. Cytosolic GSTase activities were nearly two times less in the samples from radioactively contaminated area (Group I, SEEAED approximately 1.7 mSv) and in chemically polluted area (Group II, mean BP level 12.3 ng/m3), compared with the groups III and IV. The highest level of TBA-reactants indicative of lipid peroxidation in response to radiation was observed in Group I, while the lowest level in Group IV. The level of rLMW thiols was 2.5-4 times more in Group II comparative with Groups I, III and IV. The frequency of the genotypes in all the investigated samples corresponds to that reported for Caucasians. For the combined exposure groups, individuals with the CYP1A1 (Ile462Val) genotype (n = 5) had significantly higher levels of GST, GSSG-R and TBA reacting compounds compared to individuals with the Ile462Ile genotype (n = 14 for TBA-reactants and n = 24--for GST and GSSG-R). Despite the challenge of small numbers of individuals, stratification by exposure group for Groups I, II and III indicated significantly higher GST levels in CYP1A1 (Ile462Val) variants from Groups II and III (n = 3) compared to the Ile462Ile variants (n = 17). The data demonstrate contributions by both exposure and genotype on the detoxification of radiation and chemical damage in the human placenta.
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PMID:[Pheno-and genotyping of a placental detoxication system in ecologically unfavorable regions of Ukraine]. 1203 43

Genetic approaches to understanding the etiology of the acute leukemias are beginning to deliver meaningful insights. Polymorphic variants in xenobiotic metabolizer loci were a natural starting point to study the relevance of these changes. The finding that glutathione S-transferase (GST) T1 null variants increase leukemia risk has implicated oxidative stress in hematopoietic stem cells as an important etiological factor in acute myeloid leukemia (AML). The importance of these enzyme systems in handling specific substrates has also been confirmed by the finding of an increased risk of therapy-related leukemia in individuals with underactive variants of GSTP1 who have been exposed to a chemotherapeutic agent metabolized by this enzyme. Benzene is a well-recognized leukemogen, and genetic variants in its metabolic pathway can modulate the risk of leukemia following exposure. In particular, underactive variants of the NAD(P)H:quinone oxidoreductase 1 gene (NQO1) seem to increase the risk of AML. Other enzymes within the pathway are proving more difficult to study because of the absence of variants that significantly affect the biological activity of the enzyme under study. No effect of the myeloperoxidase (MPO) gene variants in altering the risk of AML has been seen in our studies. Another pathway recently shown to be important in determining leukemia risk is folic acid metabolism, particularly important in predisposition to acute lymphocytic leukemia (ALL). Polymorphic variants of the methylenetetrahydrofolate reductase gene (MTHFR) which impair its activity have been shown to be associated with a protective effect. This is thought to be due to an increased availability of nucleotide precursors for incorporation into DNA. This finding implicates misincorporation of uracil into DNA as an important mechanism of leukemic change in lymphoid precursors. Future studies will extend these observations but will require biological material collected from large well-controlled epidemiological studies. The technological challenges imposed by the high throughput of samples required by these studies are currently being addressed.
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PMID:Metabolic enzyme polymorphisms and susceptibility to acute leukemia in adults. 1208 44

Butyrate, one of the major products of gut fermentation, is known to inhibit proliferation, induce apoptosis and differentiation, and increase phase II enzyme activities in tumor cells, whereas little information is available on protective effects in less-transformed colon cells. The aim of this study was to investigate whether the chemoprotective mechanism of glutathione S-transferase (GST) induction by butyrate could also play a role in earlier stages of colon carcinogenesis and whether chemoresistance of cells toward the endogenous genotoxic risk factor 4-hydroxy-2-nonenal (HNE) could be a consequence of butyrate treatment. As cell models, we used the human tumor cell lines HT29 and HT29 clone 19A, a differentiated subclone with properties resembling primary colon cells. We determined the expression of GSTP1 protein (enzyme-linked immunosorbent assay), the major GST in HT29, GSTP1 mRNA (Northern blotting), GST activity, intracellular glutathione, and total protein. The genotoxic impact of HNE (100-200 microM) was compared in butyrate-treated and nontreated cells using single-cell microgel electrophoresis. Our results show that GSTP1 mRNA, GSTP1 protein, GST activity, and total protein were increased (1.2- to 2.5-fold) and glutathione levels were maintained after 24-72 h of incubation with 4 mM butyrate. Moreover, a marked reduction of HNE-induced genotoxicity was caused by preincubation with butyrate. Butyrate also induced the phosphorylation of extracellular signal-regulated kinases (ERK1/2, Western blotting) after 5-30 min, which indicates a regulation of GST expression by this signal pathway. Most effects were greater in HT29 parent cells than in clone cells. In conclusion, butyrate enhances expression of GST and other proteins in both cell lines, which leads to an enhanced chemoprotection, reducing the impact of HNE genotoxicity. Thus butyrate could play a role in early and later stages of cancer prevention by reducing exposure to relevant risk factors.
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PMID:Butyrate induces glutathione S-transferase in human colon cells and protects from genetic damage by 4-hydroxy-2-nonenal. 1209 19


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