Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.5.1.18 (glutathione S-transferase)
 22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Some six or so physiological systems, essential to normal mammalian life, are involved in poisoning; an intoxication that causes severe injury to any one of them could be life threatening. Reversible chemical reactions showing Scatchard-type binding are exemplified by CO, CN- and cyclodiene neurotoxin insecticide intoxications, and by antigen-antibody complex formation. Haemoglobin (Hb) molecular biology accounts for the allosteric co-operativity and other characteristics of CO poisoning, CN- acts as a powerful cytochrome oxidase inhibitor, and antigen binding in a deep antibody cleft between two domains equipped with epitopes for antigen-binding groups explains hapten-specific immune reactions. Covalent chemical reactions with second-order (SN2) kinetics characterize Hg and Cd poisonings, the reactions of organophosphates and phosphonates with acetylcholinesterase and neurotoxic esterase and the reaction sequence whereby Paraquat accepts electrons and generates superoxide under aerobic conditions. Indirect carcinogens require cytochrome P450 activation to form DNA adducts in target-organ DNA and cause cancer, but a battery of detoxifying enzymes clustered with the P450 system must be overcome. Thus, S-metabolism competes ineffectively with target DNA for reactive vinyl chloride (VC) metabolites, epoxide hydrolase is important to the metabolism and carcinogenicity of alfatoxins and polycyclic aromatic hydrocarbons (benzo[a]pyrene, etc.), and the non-toxic 2-naphthylhydroxylamine N-glucuronide acts as a transport form in 2-naphthylamine bladder cancer. VC liver-cancer pathogenesis is explicable in terms of the presence of the glutathione S-transferase detoxifying system in hepatocytes and its absence from the fibroblastic elements, and of the VC concentrations reaching the liver by different administrative routes. In VC carcinogenicity, chemical reactions give imidazo-cyclization products with nucleoside residues of target DNA, and in benzene leukaemia, Z,Z-muconaldehyde forms cyclic products containing a pyrrole residue linked to purine. Increased HbCO concentrations reduce the O2-carrying capacity of the blood, and the changed shape of the O2-Hb dissociation curve parallels disturbance in O2 unloading. CN- acts on electron transport and paralyses respiration. In telodrin poisoning, preconvulsive glutamine formation abstracts tricarboxylic acid intermediates incommensurately with normal cerebral respiration. Antigen-antibody complexing depletes the antibody titre, available against infection. At high doses of Cd, Cd-thionein filtered through the kidneys is reabsorbed and tubular lesions produced. Some organophosphate insecticides promote irreversible acetylcholinesterase phosphorylation and blockade nerve function, and others react with neurotoxic esterase to cause delayed neuropathy. The evidence for Paraquat pulmonary poisoning suggests a radical mechanism involving three interrelated cyclic reaction stages. The action of N- and O8 (O substituent in 6-position of the purine) demethylases explains deletion mechanisms for DNA-alkyl adducts. DNA-directed synthesis in the presence of ultimate carcinogens provides for an estimation of misincorporations, which implicate the same transversions as those found by direct mutagenicity testing. Chemical carcinogens recognize tissue-sensitive cells and modify their heritable genetic complement. Oncoproteins encoded by activated oncogenes signal the transformation of normal cells into cancer cells. The importance of the H-ras oncogene and p53 tumour-suppressor gene is stressed. Antidotal action is analysed; for example, parenteral glutamine administration to telodrin-intoxicated rats restores the depleted cerebral glutamate level and prevents seizures. Glutamate acts as anticonvulsant in petit mal epilepsy. In general, therefore, the reaction of the toxicant-related substance with the relevant target-tissue macromolecule accounts for the biochemical/biological events at a cellular level a
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PMID:Toxic action/toxicity. 1074 Aug 94

A cotton (Gossypium hirsutum L.) control and NaCl-tolerant cell line (cv Coker 312) were grown on media with or without NaCl in the presence or absence of paraquat, buthionine sulfoximine, and oxidized glutathione. On medium with 150 mM NaCl the NaCl-tolerant cell line exhibited no reduction in growth, whereas a 96% reduction was observed in the control line. The NaCl-tolerant cell line that was grown on 150 mM NaCl exhibited significantly greater catalase (341%), peroxidase (319%), glutathione reductase (287%), ascorbate peroxidase (450%), [gamma]-glutamylcysteine synthetase (224%), and glutathione S-transferase (500%) activities than the intolerant control. The NaCl-tolerant cell line had a significantly lower dehydroascorbic acid/ascorbic acid ratio. Paraquat reduced growth by 20 and 53.7%, respectively, in the NaCl-tolerant and control cell line. The NaCl-tolerant cell line also showed a slight tolerance to buthionine sulfoximine. In the buthionine sulfoximine experiments reduced glutathione restored growth in both cell lines, whereas oxidized glutathione restored growth only in the NaCl-tolerant cell line. These data indicate that the NaCl-tolerant cell line exhibited a cross-tolerance to a variety of stress variables and had a more active ascorbate-glutathione cycle.
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PMID:Antioxidant Response to NaCl Stress in a Control and an NaCl-Tolerant Cotton Cell Line Grown in the Presence of Paraquat, Buthionine Sulfoximine, and Exogenous Glutathione. 1222 22

