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)

Many studies have evaluated the cancer -preventive potential of individual bioactives from tomatoes and broccoli, but few have examined them within the context of a whole food. Male Copenhagen rats were fed diets containing 10% standard tomato powder, tomato enriched with lycopene or total carotenoids, standard broccoli floret, broccoli sprouts, or broccoli enriched with indole glucosinolates or selenium for 7 days. All broccoli diets increased the activity of colon quinone reductase (NQO1). Indole glucosinolate-enriched broccoli and selenium-enriched broccoli increased hepatic NQO1 and cytochrome P450 1A activity (P < 0.05). Standard broccoli and lycopene-enriched tomato diets down-regulated prostatic glutathione S-transferase P1 mRNA expression. Different tomato diets resulted in altered hepatic accumulation of lycopene, phytofluene, and phytoene. These results demonstrate that the bioactive content of vegetables affects both tissue content of bioactives and activity of detoxification enzymes. Enhancing bioactive content of tomatoes and broccoli may enhance efficacy in the prevention of prostate cancer.
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PMID:Feeding tomato and broccoli powders enriched with bioactives improves bioactivity markers in rats. 1965 Jun 32

Phase II enzymes are induced primarily through the common electrophile response element (EpRE) signaling. Studies performed in different cell types and with different inducer appear to indicate variation in the upstream signaling pathways involved in the induction of these phase II genes. Nonetheless, whether variation in signaling among phase II genes in the same cell with the same inducer is unclear. This study is designed to answer this question using human bronchial epithelial cells (HBE1 cells) as a model and screening with a variety of protein kinase inhibitors with varying degrees of specificity. Two electrophiles, 4-hydroxynonenal (HNE) and acrolein, induced the expression of phase II genes (GCLC, GCLM, NQO1, NQO2, HO-1, and GSTM-1). Nrf2 silencing significantly decreased the induction of all of these genes, confirming the involvement of Nrf2-EpRE signaling. ERK and p38MAPK inhibitors had no effect, while a JNK inhibitor abrogated the GCLC and GCLM induction by HNE, but not that by acrolein. Among the PKC inhibitors used, one eliminated gene induction by HNE and acrolein, while two others showed no effects. One PI3K inhibitor decreased the induction of GCLM, NQO1, NQO2 and HO-1, but not GCLC and GST-M1; on the other hand, the inhibitory effects of another PI3K inhibitor on gene induction seems to be gene- and inducer- specific. In conclusion, our data suggest that although phase II genes are coordinately induced through Nrf2-EpRE signaling by electrophiles, the upstream signaling pathways involved are gene- and inducer- specific. It is also suggested that commercial kinase inhibitors may produce non-specific effects on phase II gene expression via mechanisms unrelated to their purported specificity.
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PMID:Signaling pathways involved in phase II gene induction by alpha, beta-unsaturated aldehydes. 1965 97

Our previous study demonstrated that methanolic extract of Inula helenium (Elecampane) has the potential to induce detoxifying enzymes such as NAD(P)H:(quinone acceptor) oxidoreductase 1 (EC 1.6.99.2) (NQO1, QR) activity and glutathione S-transferase (GST) and found isoalantolactone and alantolactone as the active components. In this study we investigated the detoxifying enzyme-inducing potential of isoalantolactone, which is present in I. helenium and has a structure similar to that of alantolactone. The compound induced QR in a dose-dependent manner in both Hepa1c1c7 cells and its mutant BPRc1 cells lacking the arylhydrocarbon receptor translocator. Like with most phase 2 enzyme inducers, other phase 2 detoxifying enzymes, including GST, glutathione reductase, gamma-glutamylcysteine synthetase, and heme oxygenase-1, were also induced by isoalantolactone in a dose-dependent manner in the cultured cells. Furthermore, isoalantolactone caused a proportionate increase in luciferase activity depending upon concentration and exposure time in the reporter assay in which HepG2-C8 cells, transfectants carrying antioxidant response element-luciferase gene, were used. The nuclear translocation of nuclear factor-E2-related factor 2 (Nrf2) was stimulated by the compound and attenuated by phosphatidylinositol 3-kinase inhibitors such as LY294002 and wortmannin. In conclusion, isoalantolactone is a candidate for chemoprevention and acts as potent phase 2 enzyme inducer by stimulating the accumulation of Nrf2 in the nucleus.
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PMID:Isoalantolactone from Inula helenium caused Nrf2-mediated induction of detoxifying enzymes. 1985 67

