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)

Development of phosphotyrosyl (pTyr) mimetics which are stable to protein-tyrosine phosphatases (PTPs), yet can retain biological potency when incorporated into peptides, is an active area of drug development. Since a majority of pTyr mimetics derive their "phosphofunctionality" from phosphorus-containing moieties, such as phosphonates, evolution of new inhibitors and modes of prodrug derivatization have been restricted to chemistries appropriate for phosphorus-containing moieties. A new, nonphosphorus-containing pTyr mimetic has recently been reported, L-O-(2-malonyl)tyrosine (OMT,5), which can be incorporated into peptides that exhibit good PTP and Src homology 2 (SH2) domain inhibitory potency. For phosphonate-based pTyr mimetics such as phosphonomethyl phenylalanine (Pmp,2) introduction of fluorines alpha to the phosphorus has provided higher affinity pTyr mimetics. This strategy has now been applied to OMT, and herein is reported 4'-O-[2-(2-fluoromalonyl)]-L-tyrosine (FOMT,6) a new fluorine-containing nonphosphorus pTyr mimetic. Incorporation of FOMT into appropriate peptides results in good inhibition of both PTP and SH2 domains. In an assay measuring the inhibition of PTP 1B-mediated dephosphorylation of phosphorylated insulin receptor, the peptide Ac-D-A-D-E-X-L-amide exhibited a 10-fold enhancement in inhibitory potency for X = FOMT (19) (IC(50) = 10 microM) relative to the unfluorinated peptide, X = OMT (18) (IC(50) = 10 microM. Molecular modeling indicated that this increased affinity may be attributable to new hydrogen-bonding interactions between the fluorine and the enzyme catalytic site, and not due to lowering of pKa values. In a competition binding assay using the p85 PI 3-kinase C-terminal SH2 domain GST fusion construct, the inhibitory peptide, Ac-D-X-V-P-M-L-amide, showed no enhancement of inhibitory potency for X = FOMT (22) (IC(50) = 18 microM) relative to the unfluorinated peptide, X = OMT (21) (IC(50) = 14 microM). The use of FOMT would therefore appear to have particular potential for the development of PTP inhibitors.
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PMID:4'-O-[2-(2-fluoromalonyl)]-L-tyrosine: a phosphotyrosyl mimic for the preparation of signal transduction inhibitory peptides. 867 36

The potent mutagen, 5-fluoroquinoline (5-FQ), and non-mutagenic 3-fluoroquinoline (3-FQ) were tested for hepatocarcinogenicity using a medium-term assay system employing quinoline, a moderately mutagenic hepatocarcinogen, as a reference. F344 male rats were given a single i.p. injection of a submanifestational dose of diethylnitrosamine (DEN, 200 mg/kg). Then, quinoline, 3-FQ, or 5-FQ at two doses (0.1%, and 0.05%) was added to their diet for a period of 6 weeks, starting from 2 weeks after the DEN injection. Control groups were administered DEN alone. All rats were subjected to a partial (two-thirds) hepatectomy at the end of week 3 and sacrificed at the end of week 8. The number and areas of GST-P (placental glutathione S-transferase)-positive foci induced in the liver increased significantly as a result of treatment with 0.1% quinoline, and this increase was dramatic with 5-FQ at both doses, whereas no increases were noted with 3-FQ at either dose. Thus, the results of the medium-term carcinogenicity assay predicted that quinoline, a hepatocarcinogen, would be deprived of carcinogenicity by fluorine atom substitution at position 3, and would conversely be endowed with a higher carcinogenic capacity by substitution at position 5. A semi-quantitative relationship was demonstrated between carcinogenic and mutagenic potencies.
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PMID:Modification of the carcinogenic potency of quinoline, a hepatocarcinogen, by fluorine atom substitution: evaluation of carcinogenicity by a medium-term assay. 901 4

An excess of sodium fluoride (135 mg F/kg body weight) was given in a single oral dose to male Wistar rats. Effects were investigated of fluoride-induced acute kidney intoxication on the time-dependent variations of urine volume. Also, of urinary fluoride ion (F-), alpha-glutathione-S-transferase (alpha-GST), N-acetyl-beta-D-glucosaminidase (NAG), and creatinine (CR) concentrations. Fluoride administration strongly affects these urinary biochemical indices. Of the several biomarkers studied, alpha-GST is particularly useful as marker of S3 proximal tubule damage. We found that alpha-GST shows the strongest and more durable changes as a result of the large dose of F- given to the experimental animals. Our results suggest that the toxic effect of F- on the kidney may be more pronounced in the proximal tubule than the glomeruli region, and that the disorder of the proximal tubule is more serious in the S3 segment than S1 or S2 segment. Alpha-GST proved to be a useful marker for the early detection and long-term observation of proximal renal tubular injury resulting from F- intoxication. The animal model should help to establish guidelines for the treatment of industrial workers suffering from acute renal failure resulting from accidental exposure to fluoride.
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PMID:Urinary biomarkers monitoring for experimental fluoride nephrotoxicity. 945 82