The effect of paraquat on the activities of antioxidant defense and detoxifying enzymes of the white-rot fungus Funalia trogii was determined. Paraquat increased the activities of glutathione reductase (GR), glutathione transferase (GT) and superoxide dismutase at 1 mmol/L, while at 0.1 mmol/L it did not affect the activity of GR and GT. It depressed the catalase activity and the amount of glutathione at all concentrations used. Paraquat treatment probably depresses antioxidant defense components such as catalase and glutathione.
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PMID:Effect of paraquat on cellular defense enzymes and glutathione level of Funalia trogii. 1242 20

Paraquat (PQ) is a cationic nonselective bipyridyl herbicide widely used to control weeds and grasses in agriculture. Epidemiologic studies indicate that exposure to pesticides can be a risk factor in the incidence of Parkinson's disease (PD). A strong correlation has been reported between exposure to paraquat and PD incidence in Canada, Taiwan, and the United States. This correlation is supported by animal studies showing that paraquat produces toxicity in dopaminergic neurons of the rat and mouse brain. However, it is unclear how paraquat triggers toxicity in dopaminergic neurons. Based on the prooxidant properties of paraquat, it was hypothesized that paraquat may induce oxidative stress-mediated toxicity in dopaminergic neurons. To explore this possibility, dopaminergic SH-SY5Y cells were treated with paraquat, and several biomarkers of oxidativestress were measured. First, a specific dopamine transporter inhibitor GBR12909 significantly protected SY5Y cells against the toxicity of paraquat, indicating that paraquat exerts its toxicity by a mechanism involving the dopamine transporter (DAT). Second, paraquat increased intracellular levels of reactive oxygen species (ROS), but decreased the levels of glutathione. Third, paraquat inhibited glutathione peroxidase activity, but did not affect glutathione reductase activity. On the other hand, paraquat increased GST activity by 24 h, after which GST activity returned to the control value at 48 h. Fourth, paraquat dissipated mitochondrial transmembrane potential (MTP). Fifth, paraquat produced increases of malondialdehyde (MDA) and protein carbonyls, as well as DNA fragmentation, indicating oxidative damage to major cellular components. Sixth, paraquat increased the protein level of heme oxygenase-1 (HO-1). Taken together, these findings verify our hypothesis that paraquat produces oxidative stress-mediated toxicity in SH-SY5Y cells. Thus, current findings suggest that paraquat may induce the pathogenesis of dopaminergic neurons through oxidative stress.
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PMID:The bipyridyl herbicide paraquat produces oxidative stress-mediated toxicity in human neuroblastoma SH-SY5Y cells: relevance to the dopaminergic pathogenesis. 1626 88

Paraquat (PQ) is a well-known pneumotoxicant and provides an established model of oxidative stress. This study focused on the transcriptional response to PQ-driven oxidative stress in rat lungs during an early phase post-injection. Rats were sacrificed at 3 h and 24 h after PQ injection (i.p., 20 mg/kg b.w.), and at 3 h after a second injection (i.p., 20 mg/kg b.w.). The left lungs were rapidly excised and used immediately for RNA preparation. The lung tissues did not show any pathological damage microscopically. Differential expression of RNAs in the lung at 3 h was investigated using a DNA array system. Fifteen genes showed a >1.7-fold change in expression level, which was confirmed by real-time PCR. Five genes related to oxidative stress, TRX, HO-1, GST-Yc, NQO-1, and RL/IF-1, and one gene, CLK3, whose function is unknown, showed a significant increase in their expression due to PQ injection. Two genes, HO-1 and NQO-1, that showed 3- and 2-fold increases at 3-h post-injection, were localized by immunohistochemistry. HO-1 was expressed in the bronchial epithelial cells, some type II cells and macrophages of control lungs, and the cells, especially the bronchial epithelial cells, were strongly stained 3 h following PQ treatment. Immunohistochemical analysis of NQO-1 also showed an increase in positive staining in the bronchial epithelial cells of PQ-treated lung sections. The expression of CYP2C6, 2C7, and 2C12, which are specific to or dominant in female liver, decreased markedly, while the male-specific CYP2C13 and 2C11 showed an increase or no effect. Further investigation is needed to clarify the role of these CYP2C family genes on the early phase of PQ toxicity. These results indicate that the acclimation to oxidative stress is already a highly complex process at the onset of PQ-induced damage and that the genes described herein may prove to be major contributors to the subsequent pulmonary fibrosis.
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PMID:Gene expression in rat lungs during early response to paraquat-induced oxidative stress. 1632 9

