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)

Inappropriate exposure of neonatal sheep to estrogen during critical developmental periods inhibits or retards endometrial gland morphogenesis and reduces uterine growth. Studies were conducted to identify mechanisms mediating estrogen disruption of neonatal ovine uterine development by analysis of candidate growth factor systems and using suppression subtraction hybridization (SSH). In study 1, sheep were exposed either to corn oil as a control or to estradiol valerate (EV) from birth to Postnatal Day (PND) 14, which ablated endometrial gland development. Estradiol valerate decreased uterine FGF7 (fibroblast growth factor 7) and MET (hepatocyte growth factor receptor) expression and increased INHBA (inhibin betaA). The SSH identified a number of genes responsive to EV, which included GSTM3 (glutathione S-transferase), IDH1 (cytosolic NADP-isocitrate dehydrogenase), PECI (peroxisomal D(3),D(2)-enoyl-coenzyme A isomerase), OAS1 (2',5'-oligoadenylate 40/46-kDa synthetase), IGFBP3 (insulin-like growth factor-binding protein-3), TEGT (testis-enhanced gene transcript), CXCL10 (interferon-gamma-inducible protein 10), and IGLV (immunoglobulin V). These mRNAs were expressed predominantly in the endometrial epithelia (GSTM3, IDH1, PEC1, OAS1, and TEGT), stroma (IGFBP3), or immune cells (CXCL10 and IGLV). In study 2, effects of estrogen exposure on uterine gene expression were determined during three different critical developmental periods (PNDs 0-14, 14- 28, and 42-56). Estrogen exposure decreased expression of the SSH-identified genes, particularly those from PNDs 0-14. These studies suggest that estrogen disruption of postnatal uterine development involves period-specific effects on expression of genes predominantly in the endometrial epithelium. The SSH-identified, estrogen-disrupted genes represent new candidate regulators of postnatal endometrial adenogenesis.
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PMID:Estrogen disruption of neonatal ovine uterine development: effects on gene expression assessed by suppression subtraction hybridization. 1597 82

The glutathione S-transferase (GSTs) are polymorphic supergene family of detoxification enzymes that are involved in the metabolism of numerous potential carcinogens. Several allelic variants of polymorphic GSTs show impaired enzyme activity and are suspected to increase the susceptibility to various cancers. To find out the association of GST variants with risk of gallbladder cancer, the distribution of polymorphisms in the GST family of genes (GSTT1, GSTM1, GSTP1, and GSTM3) were studied in 106 cancer patients and 201 healthy controls. Genotypes were analysed by polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (RFLP). The frequencies of GSTM1 null and GSTM3*BB genotypes did not differ between patients and controls. The overall frequency of GSTT1 null was lower in cases as compared with controls (p=0.003, Odds ratio (OR) = 0.2, 95% confidence interval (CI), 0.1-0.6). After sex stratification, the GSTT1 null frequency was reduced only in female patients (p=0.008, OR = 0.2, 95% CI = 0.1-0.6). However, the GSTP1, ile/val genotype and the val allele were significantly higher in cases than controls (p=0.013, OR = 1.9, 95% CI = 1.1-3.1; p=0.027, OR = 1.5, 95% CI = 1.0-2.1), respectively. To study gene-gene interactions, a combined risk of gallbladder cancer due to ile/val or val/val were calculated in combination with null alleles of GSTM1 and GSTT1 or the *B allele of GSTM3, but there was no enhancement of risk. Gallstones were present in 57.5% of patients with gallbladder cancer, but there were no significant differences between allelic/genotype frequencies of the studied GST genes polymorphisms between patients with or without gallstones. To best of our knowledge, this is the first paper showing ile/val genotypes and val allele of GSTP1 to be associated with higher risk of gallbladder cancer.
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PMID:Genetic polymorphisms in GSTM1, GSTT1, GSTP1, GSTM3 and the susceptibility to gallbladder cancer in North India. 1676 Jan 34

