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)

The nitrosated form of cimetidine (Tagamet), nitrosocimetidine (NC), belongs to a group of nitrosoamidines in which the mutagenic and carcinogenic properties of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) have been studied in detail. The common mechanism of action of these compounds is that nucleophilic atoms can attack their iminocarbon, thereby leading to the formation of alkyldiazohydroxide and, subsequently of an alkylating and mutagenic diazonium ion. A competitive, non-mutagenic pathway involves denitrosation, which is strongly dependent on pH and can be enhanced by glutathione transferase. The influence of different thiols (e.g. glutathione and the L- and D-forms of N-acetylcysteine (L-NAC and D-NAC respectively] at different extra- and intracellular concentrations on the mutagenicity of these nitrosoamidines in V79 cells has been studied in the present investigation. The results demonstrate that the mutagenicity of MNNG and ENNG is highly dependent on where their reaction with thiols takes place. Thus, an increase in the intracellular glutathione level in combination with treatment with MNNG (or ENNG) in thiol-free medium elevated the mutagenicity, whereas treatment with thiols in the medium reduced mutagenicity. The mutagenicity of NC was, on the other hand, only slightly affected by increasing extra- or intracellular thiol levels. The dependence of NC-induced mutagenicity on thiols was indicated, however, by the finding that depletion of intracellular glutathione reduced this mutagenicity almost completely. The effects of treatments with thiols alone or in combination with glutathione transferases suggest that, under our assay conditions (e.g. physiological pH and thiol levels, in combination with low levels of the nitrosoamidines), no denitrosation occurs. On the contrary, our results indicate that intracellular thiols, and possibly glutathione transferases, potentiate the production of mutagenic species from these nitrosamidines.
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PMID:Thiol-enhanced decomposition of MNNG, ENNG, and nitrosocimetidine: relationship to mutagenicity in V79 Chinese hamster cells. 202 48

The hepatotoxicity of the anticonvulsant drug valproic acid may be associated with the formation of potentially reactive metabolites, one of which is (E)-2-propyl-2,4-pentadienoic acid ((E)-2,4-diene VPA). This report describes the characterization of new GSH-related conjugates of this diene. Bile samples collected from male Sprague-Dawley rats dosed ip with (E)-2,4-diene VPA (100 mg/kg) were analyzed by LC/MS/MS. Initial Q1 parent in scanning indicated that the daughter ions m/z 162 and 123 could be derived from the ions at m/z 624 and 480, respectively. Subsequent collision-induced dissociation (CID) of these parent ions revealed a common neutral loss of 176 Da which is diagnostic for glucuronides. A similar neutral loss of 176 Da was observed in daughter ion spectra of the biliary metabolites arising from [2H7]-4-ene VPA dosed ip to rats, where the ion fragments containing the VPA portion were 7 amu higher than those derived from the unlabeled drug. CID of the ion at m/z 624 also gave fragments characteristics for GSH conjugates such as the loss of glycine and glutamate moieties. Based on the MS data, the metabolites were assigned the diconjugate structures 1-O-(2-propyl-5-(glutathion-S-yl)-3-pentenoyl)-beta-D-glucur onide (5-GS-3-ene VPA-glucuronide I, MH+, 624) and the corresponding 5-NAC-3-ene VPA-glucuronide (MH+, 480). Further proof of structural identity was obtained from 1H NMR of HPLC-purified metabolites. The amount of biliary 5-GS-3-ene VPA-glucuronide I was 7-fold greater than the corresponding 5-GS-3-ene VPA, the sum of the two metabolites accounting for 6.6% of the dose. Incubation of 1-O-(2-propyl-2,4-pentadienoyl)-beta-D-glucuronide (2,4-diene VPA-glucuronide) with GSH in the presence or absence of GST enzyme led to the formation of 5-GS-3-ene VPA-glucuronide I which was readily detected by LC/MS/MS, suggesting that in vivo the diconjugate may arise from the reaction of GSH with 2,4-diene VPA-glucuronide. To our knowledge, this is the first recorded instance in which glucuronide formation activates a drug to further conjugate with GSH via a Michael addition reaction.
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PMID:Bioactivation of a toxic metabolite of valproic acid, (E)-2-propyl-2,4-pentadienoic acid, via glucuronidation. LC/MS/MS characterization of the GSH-glucuronide diconjugates. 883 57