Dissolved organic matter from natural sources (DNOM) is omnipresent in aquatic ecosystems. Besides affecting bioavailability of substances including xenobiotics, it directly influences physico-chemistry of the habitat and there is increasing evidence for it is interaction with organisms. We investigated direct and interacting effects of DNOM from three sources, Lake Valkea-Kotinen, Svartberget Brook, and Lake Fuchskuhle with the herbicide paraquat on the oligochaete worm Lumbriculus variegatus. Bioavailability of paraquat to L. variegates as well as activities of antioxidative enzymes catalase (CAT) and peroxidase (POD) and biotransformation enzyme soluble glutathione S-transferase (sGST) were assessed without and in the presence of DNOM. Furthermore, metabolic heat dissipation due to the exposure was quantified. Uptake of paraquat into the worms was concentration dependently reduced by DNOM, and with differences concerning the DNOM sources. sGST and CAT responded with increased activities to DNOM (5 and 25 mg C l-1) and paraquat (5.0, 50, and 500 microg l-1) separately. Paraquat at 5.0 microg l-1 and DNOM in combination caused increased activities of sGST, especially at 5 mgC l-1, but inhibition of CAT activities. The latter probably occurred due to saturation of the enzyme. Changes in enzyme activities were independent from the source of DNOM. Increasing DNOM concentrations raised metabolic heat dissipation in L. variegatus with maximum at 3h of exposure. In the combined treatments, metabolic heat dissipation changed more due to the source of DNOM than due to the bioavailability of paraquat.
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PMID:Bioaccumulation of paraquat by Lumbriculus variegatus in the presence of dissolved natural organic matter and impact on energy costs, biotransformation and antioxidative enzymes. 1682 45

Paraquat (PQ)-induced pulmonary toxicity is characterized by initial development of pulmonary edema, infiltration of inflammatory cells, and damage to the alveolar epithelium, which may progress to severe fibrosis. However, the exact role of PQ in the progression of the pathogenesis has not been clearly established. To understand the mechanism of PQ in pulmonary toxicity, we developed an animal model of PQ-induced lung injury by intranasal instillation of PQ solution using C57Black/6J mice. Twenty microliters of PQ solution (0.01, 0.01, and 0.04 mg/mouse) was applied through the nares, and the same amount of vehicle was applied in control mice. The pathological progression of lung pathology in our mouse model was very similar to that of patients suffering from PQ poisoning. The lungs of some animals exposed to PQ showed acute fulmination, resulting in death from 5 days post-exposure, but others showed a more protracted injury, resulting in typical pulmonary fibrosis at 3 weeks. Using this PQ-poisoned mouse model, we examined the gene expression at the initial destructive phase (within 5 days) that fibrosis has not completely developed. We prepared RNAs after 6h, 24h, and 5 days and examined the changes of the expression levels for 45 selected genes. The genes showing >2-fold increase at 6h or a time-dependent decrease during this experimental period may be the early markers for the destructive phase. These genes are Mt1, Mt2, Hmox1, Gcl, GR, IL-6, IL-13, Txn1, Fas, FasL, Lpin2, Mmp1a, Mmp12, Sfp-B, Sfp-D, CAT, EC-SOD, GST, and Pltp. On the other hand, the genes involved in the development of fibrosis, such as procollagen, Fn1, Eln, SMA, and Mmp9, Timp1 were significantly increased on day 5, not at 6h nor at 24h, after PQ treatment (the late marker). The genes showing a significant increase (Mmp3 and Mmp8) or decrease (VEGFA) at 24h and 5 days and not at 6h may be also the late markers. These changes in gene expression, which are equalled to functional activities of proteins, will be the targets for future studies focused on the development on PQ-induced pulmonary damage.
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PMID:Mouse model of paraquat-poisoned lungs and its gene expression profile. 1721 68

