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)

Nuclear receptors such as constitutive androstane receptor (CAR) and pregnane X receptor (PXR) regulate the transcription of cytochromes P450 and transporters. We investigated whether quantitative and functional changes in CAR and PXR could affect bilirubin detoxification in chronic arthritis. The CAR mRNA level was significantly decreased in the liver of mice with collagen-induced arthritis (CIA) compared with control mice. In normal mice treated with CAR agonists, relatively rapid elimination of bilirubin was observed after its intravenous injection. Next, we investigated the effects of CAR on bilirubin-detoxifying enzymes and transporters in arthritis. The mRNA levels of organic anion transporter peptide (OATP) 2, glutathione S-transferase (GST) A1, and GSTA2 were decreased in CIA mice, whereas the mRNA levels of OATP4, UDP-glucuronosyl-transferase 1A1, and multidrug resistance-associated protein 2 remained unchanged. The protein levels and transport activities of OATP2 were also decreased in CIA mice. Furthermore, the CIA mice actually exhibited retarded elimination of bilirubin after its intravenous injection. These results indicate that alterations to CAR during arthritis affect the elimination of bilirubin because of changes in multiple bilirubin-detoxifying enzymes and transporters.
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PMID:Effects of alterations in CAR on bilirubin detoxification in mouse collagen-induced arthritis. 1710 61

Inflammatory bowel diseases, chronic inflammatory disorders, have been strongly linked with an increased risk of the development of colorectal cancer. Understanding the etiology of these diseases is pivotal for the improvement of currently available strategies to fight against inflammatory bowel disease, and more importantly, to prevent colorectal cancer. Nuclear factor-erythroid 2-related factor 2 (Nrf2) has been known to be a transcriptional factor which plays a crucial role in cytoprotection against inflammation, as well as oxidative and electrophilic stresses. The aim of this study is to investigate the role of Nrf2 in the regulation of dextran sulfate sodium (DSS)-induced experimental colitis in mice. Nrf2-deficient mice were found to be more susceptible to DSS-induced colitis as shown by the increased severity of colitis following 1 week of oral administration of 1% DSS. The increased severity of colitis in Nrf2(-/-) mice was found to be associated with decreased expression of antioxidant/phase II detoxifying enzymes including heme-oxygenase-1, NAD(P)H-quinone reductase-1, UDP-glucurosyltransferase 1A1, and glutathione S-transferase Mu-1. In addition, proinflammatory mediators/cytokines such as COX-2, inducible nitric oxide, interleukin 1beta, interleukin 6, and tumor necrosis factor alpha were significantly increased in the colonic tissues of Nrf2(-/-) mice compared with their wild-type (Nrf2+/+) counterparts. In summary, we show for the first time that mice lacking Nrf2 are more susceptible to DSS-induced colitis. Our data suggests that Nrf2 could play an important role in protecting intestinal integrity, through regulation of proinflammatory cytokines and induction of phase II detoxifying enzymes.
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PMID:Nrf2-deficient mice have an increased susceptibility to dextran sulfate sodium-induced colitis. 1717 49

Maternal tobacco consumption is considered as a risk factor for nonsyndromic oral clefts. However, this risk is moderate and may be modulated by genetic susceptibilities, including variants of the TGFA, TGFB3 and MSX1 developmental genes and polymorphisms of genes of the CYP (1A1, 2E1) and GST (M1, T1) families involved in metabolic pathways of tobacco smoke compounds. This French case-control study (1998-2001; 240 nonsyndromic cases, 236 controls) included a case-parent design (175 triad-families) that made it possible to distinguish the direct effect of the child's genotype and maternally mediated effects. Maternal smoking during the first trimester of pregnancy was not associated with the oral cleft risk in this population, but we observed statistically significant increased risks associated with maternal exposure to environmental tobacco smoke (ETS). No variant of any of the three developmental genes was significantly associated with oral cleft. The fetal CYP1A1*2C variant allele was associated with a statistically significant decreased risk, compared with the homozygous wild-type: relative risk = 0.48, 95% confidence interval: 0.2, 1.0. Suggestive reduced risks were also observed for the maternal CYP1A1*2C allele and the fetal CYP2E1*5 allele. The GSTM1 and GSTT1 deletions appeared to play no role. Our findings suggest some interactions, with the strongest between ETS and CYP1A1 or MSX1 and between maternal smoking and CYP2E1. We did not confirm the maternal smoking-infant GSTT1 null interaction previously reported by other investigators.
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PMID:Genetic susceptibilities in the association between maternal exposure to tobacco smoke and the risk of nonsyndromic oral cleft. 1869 32