We investigated here the combined effect of GeO(2) and radiation on cell viability. Cells were treated with 0 to 22 mM GeO(2) for 12 h followed by 1 Gy X irradiation. A synergistic cytotoxic effect was observed for the combined treatment with a dose-dependent reduction of cell viability. Complete survival curves showed a 2.3- and 2.75-fold increase in radiosensitivity for 50% cell death in the presence of 5 and 15 mM GeO(2), respectively. The increased radiosensitivity also occurred when GeO(2) was given either 4 h prior to irradiation or immediately after radiation exposure. GeO(2) did not affect the total soluble thiol content or the activities of catalase and glutathione S-transferase. Analysis of the production of reactive oxygen species (ROS) revealed that the combined treatment dramatically increased the synthesis of ROS. Addition of N-acetyl cysteine (NAC, 20 mM) decreased the production of ROS in cells. NAC, however, increased cell viability only slightly after treatment with GeO(2) and radiation. Thus increased production of ROS makes little or no contribution to the observed death. The combination of GeO(2) and X radiation, however, significantly increased the frequency of DNA double-strand breaks (DSBs). Notably, the presence of GeO(2) also reduced the efficiency of DNA repair. We conclude that treatment with GeO(2) followed by X irradiation increases DNA DSBs and cell death.
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PMID:Germanium oxide enhances the radiosensitivity of cells. 1260 Feb 42

Alpha-synuclein is a pathological component of Parkinson's disease by constituting the filamentous component of Lewy bodies. Phthalocyanine (Pc) effects on the amyloidosis of alpha-synuclein have been examined. The copper complex of phthalocyanine tetrasulfonate (PcTS-Cu(2+)) caused the self-oligomerization of alpha-synuclein while Pc-Cu(2+) did not affect the protein, indicating that introduction of the sulfonate groups was critical for the selective protein interaction. The PcTS-Cu(2+) interaction with alpha-synuclein has occurred predominantly at the N-terminal region of the protein with a K(d) of 0.83 microM apart from the hydrophobic NAC (non-Abeta component of Alzheimer's disease amyloid) segment. Phthalocyanine tetrasulfonate (PcTS) lacking the intercalated copper ion also showed a considerable affinity toward alpha-synuclein with a K(d) of 3.12 microM, and its binding site, on the other hand, was located at the acidic C-terminus. These mutually exclusive interactions between PcTS and PcTS-Cu(2+) toward alpha-synuclein resulted in distinctive features on the kinetics of protein aggregation, morphologies of the final aggregates, and their in vitro cytotoxicities. The PcTS actually suppressed the fibrous amyloid formation of alpha-synuclein, but it produced the chopped-wood-looking protein aggregates. The aggregates showed rather low toxicity (9.5%) on human neuroblastoma cells (SH-SY5Y). In fact, the PcTS was shown to effectively rescue the cell death of alpha-synuclein overexpressing cells caused by the lactacystin treatment as a proteasome inhibitor. The anti-aggregative and anti-amyloidogenic properties of PcTS were also demonstrated with alcohol dehydrogenase, glutathione S-transferase, and amyloid beta/A4 protein under their aggregative conditions. The PcTS-Cu(2+), on the other hand, promoted the protein aggregation of alpha-synuclein, which gave rise to the fibrillar protein aggregates whose cytotoxicity became significant to 35.8%. Taken together, the data provided in this study indicate that PcTS/PcTS-Cu(2+) could be considered as possible candidates for the development of therapeutic or prophylactic strategies against the alpha-synuclein-related neurodegenerative disorders.
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PMID:Phthalocyanine tetrasulfonates affect the amyloid formation and cytotoxicity of alpha-synuclein. 1503 41

The cytotoxic activity of Brostallicin was previously shown to be enhanced in the presence of high glutathione and glutathione transferase levels. We hypothesized that thiol antioxidants, N-acetylcysteine and Silibinin, could potentiate Brostallicin's cytotoxicity in a similar way. HepG2 and CNE-2 cells were treated with N-acetylcysteine, Silibinin and Brostallicin, either alone or in combination. Surprisingly, we found that NAC and Silibinin had adverse effects on Brostallicin's cytotoxicity. The mechanism underlying the interaction involved the apoptotic pathway as we demonstrated an increase in Bcl-2 protein levels and decrease in caspase 3 activity with the Silibinin-Brostallicin combination.
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PMID:Combination of thiol antioxidant Silibinin with Brostallicin is associated with increase in the anti-apoptotic protein Bcl-2 and decrease in caspase 3 activity. 1611 2