GSTs from adult Drosophila melanogaster have been partially purified using three different affinity chromatography media and separated by 2-DE. Nine GSTs have been identified by MALDI-TOF MS. In the absence of special treatments, eight GSTs could be positively identified. These were DmGSTs D1 (the dominant Delta isoform which was present in five protein zones of differing pI) and D3 (and possibly also D5); the Epsilon-class GSTs E3, 6, 7 and 9 and a previously uncharacterised, probable member of the class, CG16936. The Sigma-class DmGSTS1 was prominent. DmGSTD2 was detected only after pretreatment of the flies with Phenobarbital (PhB). Treatment with Paraquat (PQ) led to an increase in the total GST activity, as measured with the substrates 1-chloro-2,4-dinitrobenzene (CDNB) and 3,4-dichloro-nitrobenzene (DCNB) and an increase in the relative amounts of the D1, D3, E6 and E7 isoforms. PhB treatment led to increases in the relative amounts of the D1, D2, E3, E6, E7 and E9 isoforms detected with a possible depression in the relative amount of GSTS1. CG16936 was unaffected by either pretreatment.
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PMID:Studies on the glutathione S-transferase proteome of adult Drosophila melanogaster: responsiveness to chemical challenge. 1790 71

In the central nervous system oxidative stress has been implicated in the pathology of several neurological disorders. The ability to withstand reactive oxygen species and oxidative stress are essential for survival and therefore all aerobic cells are endowed with chemical and enzymatic antioxidative defense systems. The purpose of the present study was to investigate the antioxidative response at the transcriptional level following exposure of primary astrocytes to a pro-oxidant, Paraquat (PQ). This was done by investigating the time-dependent expression of selected genes encoding the antioxidative enzymes Mn- and CuZn superoxide dismutase (SOD) and catalase as well as the transcription factor component AP-1. Paraquat induced the expression of Mn- and CuZn SOD, catalase and decreases the expression of c-jun (a part of AP-1). Furthermore, the gene expression profiles were investigated after exposure to PQ using a commercial cDNA membrane array containing 207 genes from key oxidative stress pathways. The gene expression pattern clearly indicated that 60 microM PQ for 48 h induces genes related to oxidative stress, detoxification, mitotic arrest, DNA repair, and apoptosis. The PQ (48 h)-induced expressions of genes identified in cDNA array were confirmed by Northern blot analysis, which revealed a statistical significant up-regulation of genes involved in oxidative stress, detoxification, and DNA repair/synthesis and includes heme oxygenase-1 (11-fold), NAD(P)H dehydrogenase (8-fold), glutathione S-transferase P (7-fold), glucose-regulated 78-kDa protein (7-fold), glucose-regulated 75-kDa protein (6-fold), and growth-arrest and DNA-damage-inducible protein 45 (4.5-fold) and minor changes for heat shock 10-kDa protein, NADPH-cytochrome P450 reductase, heme oxygenase-2, proliferating cell nuclear antigen, and Bcl-2-associated death promoter. Thus, we could demonstrate a PQ-inducible effect of the mRNA of antioxidative enzymes, as well as the mRNAs of possible enzymes involved in the protection against oxidative stress.
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PMID:Characterization of the transcriptional profile in primary astrocytes after oxidative stress induced by Paraquat. 1793 86

The effects of the herbicides 1,1'-dimethyl-4,4'-bipyridylium dichloride (paraquat), 3,6-dichloro-2-metoxybenzoic acid (dicamba) and 2,4-dichlorophenoxyacetic acid (2,4-D) on cell growth of non-green potato tuber calli are described. We attempted to relate the effects with toxicity, in particular the enzymes committed to the cellular antioxidant system. Cell cultures were exposed to the herbicides for a period of 4 weeks. Cellular integrity on the basis of fluorescein release was strongly affected by 2,4-D, followed by dicamba, and was not affected by paraquat. However, the three herbicides decreased the energy charge, with paraquat and 2,4-D being very efficient. Paraquat induced catalase (CAT) activity at low concentrations (1 microM), whereas at higher concentrations, inhibition was observed. Dicamba and 2,4-D stimulated CAT as a function of concentration. Superoxide dismutase (SOD) activity was strongly stimulated by paraquat, whereas dicamba and 2,4-D were efficient only at higher concentrations. Glutathione reductase (GR) activity was induced by all the herbicides, suggesting that glutathione and glutathione-dependent enzymes are putatively involved in the detoxification of these herbicides. Paraquat slightly inhibited glutathione S-transferase (GST), whereas 2,4-D and dicamba promoted significant activation. These results indicate that the detoxifying mechanisms for 2,4-D and dicamba may be different from the mechanisms of paraquat detoxification. However, the main cause of cell death induced by paraquat and 2,4-D is putatively related with the cell energy charge decrease.
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PMID:Comparative effects of the herbicides dicamba, 2,4-D and paraquat on non-green potato tuber calli. 1843 36


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