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)

The naturally occurring polycationic polyamines including putrescine, spermidine, and spermine play an important role in cell growth, differentiation, and gene expression. However, circulating polyamines are potential substrates for several oxidizing enzymes including copper-containing serum amine oxidase. These enzymes are capable of oxidizing serum polyamines to several toxic metabolites including aldehydes and H(2)O(2). In this study, we investigated the effects of polyamines as inducers of phase 2 enzymes and other genes that promote cell survival in a cell culture system in the presence of bovine serum. Spermidine and spermine (50 microM) increased NAD(P)H quinone oxidoreductase (NQO1) activity up to 3-fold in murine keratinocyte PE cells. Transcript levels for glutathione S-transferase (GST) A1, GST M1, NQO1, gamma-glutamylcysteine ligase regulatory subunit, and UDP-glucuronyltransferase 1A6 were significantly increased by spermidine and this effect was mediated through the antioxidant response element (ARE). The ARE from the mouse GST A1 promoter was activated about 9-fold by spermine and 5-fold by spermidine treatment, but could be inhibited by the amine oxidase inhibitor, aminoguanidine, suggesting that acrolein or hydrogen peroxide generated from polyamines by serum amine oxidase may be mediators for phase 2 enzyme induction. Elevations of ARE-luciferase expression and NQO1 enzyme activity by spermidine were not affected by catalase, while both were completely repressed by aldehyde dehydrogenase treatment. Direct addition of acrolein to PE cells induced multiple phase 2 genes and elevated nuclear levels of Nrf2, a transcription factor that binds to the ARE. Expression of mutant Nrf2 repressed the activation of the ARE-luciferase reporter by polyamines and acrolein. These results indicate that spermidine and spermine increase the expression of phase 2 genes in cells grown in culture through activation of the Nrf2-ARE pathway by generating the sulfhydryl reactive aldehyde, acrolein.
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PMID:Induction of phase 2 enzymes by serum oxidized polyamines through activation of Nrf2: effect of the polyamine metabolite acrolein. 1276 45

Nicotinamide adenine dinucleotide (phosphate) reduced:quinone oxidoreductase (NQO1) and glutathione S-transferase (GST) M1 are phase II enzymes important in response to oxidative stress, such as occurs during exposure to ozone. We examined the relationship between functionally significant polymorphisms in NQO1 (Pro187Ser) and GSTM1 (homozygous deletion) and asthma risk in children with high lifetime exposure to ozone. We enrolled children with asthma from the allergy referral clinic at a public pediatric hospital in Mexico City, together with their parents. We assayed for the Pro187Ser polymorphism in NQO1 using a polymerase chain reaction-restriction fragment length polymorphism assay and for the presence of GSTM1 by polymerase chain reaction among 218 case-parent triads. We did not find strong evidence of an association between NQO1 genotype alone and asthma risk. However, among subjects with homozygous deletion of GSTM1, carriers of a serine allele were at significantly reduced risk of asthma compared with Pro/Pro homozygotes (relative risk = 0.4; 95% confidence interval, 0.2-0.8). The p value for difference in relative risk for NQO1 by GSTM1 genotype = 0.013. These data are consistent with a protective effect of the NQO1 Ser allele in this population of GSTM1-null children with high ozone exposure.
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PMID:Nicotinamide adenine dinucleotide (phosphate) reduced:quinone oxidoreductase and glutathione S-transferase M1 polymorphisms and childhood asthma. 1296 68

Wild carp, Cyprinus carpio, were sampled in January and March 2000 in a section of the Anoia River (NE Spain) known to be polluted by estrogenic compounds. At each sampling time, three groups were distinguished: (1) apparently normal males; (2) apparently normal females; and (3) affected fish. The latter were characterized by the simultaneous development of male and female tissue in their gonads at a macroscopical level (six out of 31 fish sampled at this particular point), or testicular atrophy (three out of 31). Plasmatic and hepatic vitellogenin (VTG) levels and plasma testosterone (T) and estradiol (E2) were measured to observe the particular estrogenic response of the affected fish. Moreover, the response in the xenobiotic metabolizing capacity in liver was tested. This involved the analysis of mixed function oxygenase (MFO) system such as: total cytochrome P450 content, NAD(P)H cytochrome c reductases and the associated CYP1A1, EROD activity. Also, glutathione S-transferase (GST) and UDP-glucuronosyltransferase (UDPGT) as detoxifying enzymes were measured. Our results showed: (1) a highly variable VTG content in all fish groups; (2) an increase in sex hormones content in March for the female group; and (3) an enhanced xenobiotics metabolism in the affected fish group, measured as total cytochrome P450, EROD activity in the January survey and cytosolic GST in March. The observed increase in VTG, sex hormones and in most of the enzymatic activities from January to March that could also be attributed to higher water temperature.
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PMID:Feminization of wild carp, Cyprinus carpio, in a polluted environment: plasma steroid hormones, gonadal morphology and xenobiotic metabolizing system. 1455 96

NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a member of the short chain dehydrogenase/reductase (SDR) family, is responsible for the biological inactivation of prostaglandins. Sequence alignment within SDR coupled with molecular modeling analysis has suggested that Gln-15, Asp-36, and Trp-37 of 15-PGDH may determine the coenzyme specificity of this enzyme. Site-directed mutagenesis was used to examine the important roles of these residues. Several single mutants (Q15K, Q15R, W37K, and W37R), double mutants (Q15K-W37K, Q15K-W37R, Q15R-W37K, and Q15R-W37R), and triple mutants (Q15K-D36A-W37R and Q15K-D36S-W37R) were prepared and expressed as glutathione S-transferase (GST) fusion proteins in Escherichia coli and purified by GSH-agarose affinity chromatography. Mutants Q15K, Q15R, W37K, W37R, Q15K-W37K, and Q15R-W37K were found to be inactive or almost inactive with NADP+ but still retained substantial activity with NAD+. Mutant Q15K-W37R and mutant Q15R-W37R showed comparable activity for NAD+ and NADP+ with an increase in activity nearly 3-fold over that of the wild type. However, approximately 30-fold higher in K(m) for NADP+ than that of the wild type enzyme for NAD+ was found for mutants Q15K-W37R and Q15R-W37R. Similarly, the K(m) values for PGE(2) of mutants were also shown to increase over that of the wild type. Further mutation of Asp-36 to either an alanine or a serine of the double mutant Q15K-W37R (i.e., triple mutants Q15K-D36A-W37R and Q15K-D36S-W37R) rendered the mutants exhibiting exclusive activity with NADP+ but not with NAD+. The triple mutants showed a decrease in K(m) for NADP+ but an increase in K(m) for PGE(2). Further mutation at Ala-14 to a serine of a triple mutant (Q15K-D36S-W37R) decreased the K(m) values for both NADP+ and PGE(2) to levels comparable to those of the wild type. These results indicate that the coenzyme specificity of 15-PGDH can be altered from NAD+ to NADP+ by changing a few critical residues near the N-terminal end.
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PMID:Critical residues for the coenzyme specificity of NAD+-dependent 15-hydroxyprostaglandin dehydrogenase. 1459 57

Estradiol (E2) has been linked to both, protection against damage associated with chronic diseases or exposure to chemicals, and to the incidence of cancer. In its protective role, E2 appears to attenuate oxidative stress while as a carcinogen, E2 damages macromolecules via formation of reactive catechol metabolites. Alterations in the expression of antioxidant and xenobiotic metabolizing enzymes upon administration of pharmacological doses of E2 have been previously identified, but the effect of chronic exposure to low concentrations of E2 on activities of those enzymes in liver is unclear. The August-Copenhagen Irish (ACI) rat is more sensitive to estrogen-induced carcinogenesis than the Sprague-Dawley rat. Accordingly, the effect of treatment of female ACI and Sprague-Dawley rats for 6 weeks with E2 on activities of NAD(P)H quinone oxidoreductase 1 (NQO1), glutathione peroxidase, glutathione S-transferase (GST), phenol sulfotransferase (SULT1A1), cytochrome P450 (CYP450) and UDP-glucuronosyltransferase (UGT) was studied. Basal expression of these enzymes was similar in livers from both strains prior to exposure to E2. However, only NQO1 and GST activity was increased (3- and 2.5-fold, respectively) in liver cytosol of ACI rats treated with E2. In contrast, only NQO1 activity was increased modestly in livers of Sprague-Dawley rats. Other enzymes were not significantly affected in the livers of ACI or Sprague-Dawley rats following chronic treatment with E2. The selective induction of NQO1 and GST activity suggests that under physiological conditions, E2 may protect against oxidative stress via elevation of these antioxidant enzymes. The marked induction of NQO1 and GST in the ACI rat indicates a potential for this strain to be used as a model to study the E2-mediated modulation of these enzymes in tissues that are either sensitive to E2 carcinogenesis or to its protective effects.
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PMID:Induction of NAD(P)H quinone oxidoreductase and glutathione S-transferase activities in livers of female August-Copenhagen Irish rats treated chronically with estradiol: comparison with the Sprague-Dawley rat. 1467 40