Solid organ transplant recipients are at higher risk of non-melanoma skin cancer (NMSC), especially basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Genetic alterations in the production of detoxifying enzymes such as glutathione S-transferase (GST) and CYP1A1 may enhance this risk. We investigated the frequency of GST genotypes (GSTM1, GSTM3, GSTT1 and GSTP1) and CYP1A1 in 239 transplant recipients: 107 cases with NMSC and 132 controls free from NMSC matched for type of transplanted organ, duration of transplantation, sex and age. Allele GSTP1*A was associated with a higher risk of NMSC [odds ratio (OR) 1.7 (1.1-2.5); P = 0.017]. Homozygosity for allele GSTP1 Val(105) was lower in cases [OR 0.3 (0.1-0.8); P = 0.012], especially in patients with SCC [OR 0.1 (0.0-0.7); P = 0.012]. A higher risk of BCC was found in patients with GSTM1 null/null [null/null versus A + B, OR 3.1 (1.4-6.8); P = 0.003]. Analysis of allelism and interaction between allelic variants showed significant association between combined GSTM1 and CYP1A1 Val(462) genotypes, where individuals homozygous for the risk allele GSTM1 null and carrying also the allele CYP1A1 Val(462), show a higher risk of developing NMSC [OR 4.5 (1.1-21.4); P = 0.03], especially SCC [OR 6.5 (1.4-34.4); P = 0.01]. GSTP1 polymorphisms are associated with both BCC and SCC risk. GSTM1 polymorphisms seem to be involved in BCC risk, while GSTM1 null/null genotype combined with CYP1A1 allele Val(462) are associated with a higher risk for SCC, indicating that allelism and/or interactions between allelic variants at other loci may also influence the risk of NMSC, particularly SCC.
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PMID:Glutathione S-transferase and CYP1A1 gene polymorphisms and non-melanoma skin cancer risk in Italian transplanted patients. 1708 62

High consumption of cruciferous vegetables has been associated with reduced kidney cancer risk in many studies. Isothiocyanates, thought to be responsible for the chemopreventive properties of this food group, are conjugated to glutathione by glutathione S-transferases (GSTs) before urinary excretion. Modification of this relationship by host genetic factors is unknown. We investigated cruciferous vegetable intake in 1097 cases and 1555 controls enrolled in a multicentric case-control study from the Czech Republic, Poland, Romania and Russia. To assess possible gene-diet interactions, genotyped cases (N = 925) and controls (N = 1247) for selected functional or non-synonymous polymorphisms including the GSTM1 deletion, GSTM3 3 bp deletion (IVS6 + 22-AGG) and V224I G>A substitution, GSTT1 deletion and the GSTP1 I105V A>G substitution. The odds ratio (OR) for low (less than once per month) versus high (at least once per week) intake of cruciferous vegetables was 1.29 [95% confidence interval (CI): 1.02-1.62; P-trend = 0.03]. When low intake of cruciferous vegetables (less than once per month) was stratified by GST genotype, higher kidney cancer risks were observed among individuals with the GSTT1 null (OR = 1.86; 95% CI: 1.07-3.23; P-interaction = 0.05) or with both GSTM1/T1 null genotypes (OR = 2.49; 95% CI: 1.08-5.77; P-interaction = 0.05). These data provide additional evidence for the role of cruciferous vegetables in cancer prevention among individuals with common, functional genetic polymorphisms.
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PMID:Glutathione S-transferase polymorphisms, cruciferous vegetable intake and cancer risk in the Central and Eastern European Kidney Cancer Study. 1761 61

