Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epidemiologic studies have found an inverse association between consumption of tomato products and the risk of certain types of cancers. However, the mechanisms underlying this relationship are not completely understood. One mechanism that has been suggested is induction of phase II detoxification enzymes. Expression of phase II enzymes is regulated by the antioxidant response element (ARE) and the transcription factor Nrf2 (nuclear factor E2-related factor 2). In this study, we determined the role of this transcription system in the induction of phase II enzymes by carotenoids. We found that in transiently transfected cancer cells, lycopene transactivated the expression of reporter genes fused with ARE sequences. Other carotenoids such as phytoene, phytofluene, beta-carotene, and astaxanthin had a much smaller effect. An increase in protein as well as mRNA levels of the phase II enzymes NAD(P)H:quinone oxidoreductase and gamma-glutamylcysteine synthetase was observed in nontransfected cells after carotenoid treatment. Ethanolic extract of lycopene containing unidentified hydrophilic derivatives of the carotenoid activated ARE with similar potency to lycopene. The potency of the carotenoids in ARE activation did not correlate with their effect on intracellular reactive oxygen species and reduced glutathione level, which may indicate that ARE activation is not solely related to their antioxidant activity. Nrf2, which is found predominantly in the cytoplasm of control cells, translocated to the nucleus after carotenoid treatment. Interestingly, part of the translocated Nrf2 colocalized with the promyelocytic leukemia protein in the promyelocytic leukemia nuclear bodies. The increase in phase II enzymes was abolished by a dominant-negative Nrf2, suggesting that carotenoid induction of these proteins depends on a functional Nrf2 and the ARE transcription system.
Mol Cancer Ther 2005 Jan
PMID:Carotenoids activate the antioxidant response element transcription system. 1565 64

The herbicide paraquat (PQ) forms reactive oxygen species during enzymatic activation. We examined the effect of PQ on the relative levels of gene expression of antioxidant enzymes and glutathione (GSH) status in lungs of rats exposed to 20 mg/kg PQ. At 16 h after PQ intake, the mRNA expression level of glutathione reductase (GR) showed the greatest increase, and those of catalase (CAT) and manganese-superoxide dismutase (MnSOD) showed more modest increases. In contrast, PQ had little or no effect on the levels of mRNAs for copper/zinc-superoxide dismutase (CuZnSOD) and glutathione peroxidase (GPX). These findings indicate that CAT and MnSOD are coordinated and play a major role in removal of oxidants. On the other hand, PQ caused a significant increase in the GSH level in the lungs, but not in the liver. This increase in the lungs was, at least in part, caused by stimulation of the gamma-glutamylcysteine synthetase gene. However, the expression of GPX mRNA was not stimulated as described above. Because GSH is a substrate for GPX and serves as a scavenger of hydroxyl radicals, the increase in GSH as well as GR expression may be insignificant. This imbalance may be a result of oxidative stress due to PQ.
Int J Mol Med 2005 Apr
PMID:Changes in gene expression level for defense system enzymes against oxidative stress and glutathione level in rat administered paraquat. 1575 33

Glutamate-cysteine ligase catalytic subunit (GCLC) is regulated transcriptionally by Nrf1 and Nrf2. tert-Butylhydroquinone (TBH) induces human GCLC via Nrf2-mediated trans activation of the antioxidant-responsive element (ARE). Interestingly, TBH also induces rat GCLC, but the rat GCLC promoter lacks ARE. This study examined the role of Nrf1 and Nrf2 in the transcriptional regulation of rat GCLC. The baseline and TBH-mediated increase in GCLC mRNA levels and rat GCLC promoter activity were lower in Nrf1 and Nrf2 null (F1 and F2) fibroblasts than in wild-type cells. The basal protein and mRNA levels and nuclear binding activities of c-Jun, c-Fos, p50, and p65 were lower in F1 and F2 cells and exhibited a blunted response to TBH. Lower c-Jun and p65 expression also occurs in Nrf2 null livers. Levels of other AP-1 and NF-kappaB family members were either unaffected (i.e., JunB) or increased (i.e., Fra-1). Overexpression of Nrf1 and Nrf2 in respective cells restored the rat GCLC promoter activity and response to TBH but not if the AP-1 and NF-kappaB binding sites were mutated. Fra-1 overexpression lowered endogenous GCLC expression and rat GCLC promoter activity, while Fra-1 antisense had the opposite effects. In conclusion, Nrf1 and Nrf2 regulate rat GCLC promoter by modulating the expression of key AP-1 and NF-kappaB family members.
Mol Cell Biol 2005 Jul
PMID:Nrf1 and Nrf2 regulate rat glutamate-cysteine ligase catalytic subunit transcription indirectly via NF-kappaB and AP-1. 1598 9