The present study was designed to understand the oxidative stress potential of fenthion, an organophosphate (OP) pesticide and its involvement in glutathione metabolism modulated buthionine sulfoximine (BSO, 50 mg/kg) and N-acetylcysteine (NAC, 100 mg/kg) in the brain of fish, Oreochromis niloticus. A sublethal fenthion concentration (0.45 mg/L) was applied for 24, 48, and 96 h together with injection with BSO or NAC; following treatment, recovery periods for 24, 48, and 96 h were allowed. Total glutathione (tGSH), oxidized glutathione (GSSG), lipid peroxidation, protein level, and GSH-related enzyme activities were analyzed by using spectrophotometric methods. Fenthion in applied concentration did not change GSH levels, but increased GSSG levels. BSO application in fenthion exposure caused a depletion in GSH, while increasing the GSSG levels. Glutathione peroxidase (GPx; EC 1.11.1.9) specific activity increased in fenthion-applied groups at 24-h treatment. gamma-Glutamylcysteinyl synthetase (gamma-GCS; EC 6.3.2.2) was not detected in the brain. NAC injection in fenthion treatment decreased GSH and increased GSSG levels and GST activity. In conclusion, fenthion in sublethal concentration induced an oxidative stress processes in brain. BSO application provided an evidence for the involvement of fenthion in GSH metabolism. NAC elevated the fenthion-induced effects in spite of its antioxidant properties. Recovery period for 96 h was not adequate to eliminate the fenthion-induced changes.
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PMID:In vivo effects of fenthion on oxidative processes by the modulation of glutathione metabolism in the brain of Oreochromis niloticus. 1800 Aug 50

Many studies have investigated the effects of glutathione S-transferase (GST) polymorphisms on cancer incidence in people exposed to carcinogenic polycyclic aromatic hydrocarbons (PAHs). The basis for this is that the carcinogenic bay region diol epoxide metabolites of several PAH are detoxified by GSTs in in vitro studies. However, there are no reports in the literature on the identification in urine of the mercapturic acid metabolites that would result from this process in humans. We addressed this by developing a method for quantitation in human urine of mercapturic acids which would be formed from angular ring diol epoxides of phenanthrene (Phe), the simplest PAH with a bay region, and a common environmental pollutant. We prepared standard mercapturic acids by reactions of syn- or anti-Phe-1,2-diol-3,4-epoxide and syn- or anti-Phe-3,4-diol-1,2-epoxide with N-acetylcysteine. Analysis of human urine conclusively demonstrated that the only detectable mercapturic acid of this type--N-acetyl-S-(r-4,t-2,3-trihydroxy-1,2,3,4-tetrahydro-c/t-1-phenanthryl)-L-cysteine (anti-PheDE-1-NAC)--was derived from the 'reverse diol epoxide', anti-Phe-3,4-diol-1,2-epoxide, and not from the bay region diol epoxides, syn- or anti-Phe-1,2-diol-3,4-epoxide. Levels of anti-PheDE-1-NAC in the urine of 36 smokers were (mean +/- SD) 728 +/- 859 fmol/ml urine. The results of this study provide the first evidence for a mercapturic acid of a PAH diol epoxide in human urine, but it was not derived from a bay region diol epoxide as molecular epidemiologic studies have presumed, but rather from a reverse diol epoxide, representative of metabolites with little if any carcinogenic activity. These results demonstrate the need for integration of genotyping and phenotyping information in molecular epidemiology studies.
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PMID:Analysis of phenanthrene diol epoxide mercapturic acid detoxification products in human urine: relevance to molecular epidemiology studies of glutathione S-transferase polymorphisms. 1847 46