We recently showed that zerumbone, a sesquiterpene found in subtropical ginger, suppresses colonic tumor marker formation in rats and induces apoptosis in colon cancer cell lines. In our present study, the anti-tumor initiating and promoting activities of zerumbone in mouse skin were evaluated using a conventional 2-stage carcinogenesis model. A single topical pretreatment to mouse skin (2 micromol) 24 hr before application of dimethylbenz[a]anthracene (0.2 micromol) markedly suppressed tumor incidence by 60% and the number of tumors by 80% per mouse. Repeated pretreatment (16 nmol) twice weekly during the post-initiation phase reduced the number of 12-O-tetradecanoylphorbol-13-acetate (TPA, 1.6 nmol)-induced tumors by 83% as well as their diameter by 57%. Multiple reverse transcriptase (RT) PCR experiments revealed that zerumbone (2 micromol) enhanced the mRNA expression level of manganese superoxide dismutase, glutathione peroxidase-1, glutathione S-transferase-P1 and NAD(P)H quinone oxidoreductase in the epidermis, but not that of cytochrome p450 1A1 or 1B1. Further, it diminished TPA-induced cyclooxygenase-2 protein expression and phosphorylation of extracellular signal-regulated kinase 1/2, while pretreatment(s), in either the priming or activation stage or both, reduced double TPA application-induced hydrogen peroxide formation and edema induction by 29% to 86%, respectively. Histologic examination revealed that pretreatment(s) with zerumbone suppressed leukocyte infiltration and reduced proliferating cell nuclear antigen-labeling indices. Together, our results indicate that zerumbone is a promising agent for the prevention of both tumor initiating and promoting processes, through induction of anti-oxidative and phase II drug metabolizing enzymes as well as attenuation of proinflammatory signaling pathways.
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PMID:Zerumbone, a sesquiterpene in subtropical ginger, suppresses skin tumor initiation and promotion stages in ICR mice. 1512 79

The effects of in vivo exposure to a natural and synthetic estrogen upon three hepatic phase II enzyme pathways involved in cellular protection against reactive intermediates were investigated in the largemouth bass (Micropterus salmoides). The pathways analyzed included glutathione S-transferases (GST), glutathione (GSH) biosynthesis and NAD(P)H-dependent quinone reductase (QR). Following exposure to 17-beta estradiol (E2, a model natural estrogen; 2 mg/kg, i.p.) or 4-nonylphenol (NP, a model synthetic estrogen; 5 mg/kg and 50 mg/kg, i.p.), serum vitellogenin concentrations in male fish were markedly increased. Exposure to E2 did not affect steady-state GST-A mRNA expression, although GST catalytic activity toward 1-chloro 2,4-dinitrobenzene (CDNB) was elevated at 48 h post-injection. In addition, the rates of bass liver GST-4-hydroxy-2-nonenal (GST-4HNE) conjugation were elevated by E2 exposure at all timepoints. In contrast, exposure to NP decreased steady-state GST-A mRNA levels, but did not alter GST catalytic activities. Hepatic GSH levels were not significantly affected by exposure to either compound, although a trend towards increased GSH biosynthesis was observed with both compounds. Although bass liver quinone reductase catalyzed 2,6-dichloroindophenol (DCP) reduction, unlike in rodents, these catalytic activities were not inhibited by dicoumarol. Exposure to 5 mg/kg NP significantly increased hepatic QR activities. Collectively, our data suggest that exposure to E2 or NP alters the ability of largemouth bass to biotransform environmental chemicals through glutathione S-transferase and quinone reductase catalytic pathways.
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PMID:Effects of 17-beta estradiol and 4-nonylphenol on phase II electrophilic detoxification pathways in largemouth bass (Micropterus salmoides) liver. 1517 48