Glutathione S-transferase (GST) zeta (GSTZ1-1) plays a significant role in the catabolism of phenylalanine and tyrosine, and a deficiency of GSTZ1-1 results in the accumulation of maleylacetoacetate and its derivatives maleylacetone (MA) and succinylacetone. Induction of GST subunits was detected in the liver of Gstz1(-/-) mice by Western blotting with specific antisera and high-performance liquid chromatography analysis of glutathione affinity column-purified proteins. The greatest induction was observed in members of the mu class. Induction of NAD(P)H:quinone oxidoreductase 1 and the catalytic and modifier subunits of glutamate-cysteine ligase was also observed. Many of the enzymes that are induced in Gstz1(-/-) mice are regulated by antioxidant response elements that respond to oxidative stress via the Keap1/Nrf2 pathway. It is significant that diminished glutathione concentrations were also observed in the liver of Gstz1(-/-) mice, which supports the conclusion that under normal dietary conditions, the accumulation of electrophilic intermediates such as maleylacetoacetate and MA results in a high level of oxidative stress. Elevated GST activities in the livers of Gstz1(-/-) mice suggest that GSTZ1-1 deficiency may alter the metabolism of some drugs and xenobiotics. Gstz1(-/-) mice given acetaminophen demonstrated increased hepatotoxicity compared with wild-type mice. This toxicity may be attributed to the increased GST activity or the decreased hepatic concentrations of glutathione, or both. Patients with acquired deficiency of GSTZ1-1 caused by therapeutic exposure to dichloroacetic acid for the clinical treatment of lactic acidosis may be at increased risk of drug- and chemical-induced toxicity.
Mol Pharmacol 2006 Feb
PMID:Deficiency of glutathione transferase zeta causes oxidative stress and activation of antioxidant response pathways. 1627 72

Multidrug resistance of cancer cells can be intrinsic or acquired and occurs due to various reasons, including increased repair of genotoxic damage, an enhanced ability to remove/detoxify chemical agents, or reactive oxygen species (ROS), and repression of apoptosis. Human A2780/100 ovarian carcinoma cells exhibit resistance to DNA cross-linking agents, chlorambucil (Cbl), cisplatin (Cpl), melphalan (Mel), and ionizing radiation (IR) compared to the parental cell line, A2780. In the present study, we show that when A2780/100 and A2780 cells were treated with Cbl, GSH was extruded via methionine or cystathionine-inhibitable transporters of intact plasma membrane. GSH loss was followed by a rapid increase in ROS levels. The resistant, but not drug-sensitive cells normalized the intracellular GSH concentration along with ROS levels within 4-6 h after Cbl addition, and survived drug treatment. Normalization of GSH and ROS levels in A2780/100 cells correlated well with elevated gamma-glutamylcysteine synthetase (gamma-GCS) activity (10 +/- 1.8-fold over A2780 cells). Ectopic overexpression of the gamma-GCS heavy subunit in drug-sensitive cells nearly restored GSH and ROS to pre-treatment levels consequently increased cellular resistance to genotoxic agents (Cbl, Cpl, and IR), while overexpression of gamma-GCS light subunit had no such effects. Thus, in our model system, drug-resistant cells have the inherent ability to maintain increased gamma-GCS activity, reestablish physiological GSH, and cellular redox state and maintain increased cellular resistance to DNA cross-linking agents and IR.
Mol Carcinog 2006 Sep
PMID:Enhanced gamma-glutamylcysteine synthetase activity decreases drug-induced oxidative stress levels and cytotoxicity. 1649 84