A protective role of glucosinolates in prostate cancer development might be mediated by the induction of biotransformation enzymes. These enzymes, enhancing the elimination of carcinogens from the body, are known to be polymorphic. Therefore, we evaluated whether a possible association between glucosinolate intake and prostate cancer risk is modified by polymorphisms in GSTT1, GSTM1, GSTA1, GSTP1, or NOQ1 genes. A case-control study including 248 prostate cancer cases and 492 matched controls was nested in the prospective European Prospective Investigation into Cancer and Nutrition-Heidelberg cohort. At baseline, participants provided dietary and lifestyle data and blood samples, which were used for genotyping and measurement of serum glutathione S-transferase-alpha concentration. Odds ratios and 95% confidence intervals were calculated by conditional logistic regression. We found an inverse association of glucosinolate intake with prostate cancer risk (adjusted odds ratio, 0.72 per 10 mg/d increment; 95% confidence interval, 0.53-0.96). Stratification by genotype showed significantly reduced risks for subjects with wild-type of NQO1 (C609T) compared with CT or TT carriers (P(interaction) = 0.04). Those with deletions in both GSTM1 and GSTT1 genes combined had a significantly reduced risk with increasing glucosinolate intake (P(interaction) = 0.01). There was no effect modification of glucosinolate intake and cancer risk by GSTA1 (G-52A) or GSTP1 (A313G) genotype, but serum glutathione S-transferase-alpha concentrations were inversely associated with prostate cancer. This study showed that the inverse association between glucosinolate intake and prostate cancer risk was modified by NQO1 (C609T) and GSTM1 and GSTT1 deletion polymorphisms. This information will help to further elucidate the mechanism of action of potentially protective substances in vivo.
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PMID:Dietary glucosinolate intake, polymorphisms in selected biotransformation enzymes, and risk of prostate cancer. 2005 32

Our preliminary experiment demonstrated that a n-hexane/EtOH (9:1, volume) extract of Glycyrrhiza uralensis (licorice) caused a significant induction of NAD(P)H:oxidoquinone reductase (NQO1), one of the well-known phase 2 detoxifying enzymes. We isolated dehydroglyasperin C (DGC) as a potent phase 2 enzyme inducer from licorice. DGC induced NQO1 both in wild-type murine hepatoma Hepa1c1c7 and ARNT-lacking BPRc1 cells, indicating that the compound is a monofunctional inducer. The compound induced not only NQO1 but also some other phase 2 detoxifying/antioxidant enzymes, such as glutathione S-transferase, gamma-glutamylcysteine synthase, glutathione reductase, and heme oxygenase 1. Similar to most monofunctional inducers, DGC caused the accumulation of Nrf2 in the nucleus in dose- and time-dependent manners and thereby activated expression of phase 2 detoxifying enzymes. It also resulted in a dose-dependent increase in the luciferase activity in the reporter assay, in which HepG2-C8 cells transfected with antioxidant response element (ARE)-luciferase construct were used, suggesting that the induction of phase 2 detoxifying and antioxidant enzymes could be achieved through the interaction of Nrf2 with the ARE sequence in the promoter region of their genes.
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PMID:Dehydroglyasperin C isolated from licorice caused Nrf2-mediated induction of detoxifying enzymes. 2008 9