Polychlorinated biphenyls (PCBs) have promoting activity in the liver, which may be brought about in part by the induction of oxidative stress. In this study we examined the effects of several antioxidant phytochemicals on the tumor promoting activity of 3,3',4'4-tetrachlorobiphenyl (PCB-77). Female Sprague Dawley rats were first injected with diethylnitrosamine (DEN, 150 mg/kg) and one week later the rats were fed an AIN-93 based purified diet or the same diet containing ellagic acid (0.4%), beta-carotene (0.5%), curcumin (0.5%), N-acetyl cysteine (NAC, 1.0%), coenzyme CoQ10 (CoQ10, 0.4%), resveratrol (0.005%), lycopene (10% as Lycovit, which contains 10% lycopene), or a tea extract (1%, containing 16.5% epigallocatechin-3-gallate [EGCG] and 33.4% total catechins). Rats were fed the diets for the remainder of the study. After three weeks, 2/3 of the control rats and all of the antioxidant diet-fed rats were injected i.p. with PCB-77 (300 micromol/kg) every other week for four injections. All rats were euthanized ten days after the last PCB injection. The rats that received PCB-77 alone showed an increase in the number and size of placental glutathione S-transferase (PGST)-positive foci in the liver. Lycopene significantly decreased the number of foci, while curcumin and CoQ10 decreased the size of the foci. In contrast, ellagic acid increased the number but decreased the size of the foci. All of the other phytochemicals showed only slight or no effects. Compared with the PCB-77 group, CoQ10 increased cell proliferation in normal hepatocytes, whereas the other antioxidants had no effect in either normal or PGST-positive hepatocytes. These findings show that none of the antioxidant phytochemicals produced a clear decrease in the promoting activity of PCB-77.
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PMID:Effect of antioxidant phytochemicals on the hepatic tumor promoting activity of 3,3',4,4'-tetrachlorobiphenyl (PCB-77). 1879 25

N-Acetyl-L-cysteine, a low-molecular weight thiol compound, with two different doses was used to prevent fenthion, an organophosphorus insecticide and acaricide, related oxidative stress in the brain of a model organism, Cyprinus carpio. Fish were exposed to sub-lethal and nominal concentration of fenthion after intraperitoneal injection of 0.5 or 400 mg/kg NAC. Brain tissues were then dissected and homogenized to analyse GSH, GSSG, TBARS, and protein contents. Enzymes that constitute the first line antioxidant defence, namely SOD and CAT, GSH-related enzymes, GR and GST, together with AChE activities were also determined spectrophotometrically. Fenthion did not cause any alteration in SOD and CAT activities while increasing GSH content, GSH/GSSG ratio and GST specific enzyme activity and decreasing GSSG, TBARS, and protein contents. Although, the highest induction in SOD and GST enzymes activities and the highest increase in GSH content were observed in the 0.5 mg/kg NAC-injected fish, their protein contents showed a decrease. 400 mg/kg NAC impeded the activation of the GST enzyme and a higher decrease in lipid peroxidation was observed. Fish were also protected against protein depletion by the higher dose NAC application. AChE activity was not influenced by fenthion exposure. Xenobiotic and GSH transporters may cause mild oxidative stress conditions in brain. Cellular redox status could trigger a series of reactions that result in an increase in SOD activity and a decrease in protein content. Based on the present results, it was suggested that the usefulness of NAC against fenthion depends on applied dose and tissue characteristics. Species-specifity and concentration selection should be taken into consideration in studies dealing with anticholinesterases.
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PMID:N-Acetylcysteine provides dose-dependent protection against fenthion toxicity in the brain of Cyprinus carpio L. 1944 91

Methylmercury (MeHg) has been suggested to exert cytotoxicity through multiple mechanisms, but the precise biochemical machinery has not been fully defined. This study was aimed at investigating the time-course (0-24h) effect of 2mg/L MeHg on cell death in human HepG2 cells. MeHg decreased cell viability in a time-dependent manner, which was concomitant with increased LDH leakage, reduced GSH levels, CAT activity and altered activity of the antioxidant enzymes GPx and GR at the longest times of incubation (16 and 24h). Activity of the detoxifying enzyme GST was also early enhanced (2h). Caspase-3 activity reached a maximum value at 8h and continued increased up to 24h. This feature was preceded by an enhancement in the caspase-9 activity (2h), whereas caspase-8 activity remained unchanged. MeHg early diminished Bcl-x(L)/Bcl-x(S) ratio and increased levels of the pro-apoptotic Bax and Bad. Moreover, MeHg-induced cytotoxicity was completely inhibited by the antioxidants (GSH and NAC) and notably by the mitochondrial complex I inhibitor rotenone, but not by the NADH oxidase inhibitor DPI. In summary, MeHg induced an oxidative stress responsible for apoptosis in HepG2 cells through direct activation of the caspase cascade and altered the cellular antioxidant and detoxificant enzymatic system to later provoke necrosis at later stages.
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PMID:Molecular mechanisms of methylmercury-induced cell death in human HepG2 cells. 2022 30


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