Excess production of H2O2 has been implicated in oncogenesis. The object of the present study was twofold: first, to determine the influence of chronic estradiol (E2) on the activities of selected hepatic antioxidant enzymes in female ACI rats, a strain that is highly sensitive to the induction of estrogen dependent mammary tumors; secondly, to evaluate the actions of dietary clofibrate, a peroxisome proliferator, on activities of these enzymes in control and E2-treated ACI rats. Enzymes selected for study were: NAD(P)H quinone oxidoreductase (NQO1), glutathione S-transferase (GST) and glutathione peroxidase (GPx). Cytosolic catalase (CAT) was also measured as an index of peroxisome proferation in control and E2- treated animals. E2 was administered chronically over 6 and 12 week periods from cholesterol pellet implants containing either 1 or 3 mg E2. Animals were fed AIN-76A diets with or without 0.4% clofibrate over the experimental period. NQO1 and GST but not GPx were induced to varying degrees (NQO1 about 300%, and GST about 45-97%) by chronic E2-treatment. E2-induced increases in these activities were completely prevented in rats exposed to dietary clofibrate. Dietary clofibrate also caused slight but significant reductions in baseline activities of NQO1, GST and GPx in control animals. Serum E2 levels, increased approximately 540% in a dose-dependent manner, and were not altered by dietary clofibrate. It is concluded that chronic E2 treatment markedly induces several important hepatic antioxidant enzymes in female ACI rats, and induction of these activities by E2 is inhibited completely by dietary clofibrate. Both of these actions have the potential to markedly influence the profile of E2 metabolites exported from the liver to E2 sensitive extrahepatic tissues and influence the initiation and progression of hormone-dependent tumors.
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PMID:Dietary clofibrate inhibits induction of hepatic antioxidant enzymes by chronic estradiol in female ACI rats. 1521 7

On June 9, 2003, we started free genetic tests of eight polymorphisms for health checkup examinees who attended a basic course at Nagoya University Hospital. They were informed of their genotypes within four weeks after blood donation for research purposes. The genotypes were those of alcohol dehydrogenase 2 (ADH2) Arg47His, aldehyde dehydrogenase 2 (ALDH2) Glu487Lys, NAD(P)H: quinone oxidoreductase (NQO1) C609T, glutathione S transferase M1 (GSTM1), glutathione S-transferase T1 (GSTT1), interleukin-1B (IL-1B) C-31T, and tumor necrosis factor A (TNF-A) T-1031C, angiotensin-converting enzyme (ACE) Ins/Del. In the first three months, 227 (89.4%) out of 254 examinees participated in the free tests, having been informed of the research aims, after which they consented to our use of research data. To date, there have been no complaints from the participants, indicating that the announcement of polymorphism genotypes may be accepted differently from that of hereditary disease genotypes.
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PMID:Genotype announcement in a genetic polymorphism study for health checkup examinees at Nagoya University Hospital. 1527 67

Genetic polymorphisms have the potential to predict disease susceptibility. This may be especially useful among individuals with a high-risk lifestyle, so that the genotyping could be adopted for disease prevention through modifications toward a lower-risk lifestyle. We started a program of free genotype announcements in a polymorphism study among health checkup examinees at the Nagoya University Hospital on June 9, 2003. Since such announcements remain controversial for fear of unexpected harmful effects and counseling system, the accumulated evidence on the association between disease risk and genotypes announcements in our study was reviewed in this article. The genotypes used were those of alcohol dehydrogenase 2 (ADH2) Arg47His, aldelhyde dehydlrogenase 2 (ALDH2) Glu487Lys, NAD(P)H: quinone oxidoreductase (NQO1) C609T, glutathlione S transferase M1 (GSTM1), glutathione S-transferase T1 (GSTT1), interleukin-1B (IL-1B) C-31T, and tumor necrosis factor A (TNF-A) T-1031C, angiotensin converting enzyme (ACE) Ins/Del. Since showed a potential for widespread use in health checkups, the information on the above polymorphisms seems worth documenting. Although there have been no complaints from the participants to date, careful treatments are requested.
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PMID:Associations between disease risk and eight polymorphisms adopted for genotype announcements at Nagoya University Hospital. 1527 68


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