1-Bromopropane (1-BP) was introduced as an alternative to ozone-depleting solvents. However, it was found to exhibit neurotoxicity, reproductive toxicity, and hepatotoxicity in rodents and neurotoxicity in human. However, the mechanisms underlying the toxicities of 1-BP remain elusive. The present study investigated the role of oxidative stress in 1-BP-induced hepatotoxicity using nuclear factor erythroid 2-related factor 2 (Nrf2)-null mice. Groups of 24 male Nrf2-null mice and 24 male wild-type (WT) C57BL/6J mice were each divided into three groups of eight and exposed to 1-BP at 0, 100, or 300 ppm for 8 h/day for 28 days by inhalation. Liver histopathology showed significantly larger area of necrosis in Nrf2-null mice relative to WT mice at the same exposure level. Nrf2-null mice also had greater malondialdehyde (MDA) levels, higher ratio of oxidized glutathione/reduced form of glutathione, and lower total glutathione content. The constitutive level and the increase in ratio per exposure level of glutathione S-transferase (GST) activity were lower in the liver of Nrf2-null mice than WT mice. Exposure to 1-BP at 300 ppm increased the messenger RNA levels of heme oxygenase-1 (HO-1), glutamate-cysteine ligase modifier subunit (GcLm), glutamate-cysteine synthetase (GcLc), glutathione reductase, and NAD(P)H: quinone oxidoreductase 1 (NQO1) in WT mice but not in Nrf2-null mice except for GST Yc2. Nrf2-null mice were more susceptible to 1-BP-induced hepatotoxicity. That oxidative stress plays a role in 1-BP hepatotoxicity is deduced from the low expression levels and activities of antioxidant enzymes and high MDA levels in Nrf2-null mice.
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PMID:Increased susceptibility of Nrf2-null mice to 1-bromopropane-induced hepatotoxicity. 2021 40

Xenobiotic-metabolizing genes (e.g., Cytochromes P450, GST, NAT2, and NQO1), folate metabolism genes (e.g., MTHFR and MTRR), and major histocompatibility complex genes (e.g., HLA-DQA1) play multiple roles in the organism functioning. In addition, AB0 is the most clinically significant high-polymorphic gene in transfusion and transplantation medicine. Epidemiological data show that allele frequencies of these genes exhibit ethnic and geographic diversity. Besides, little is known about frequency distribution of the major polymorphic variants in native Russians. We developed biological microchips that allow us to analyze a spectrum of allelic variants in 12 different genes: CYP1A1, CYP2D6, CYP2C9, CYP2C19, GSTT1, GSTM1, MTHFR, MTRR, NQO1, NAT2, HLA-DQA1, and AB0. Using this composite methodological platform we have studied 352 DNA samples from healthy native Russian volunteers. The allelic frequencies of gene polymorphisms obtained are close to allelic frequencies observed in some European populations, as published earlier. These data were used in comparative studies to determine predisposition to tuberculosis, lymphoma, and leukemia in adults and to childhood acute leukemia. The HLA-DQA1 and AB0 allele frequencies were used to estimate forensic population parameters for these loci.
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PMID:Microarray-based detection of CYP1A1, CYP2C9, CYP2C19, CYP2D6, GSTT1, GSTM1, MTHFR, MTRR, NQO1, NAT2, HLA-DQA1, and AB0 allele frequencies in native Russians. 2037 52

Our previous study demonstrated that methanolic extract of Chrysanthemum zawadskii Herbich var. latilobum Kitamura (Compositae) has the potential to induce detoxifying enzymes such as NAD(P)H:(quinone acceptor) oxidoreductase 1 (EC 1.6.99.2) (NQO1, QR) and glutathione S-transferase (GST). In this study we further fractionated methanolic extract of Chrysanthemum zawadskii and investigated the detoxifying enzyme-inducing potential of each fraction. The fraction (CZ-6) shown the highest QR-inducing activity was found to contain (+)-(3S,4S,5R,8S)-(E)-8-acetoxy-4-hydroxy-3-isovaleroyloxy-2-(hexa-2,4-diynyliden)-1,6-dioxaspiro [4,5] decane and increased QR enzyme activity in a dose-dependent manner. Furthermore, CZ-6 fraction caused a dose-dependent enhancement of luciferase activity in HepG2-C8 cells generated by stably transfecting antioxidant response element-luciferase gene construct, suggesting that it induces antioxidant/detoxifying enzymes through antioxidant response element (ARE)-mediated transcriptional activation of the relevant genes. Although CZ-6 fraction failed to induce hepatic QR in mice over the control, it restored QR activity suppressed by CCl(4) treatment to the control level. Hepatic injury induced by CCl(4) was also slightly protected by pretreatment with CZ-6. In conclusion, although CZ-6 fractionated from methanolic extract of Chrysanthemum zawadskii did not cause a significant QR induction in mice organs such as liver, kidney, and stomach, it showed protective effect from liver damage caused by CCl(4).
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PMID:Protection by Chrysanthemum zawadskii extract from liver damage of mice caused by carbon tetrachloride is maybe mediated by modulation of QR activity. 2046 Nov 96