Dietary fibres are indigestible food ingredients that reach the colon and are then fermented by colonic bacteria, resulting mainly in the formation of short-chain fatty acids (SCFA) such as acetate, propionate, and butyrate. Those SCFA, especially butyrate, are recognised for their potential to act on secondary chemoprevention by slowing growth and activating apoptosis in colon cancer cells. Additionally, SCFA can also act on primary prevention by activation of different drug metabolising enzymes. This can reduce the burden of carcinogens and, therefore, decrease the number of mutations, reducing cancer risk. Activation of GSTs by butyrate has been studied on mRNA, protein, and enzyme activity level by real-time RT-PCR, cDNA microarrays, Western blotting, or photometrical approaches, respectively. Butyrate had differential effects in colon cells of different stages of cancer development. In HT29 tumour cells, e.g., mRNA GSTA4, GSTP1, GSTM2, and GSTT2 were induced. In LT97 adenoma cells, GSTM3, GSTT2, and MGST3 were induced, whereas GSTA2, GSTT2, and catalase (CAT) were elevated in primary colon cells. Colon cells of different stages of carcinogenesis differed in post-transcriptional regulatory mechanisms because butyrate increased protein levels of different GST isoforms and total GST enzyme activity in HT29 cells, whereas in LT97 cells, GST protein levels and activity were slightly reduced. Because butyrate increased histone acetylation and phosphorylation of ERK in HT29 cells, inhibition of histone deacetylases and the influence on MAPK signalling are possible mechanisms of GST activation by butyrate. Functional consequences of this activation include a reduction of DNA damage caused by carcinogens like hydrogen peroxide or 4-hydroxynonenal (HNE) in butyrate-treated colon cells. Treatment of colon cells with the supernatant from an in vitro fermentation of inulin increased GST activity and decreased HNE-induced DNA damage in HT29 cells. Additional animal and human studies are needed to define the exact role of dietary fibre and butyrate in inducing GST activity and reducing the risk of colon cancer.
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PMID:Mechanisms of primary cancer prevention by butyrate and other products formed during gut flora-mediated fermentation of dietary fibre. 1938 51

Platinum drugs are among the most active and widely used agents in the treatment of different cancers. However, the great individual variability in both outcome and toxicity of platinum chemotherapy requires the identification of genetic markers that can be used to screen patients before treatment. In this study, 21 polymorphisms in 10 genes, the protein activities of which may be addressed in different aspects of cisplatin metabolism, were tested for correlations with efficacy and toxicity of cisplatin-cyclophosphamide regimen in 104 ovarian cancer patients. The glutathione S-transferase P1 (GSTP1) Ile105Val polymorphism was strongly associated with progression-free survival (chi(2)=12.12, P=0.002). The allelic status of the GSTA1 -69 C>T polymorphism correlated with the overall survival: patients with T/T genotype survived longer than C/C carriers (P=0.044). Thrombocytopenia, anemia and neuropathy were less frequent among patients with the GSTM1-null or GSTM3 intron 6 AGG/AGG genotypes. Severe neutropenia was associated with the TP53 72 Pro/Pro, XPD 312 Asp/Asn and XRCC1 399 Arg/Arg genotypes. A higher risk of nephrotoxicity was noted for patients with the heterozygous ERCC1 19007 T/C and 8092 C/A genotypes. No correlations were found between genotypes and complete tumor responses.
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PMID:Genetic polymorphisms and the efficacy and toxicity of cisplatin-based chemotherapy in ovarian cancer patients. 1978 80

Polycyclic aromatic hydrocarbons (PAHs) and other oil compounds are known to induce stress and impact health of marine organisms. Water-soluble fractions of oil contain components known to induce glutathione S-transferases (GSTs), one of the major classes of phase II detoxifying enzymes present in essentially all eukaryotic organisms. In this study, the transcriptional responses of six GSTs (GST pi, GST mu, GST omega, GST theta, GSY zeta and GST kappa) were examined in early larvae of Atlantic cod Gadus morhua exposed to five concentrations of dispersed oil (containing oil droplets and water-soluble fraction) and water-soluble fractions (WSF) of oil. When Atlantic cod larvae were exposed to WSF (containing 1.31+/-0.31microg summation PAH/L for 4 days), expression of GSTM3 and GSTO1 was significantly increased, whereas no differences in GST expression were observed in larvae exposed to a corresponding 50% lower amount of dispersed oil (containing 0.36+/-0.10 microg summation PAH/L for 4 days). The study suggest that although the oil clearly had severe negative effects on the larvae (i.e. concentration-dependent lethality and growth reduction), only minor effects on GST transcription could be observed using RNA obtained from pooled whole-larvae homogenates. This result indicates that the expression of these important detoxification enzymes is only moderately inducible at such an early developmental stage either reflecting low tolerance of cod larvae to dispersed oil or alternatively that using whole-larvae homogenates may have masked tissue-specific mRNA induction.
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PMID:Transcriptional effects on glutathione S-transferases in first feeding Atlantic cod (Gadus morhua) larvae exposed to crude oil. 2037 Nov