This study investigated the role of cellular antioxidant defense mechanisms in modulating the neurotoxicity of domoic acid (DomA), by using cerebellar granule neurons (CGNs) from mice lacking the modifier subunit of glutamate-cysteine ligase (Gclm). Glutamate-cysteine ligase (Glc) catalyzes the first and rate-limiting step in glutathione (GSH) biosynthesis. CGNs from Gclm (-/-) mice have very low levels of GSH and are 10-fold more sensitive to DomA-induced toxicity than CGNs from Gclm (+/+) mice. GSH ethyl ester decreased, whereas the Gcl inhibitor buthionine sulfoximine increased DomA toxicity. Antagonists of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate receptors and of N-methyl-D-aspartate (NMDA) receptors blocked DomA toxicity, and NMDA receptors were activated by DomA-induced l-glutamate release. The differential susceptibility of CGNs to DomA toxicity was not due to a differential expression of ionotropic glutamate receptors, as evidenced by similar calcium responses and L-glutamate release in the two genotypes. A calcium chelator and several antioxidants antagonized DomA-induced toxicity. DomA caused a rapid decrease in cellular GSH, which preceded toxicity, and the decrease was primarily due to DomA-induced GSH efflux. DomA also caused an increase in oxidative stress as indicated by increases in reactive oxygen species and lipid peroxidation, which was subsequent to GSH efflux. Astrocytes from both genotypes were resistant to DomA toxicity and presented a diminished calcium response to DomA and a lack of DomA-induced L-glutamate release. Because polymorphisms in the GCLM gene in humans are associated with low GSH levels, such individuals, as well as others with genetic conditions or environmental exposures that lead to GSH deficiency, may be more susceptible to DomA-induced neurotoxicity.
Mol Pharmacol 2006 Dec
PMID:Neurotoxicity of domoic Acid in cerebellar granule neurons in a genetic model of glutathione deficiency. 1700 Aug 61

Glutathione depletion represents a potentially important strategy to sensitize tumors to cytotoxic drugs. l-Buthionine-(R,S)-sulfoximine (l-BSO) has been studied in both preclinical and early clinical trials, but limitation on its access has led to a search for alternatives. Using a 3D molecular model of human gamma-glutamylcysteine synthetase (gamma-GCS(H)), the major subunit of the rate-limiting GSH synthetic enzyme, we virtually screened the National Cancer Institute chemical database to identify compounds that could bind to and potentially inhibit gamma-GCS(H). We identified 51 test chemicals, all with structures very distinct from l-BSO. We subjected these compounds to biological assays measuring gamma-GCS(H) inhibition and glutathione (GSH) depletion. Among 10 novel gamma -GCS inhibitors identified, 4 compounds depleted glutathione in cells, and 2 with related structures sensitized tumor cells to melphalan treatment. This work validates the use of model-based database mining and identified inhibitors of gamma-GCS(H) with novel chemical structures.
Mol Pharmacol 2007 Apr
PMID:Structure-based identification of novel human gamma-glutamylcysteine synthetase inhibitors. 1722 71