Cytochrome P450 (CYP) 1A1, glutathione S-transferase (GST) M1, and GSTT1 gene polymorphisms have been shown to be associated with several diseases. In this study, CYP1A1 MspI, GSTM1 and GSTT1 gene polymorphisms were investigated in 134 Ovambo and 207 Mongolians, and the results were compared with those from previous studies. Using polymerase chain reaction/restriction fragment length polymorphism (PCR-RFLP) the frequency of CYP1A1 MspI mutation was determined. The multiplex PCR was used to determine the GSTM1 and GSTT1 polymorphism. The frequencies of wild-type, heterozygous variant and homozygous variant of the CYP1A1 MspI genotypes were 72.4%, 25.4% and 2.2%, and 22.7%, 55.6% and 21.7% in the Ovambos and Mongolians, respectively. The frequencies of GSTM1 (null) and GSTT1 (null) genotypes were 11.2% and 35.8%, and 46.4% and 25.6% in the Ovambos and Mongolians, respectively. The CYP1A1 MspI and GSTT1 (null) genotype distribution of the Ovambos was similar to that of African-Americans and some Caucasians. In contrast, the GSTM1 (null) genotype distribution was different from that of all other populations. Among Mongolians, the CYP1A1 MspI polymorphism showed the highest mutation frequencies, GSTM1 (null) was similar to that of East Asians, and GSTT1 (null) was different from that of almost all the Asians examined.
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PMID:Cytochrome P450 1A1, glutathione S-transferases M1 and T1 polymorphisms in Ovambos and Mongolians. 1926 25

A reduction in endogenously generated reactive oxygen species in vivo delays benzo(a)pyrene (BaP)-accelerated atherosclerosis, as revealed in hypercholesterolemic mice overexpressing Cu/Zn-superoxide dismutase (SOD) and/or catalase. To understand the molecular events involved in this protective action, we studied the effects of Cu/Zn-SOD and/or catalase overexpression on BaP detoxification and on aryl hydrocarbon receptor (AhR) expression and its target gene expression in mouse aortic endothelial cells (MAECs). Our data demonstrate that overexpression of Cu/Zn-SOD and/or catalase leads to an 18- to 20-fold increase in the expression of AhR protein in MAECs. After BaP exposure, the amount of AhR binding to the cytochrome P450 (CYP) 1A1 promoter was significantly greater, and the concentrations of BaP reactive intermediates were significantly less in MAECs overexpressing Cu/Zn-SOD and/or catalase than in wild-type cells. In addition, the BaP-induced CYP1A1 and 1B1 protein levels and BaP-elevated glutathione S-transferase (GST) activity were significantly higher in these transgenic cells, in parallel with elevated GSTp1, CYP1A1, and CYP1B1 mRNA levels, compared to wild-type MAECs. Moreover, knockdown of AhR with RNA interference diminished the Cu/Zn-SOD and catalase enhancement of CYP1A1 expression, GST activity, and BaP detoxification. These data demonstrate that overexpression of Cu/Zn-SOD and/or catalase is associated with upregulation of AhR and its target genes, such as xenobiotic-metabolizing enzymes.
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PMID:Overexpression of Cu/Zn-superoxide dismutase and/or catalase accelerates benzo(a)pyrene detoxification by upregulation of the aryl hydrocarbon receptor in mouse endothelial cells. 1966 5

Estrogen is a well-known risk factor for breast cancer. Current models of breast cancer risk prediction are based on cumulative estrogen exposure but do not directly reflect mammary estrogen metabolism or address genetic variability between women in exposure to carcinogenic estrogen metabolites. We are proposing a mathematical model that forecasts breast cancer risk for a woman based on three factors: (1) estimated estrogen exposure, (2) kinetic analysis of the oxidative estrogen metabolism pathway in the breast, and (3) enzyme genotypes responsible for inherited differences in the production of carcinogenic metabolites. The model incorporates the main components of mammary estrogen metabolism, i.e. the conversion of 17beta-estradiol (E(2)) by the phase I and II enzymes cytochrome P450 (CYP) 1A1 and 1B1, catechol-O-methyltransferase (COMT), and glutathione S-transferase P1 (GSTP1) into reactive metabolites, including catechol estrogens and estrogen quinones, such as E(2)-3,4-Q which can damage DNA. Each of the four genes is genotyped and the SNP data used to derive the haplotype configuration for each subject. The model then utilizes the kinetic and genotypic data to calculate the amount of E(2)-3,4-Q carcinogen as ultimate risk factor for each woman. The proposed model extends existing models by combining the traditional "phenotypic" measures of estrogen exposure with genotypic data associated with the metabolic fate of E(2) as determined by critical phase I and II enzymes. Instead of providing a general risk estimate our model would predict the risk for each individual woman based on her age, reproductive experiences as well as her genotypic profile.
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PMID:Estrogen exposure, metabolism, and enzyme variants in a model for breast cancer risk prediction. 1971 49