The glutathione S-transferases (GSTs), a family of phase II isozymes, detoxify several carcinogens. Genetic variations in GSTs have been associated with increased risk for cancer due to a heritable deficiency in detoxification pathways for environmental carcinogens. Conflicting findings have been reported about the association between constitutive GST polymorphisms and gliomas in different populations. The present case-control study examined 78 patients with primary glioma and 347 controls from Rio de Janeiro. DNA was isolated from whole blood, and four genetic polymorphisms (GSTM1, GSTM3, GSTT1, and GSTP1) were determined by PCR-RFLP. The distributions of the genotypic frequencies of these polymorphisms did not differ significantly between cases and controls and were as expected by Hardy-Weinberg equilibrium (P > 0.05). Risk analysis did not show an association between GSTs and primary glioma, suggesting that these polymorphisms do not influence the risk of primary glioma, at least in this population in Rio de Janeiro, Brazil.
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PMID:Lack of association between glutathione S-transferase polymorphisms and primary glioma in a case-control study in Rio de Janeiro. 2039 38

The benefits of ischemic preconditioning (IPC) in reducing ischemia/reperfusion injury (IRI) remain indistinct in human liver transplantation (LT). To further understand mechanistic aspects of IPC, we performed microarray analyses as a nested substudy in a randomized trial of 10-minute IPC in 101 deceased donor LTs. Liver biopsies were performed after cold storage and at 90 minutes postreperfusion in 40 of 101 subjects. Global gene expression profiles in 6 biopsy pairs in IPC and work standard organ recovery groups at both time points were compared using the Affymetrix GeneChip Human Gene 1.0 ST array. Transcripts with >1.5-fold change and P < 0.05 were considered significant. IPC altered expression of 82 transcripts in antioxidant, immunological, lipid biosynthesis, cell development and growth, and other groups. Real-time polymerase chain reaction and immunoblotting validated our microarray data. IPC-induced overexpression of glutathione S-transferase mu transcripts (GSTM1, GSTM3, GSTM4, and GSTM5) was accompanied by increased protein expression and may contribute to a decrease in oxidative stress. However, the increased expression of fatty acid synthase may increase oxidative stress, and tumor necrosis factor ligand superfamily member 10 may promote apoptosis. These changes, in combination with decreased expression of heparin-binding epidermal growth factor-like growth factor and insulin-like growth factor binding protein-1, both of which inhibit apoptosis, may increase IRI. In our study of deceased donor LT, IPC induces changes in gene expression, some of which are potentially beneficial but some which are potentially injurious. Thus, our findings of changes in gene expression mirror the outcomes in our clinical trial.
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PMID:Global gene expression profiles of ischemic preconditioning in deceased donor liver transplantation. 2044 Jul 68

The Kashmir Valley has an elevated incidence rate of esophageal cancer (EC). Several environmental and genetic factors have been suspected for development of EC. A case-control study was performed in 135 EC patients and 195 healthy controls to analyze association of polymorphisms in glutathione S-transferase (GST) mu (GSTM1), GST theta (GSTT1), GST pi (GSTP1), GSTM3, Cytochrome P450 (CYP)1A1, and CYP2E1 genes with susceptibility to EC as well as their interaction with environmental factors such as smoking and high consumption of salted tea in Kashmir valley. All subjects were genotyped through polymerase chain reaction restriction fragment length polymorphism. Data was statistically analyzed using the chi-square test and logistic regression model. Results showed that GSTP1313 val/val and CYP2E1c1c2 genotypes imparted risk for esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma [EADC; odds ratio (OR) = 3.24, 95% confidence interval (CI) = 1.30-8.05; OR = 4.20, 95% CI = 1.65-10.70], respectively. GSTM3AB genotype/B allele was found to be associated with low risk for EC. Tobacco smoking through hukka (water pipe) and consumption of salted tea itself were high risk factors for developing EC (OR = 21.44, 95% CI = 11.63-39.54; OR = 14.86, 95% CI = 8.41-26.24), and the risks were modulated through the interaction of GSTM3AB, GSTP1val/val genotypes. In conclusion, GSTP1val/val and CYP2E1c1c2 genotypes/c2 allele increased the risk of ESCC and EADC, respectively, in the Kashmiri population; whereas GSTM3AB genotype imparted lower risk for both ESCC and EADC.
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PMID:Association of xenobiotic metabolizing enzymes genetic polymorphisms with esophageal cancer in Kashmir Valley and influence of environmental factors. 2066 21


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