This study aims to investigate the role of gamma-glutamylcysteine synthetase (gamma-GCS), the rate-limiting enzyme for glutathione (GSH) synthesis, in the c-Myc-dependent response to antineoplastic agents. We found that specific c-Myc inhibition depleted cells of GSH by directly reducing the gene expression of both heavy and light subunits of the gamma-GCS enzyme and increased their susceptibility to antineoplastic drugs with different mechanisms of action, such as cisplatin (CDDP), staurosporine (STR), and 5-fluorouracil (5-FU). The effect caused by c-Myc inhibition on CDDP and STR response, but not to 5-FU treatment, is directly linked to the impairment of the gamma-GCS expression, because up-regulation of gamma-GCS reverted drug sensitivity, whereas the interference of GSH synthesis increased drug susceptibility as much as after c-Myc down-regulation. The role of gamma-GCS in the c-Myc-directed drug response depends on the capacity of drugs to trigger reactive oxygen species (ROS) production. Indeed, although 5-FU exposure did not induce any ROS, CDDP- and STR-induced oxidative stress enhanced the recruitment of c-Myc on both gamma-GCS promoters, thus stimulating GSH neosynthesis and allowing cells to recover from ROS-induced drug damage. In conclusion, our data demonstrate that the gamma-GCS gene is the downstream target of c-Myc oncoprotein, driving the response to ROS-inducing drugs. Thus, gamma-GCS impairment might specifically sensitize high c-Myc tumor cells to chemotherapy.
Mol Pharmacol 2007 Oct
PMID:Gamma-glutamylcysteine synthetase mediates the c-Myc-dependent response to antineoplastic agents in melanoma cells. 1762 13

Growth hormone overexpression increases growth and consequently increases the metabolic rate in fishes. Therefore, the objective of this study was to evaluate the effects of growth hormone overexpression in zebrafish Danio rerio in terms of growth, oxygen consumption, reactive oxygen species production, lipid hydroperoxide content, antioxidant enzyme activity and glutamate-cysteine ligase catalytic subunit gene expression. The employed models were wild type and transgenic (hemizygous and homozygous) zebrafish expressing the Odonthestes argentinensis growth hormone gene directed by the Cyprinus carpio beta-actin promoter. Higher growth parameters were observed in the hemizygous group. The homozygous group possessed higher oxygen consumption and reactive oxygen species production. Growth hormone transgenesis causes a decrease in glutamate-cysteine ligase catalytic subunit expression, an enzyme responsible for glutathione synthesis. Although the lipid hydroperoxide content was similar between groups, we demonstrate that growth hormone overexpression has the potential to generate oxidative stress in fishes.
Comp Biochem Physiol B Biochem Mol Biol 2008 Jan
PMID:Metabolic rate and reactive oxygen species production in different genotypes of GH-transgenic zebrafish. 1793 20

Nuclear erythroid-related factor 2 (Nrf2), a redox-sensitive transcription factor, is involved in transcriptional regulation of many antioxidant genes, including glutamate-cysteine ligase (GCL). Cigarette smoke (CS) is known to cause oxidative stress and deplete glutathione (GSH) levels in alveolar epithelial cells. We hypothesized that resveratrol, a polyphenolic phytoalexin, has antioxidant signaling properties by inducing GSH biosynthesis via the activation of Nrf2 and protects lung epithelial cells against CS-mediated oxidative stress. Treatment of human primary small airway epithelial and human alveolar epithelial (A549) cells with CS extract (CSE) dose dependently decreased GSH levels and GCL activity, effects that were associated with enhanced production of reactive oxygen species. Resveratrol restored CSE-depleted GSH levels by upregulation of GCL via activation of Nrf2 and also quenched CSE-induced release of reactive oxygen species. Interestingly, CSE failed to induce nuclear translocation of Nrf2 in A549 and small airway epithelial cells. On the contrary, Nrf2 was localized in the cytosol of alveolar and airway epithelial cells due to CSE-mediated posttranslational modifications such as aldehyde/carbonyl adduct formation and nitration. On the other hand, resveratrol attenuated CSE-mediated Nrf2 modifications, thereby inducing its nuclear translocation associated with GCL gene transcription, as demonstrated by GCL-promoter reporter and Nrf2 small interfering RNA approaches. Thus resveratrol attenuates CSE-mediated GSH depletion by inducing GSH synthesis and protects epithelial cells by reversing CSE-induced posttranslational modifications of Nrf2. These data may have implications in dietary modulation of antioxidants in treatment of chronic obstructive pulmonary disease.
Am J Physiol Lung Cell Mol Physiol 2008 Mar
PMID:Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells. 1816 1


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