Hard metal consisting of a mixture of tungsten carbide (WC) and metallic cobalt (Co) was evaluated as a possible carcinogen in humans by IARC in 2003. Studies have suggested that nuclear factor erythroid 2-related factor 2 (Nrf2) constitutes one of the chemical-sensing and transcription systems that play an essential role(s) in chemical toxicity, carcinogenesis, and pathological processes. To elucidate the mechanisms of health hazards of WC-Co, effects of nano-WC-Co particles on Nrf2 signaling pathway were investigated in the present study in a JB6 cell line. After a 5 h treatment with nano-WC-Co particles, Nrf2 was released from Keap1 in the cytoplasm and translocated into the nucleus. Enzymatic activities of Nrf2 target genes, including glutathione S-transferase (GST) and NAD(P)H:quinone oxidoreductase 1 (NQO1), increased at 24 and 48 h after the treatment. Studies using reactive oxygen species (ROS) sensitive dyes indicated that ROS were produced in nano-WC-Co particle-treated cells. Pretreatment of the cells with catalase, but not sodium formate, resulted in a significant inhibitory effect on nano-WC-Co particle-induced Nrf2 target gene activation. These findings suggest that activation of Nrf2 and its downstream genes may be initiated by ROS generation, and ROS may act as a major contributor in nano-WC-Co particle-induced adverse health effects.
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PMID:Tungsten carbide-cobalt particles activate Nrf2 and its downstream target genes in JB6 cells possibly by ROS generation. 2052 45

Many phytochemicals possess cancer-preventive properties, some putatively through phase II metabolism-mediated mutagen/oxidant quenching. We applied human lung cells in vitro to investigate the effects of several candidate phytopreventive agents, including green tea extracts (GTE), broccoli sprout extracts (BSE), epigallocatechin gallate (EGCG), sulforaphane (SFN), phenethyl isothiocyanate (PEITC), and benzyl isothiocyanate (BITC), on inducing phase II enzymes glutathione S-transferase P1 (GSTP1) and NAD(P)H:quinone oxidoreductase 1 (NQO1) at mRNA and protein levels. Primary normal human bronchial epithelial cells (NHBE), immortalized human bronchial epithelial cells (HBEC), and lung adenocarcinoma cells (A549) were exposed to diet-achievable levels of GTE and BSE (0.5, 1.0, 2.0 mg/L), or individual index components EGCG, SFN, PEITC, BITC (0.5, 1.0, 2.0 micromol/L) for 24 h, 48 h, and 6 d, respectively. mRNA assays employed RNA-specific quantitative RT-PCR and protein assays employed Western blotting. We found that in NHBE cells, while GSTP1 mRNA levels were slightly but significantly increased after exposure to GTE or BSE, NQO1 mRNA increased to 2- to 4-fold that of control when exposed to GTE, BSE, or SFN. Effects on NQO1 mRNA expression in HBEC cells were similar. NQO1 protein expression increased up to 11.8-fold in SFN-treated NHBE cells. Both GSTP1 and NQO1 protein expression in A549 cells were constitutively high but not induced under any condition. Our results suggest that NQO1 is more responsive to the studied chemopreventive agents than GSTP1 in human lung cells and there is discordance between single agent and complex mixture effects. We conclude that modulation of lung cell phase II metabolism by chemopreventive agents requires cell- and agent-specific discovery and testing.
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PMID:Candidate dietary phytochemicals modulate expression of phase II enzymes GSTP1 and NQO1 in human lung cells. 2055 99


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