Arctic seabirds are exposed to a wide range of halogenated organic contaminants (HOCs). Exposure occurs mainly through food intake, and many pollutants accumulate in lipid-rich tissues. Little is known about how HOCs are biotransformed in arctic seabirds. In this study, we characterized biotransformation enzymes in chicks of northern fulmars (Fulmarus glacialis) and black-legged kittiwakes (Rissa tridactyla) from Kongsfjorden (Svalbard, Norway). Phase I and II enzymes were analyzed at the transcriptional, translational and activity levels. For gene expression patterns, quantitative polymerase chain reactions (qPCR), using gene-sequence primers, were performed. Protein levels were analyzed using immunochemical assays of western blot with commercially available antibodies. Liver samples were analyzed for phase I and II enzyme activities using a variety of substrates including ethoxyresorufin (cytochrome (CYP)1A1/1A2), pentoxyresorufin (CYP2B), methoxyresorufin (CYP1A), benzyloxyresorufin (CYP3A), testosterone (CYP3A/CYP2B), 1-chloro-2,4-nitrobenzene (CDNB) (glutathione S-transferase (GST)) and 4-nitrophenol (uridine diphosphate glucuronyltransferase (UDPGT)). In addition, the hydroxylated (OH-) polychlorinated biphenyls (PCBs) were analyzed in the blood, liver and brain tissue, whereas the methylsulfone (MeSO(2)-) PCBs were analyzed in liver tissue. Results indicated the presence of phase I (CYP1A4/CYP1A5, CYP2B, and CYP3A) and phase II (GST and UDPGT) enzymes at the activity, protein and/or mRNA level in both species. Northern fulmar chicks had higher enzyme activity than black-legged kittiwake chicks. This in combination with the higher SigmaOH-PCB to parent PCB ratios suggests that northern fulmar chicks have a different biotransformation capacity than black-legged kittiwake chicks.
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PMID:Biotransformation of PCBs in Arctic seabirds: characterization of phase I and II pathways at transcriptional, translational and activity levels. 2017 33

There is evidence that onions and garlic protect against cancer in humans. It has been suggested that this effect is partly due to the organosulfur compounds in Allium vegetables and that these substances act through induction of phase II detoxification enzymes. Here, we hypothesized that alk(en)yl thiosulfates, sodium n-propyl thiosulfate (NPTS), and sodium 2-propenyl thiosulfate (2PTS), which were identified in onions and garlic, respectively, may induce phase II enzymes. Therefore, rat hepatoma cells (H4IIE) were cultured with 1 to 100 micromol/L of NPTS or 2PTS for 48 hours at 37 degrees C; and the activities and messenger RNA (mRNA) expression levels of phase II enzymes in H4IIE cells were investigated. The effects of diallyl trisulfide and tert-butylhydroquinone, known as phase II inducers, were also examined as positive controls and compared with the responses of NPTS and 2PTS. Quinone reductase (QR) activity and mRNA expression levels of QR and epoxide hydrolase 1 were significantly increased by 2PTS (P < .05-.005). In particular, QR activity was increased at a relatively low concentration of 2PTS (10 micromol/L). However, glutathione S-transferase activity and mRNA expression levels of glutathione S-transferase A5 and uridine diphosphate glucuronosyl transferase 1A1 were not changed by 2PTS. In contrast, NPTS did not affect the activities and mRNA expression levels of these phase II enzymes. These results show that 2PTS can induce phase II enzymes, and its inductive effect is comparable or superior to that of diallyl trisulfide and tert-butylhydroquinone.
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PMID:Sodium 2-propenyl thiosulfate derived from garlic induces phase II detoxification enzymes in rat hepatoma H4IIE cells. 2065 Mar 52

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

In the present study, the distribution and nature of specific xenobiotic-metabolizing enzymes has been studied. Immunocytochemistry revealed the specific isoenzyme profile of the different cell types in mouse, rat and human skin. Constitutive levels of cytochrome P-450 1A1/A2 (CYP1A1/A2), CYP2B1/B2 and glutathione S-transferase were concentrated in the epidermis and sebaceous glands of all three species. Enzymic digestion followed by density gradient centrifugation resulted in fractions enriched in sebaceous cells, basal cells and differentiated keratinocytes. The basal and sebaceous cells of mouse skin were found to contain high levels of CYP1A1/A2, which was induced approximately 10-fold following beta-naphthoflavone pretreatment. These findings suggest that xenobiotic metabolizing enzymes exhibit a similar qualitative distribution between the cell types of rodent and human skin and that these cell types may be isolated for use in mechanistic studies involving cutaneous metabolism and toxicity.
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PMID:Distribution of xenobiotic metabolizing enzymes in skin. 2069 50


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