Quinoline, a hepatocarcinogen, mutates the bacterial tester strains in the presence of the rat liver microsomal enzymes and induces GST-P (placental glutathione S-transferase)-positive foci in a medium-term bioassay system for hepatocarcinogenesis. On the other hand, 3-fluorinated quinoline was neither mutagenic nor carcinogenic in the same assay systems, whereas, 5-fluoroquinoline was mutagenic and carcinogenic. Quinoline was recently demonstrated to be mutagenic in an in vivo mutagenicity assay system using the lacZ-transgenic mouse (MutaMouse). The present study was undertaken to know whether 3-fluoroquinoline would be devoid of in vivo mutagenicity in MutaMouse. Quinoline and 5-fluoroquinoline were also tested in the same system. Mutagenicity was evaluated in the liver, the target organ of quinoline carcinogenesis, and also in the bone marrow and testis. The results strongly indicate that fluorine-substitution at the position-3 of quinoline could be an anti-genotoxic structural modification of quinoline in a wide range of its genotoxic end-points.
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PMID:Antimutagenic structural modification of quinoline assessed by an in vivo mutagenesis assay using lacZ-transgenic mice. 963 Jun 5

A single oral dose of sodium fluoride (NaF) in aqueous solution was given to male Wistar rats. Twenty-four-hour urine samples were collected and examined to evaluate fluoride-induced acute renal damage. The following parameters were measured in 24-h urine: urine volume and urinary excretion of fluoride, N-acetyl-beta-d-glucosaminidase (NAG), alpha-glutathione-S-transferase (alpha-GST), and creatinine (CR). Fluoride exposure produced specific, dose-dependent changes of these parameters. Significant increases of fluoride and fluoride-induced polyuria were observed. NAG as specific marker of proximal convoluted tubule (PCT) function showed a significant increase when the lowest dose of fluoride was administered. At this minimal dose, alpha-GST, a specific marker for the S3 segment, did not show a significant increase but presented the strongest relationship (r = 0. 83) to fluoride dose. No significant changes were measured for CR excretion, which showed a low correlation coefficient (r = 0.36) to administered fluoride. The specific differences in the increase pattern of these parameters show that the PCT is more susceptible to damage by low-dose fluoride than the S3 segment or the glomerulus. We concluded that both NAG and alpha-GST are useful for the diagnosis of fluoride-induced acute nephrotoxicity. Proper evaluation of these urinary indices may be of help to establish the site and extent of kidney injury in acute fluoride toxicity.
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PMID:Usefulness of the assessment of urinary enzyme leakage in monitoring acute fluoride nephrotoxicity. 1044 62

Dichloroacetic acid (DCA) is a contaminant of chlorinated drinking water supplies, is carcinogenic in rats and mice, and is a therapeutic agent used for the treatment of congenital lactic acidosis. The biotransformation of DCA to glyoxylic acid is catalyzed by glutathione transferase zeta (GSTZ). Treatment of rats and human subjects with DCA increases its plasma elimination half-life and reduces the extent of DCA biotransformation in rat hepatic cytosol. In the investigation presented here, the kinetics of the DCA-induced inactivation of GSTZ, the turnover of GSTZ, and the susceptibility of GSTZ to inactivation by a panel of alpha-haloacids were studied. DCA rapidly inactivated GSTZ in both rat hepatic cytosol and intact Fischer 344 rats. The time course of inactivation in vivo was mirrored by a concomitant loss of immunoreactive GSTZ protein. The turnover of GSTZ in rat liver was 0.21 day(-1), which corresponded to a half-life of 3.3 days. The degree of GSTZ inactivation after daily administration of DCA could be predicted from the amount of inactivation after a single treatment. Other fluorine-lacking dihaloacetic acids also inactivated GSTZ, whereas alpha-monohaloacids and fluorine-containing dihaloacetic acids failed to inactivate GSTZ. These data show that the observed DCA-induced decrease in the level of DCA metabolism is caused by the inactivation of GSTZ.
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PMID:Inactivation of glutathione transferase zeta by dichloroacetic acid and other fluorine-lacking alpha-haloalkanoic acids. 1060 62

The microtubule disrupting agent 2-fluoro-1-methoxy-4-pentafluorophenylsu lfonamidobenzene (T138067) binds covalently and selectively to beta-tubulin and has been shown to evade drug-efflux pumps that confer multidrug resistance to other antimitotic drugs that are used in cancer chemotherapy (Shan et al., 1999). In addition to these resistance mechanisms, eukaryotic cells have developed other protection mechanisms that involve enzymes that modify electrophilic xenobiotics. To determine whether T138067 is a substrate for such enzymatic detoxification pathways, a metabolism study was initiated. GSH conjugation was shown to play a major role in T138067 metabolism. T138067-GSH conjugates were isolated from the culture media of T138067-treated cells and the bile of mice treated i.v. with T138067. The major T138067-GSH degradation products were also isolated from these sources. 19F NMR studies of the metabolites showed that metabolic conversions occurred through substitution of the para fluorine atom in the pentafluorophenyl ring of T138067. The T138067-GSH conjugate was also isolated from T138067 incubation buffer that had been exposed to mouse, rat, dog, or human liver slices, suggesting that this mechanism is not species-specific. All three human glutathione S-transferases (alpha, mu, and pi), which are expressed in a wide variety of tissues including human tumors, were shown to metabolize T138067 effectively in vitro. The combined data show that T138067 is being metabolized, in vitro and in vivo, predominantly via a glutathione S-transferase-mediated metabolic pathway.
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PMID:Glutathione S-transferase metabolism of the antineoplastic pentafluorophenylsulfonamide in tissue culture and mice. 1090 6

One of the major goals of a series of our studies is to explore the availability of a method for anti-genotoxic modification of carcinogens by fluorine-substitution. Quinoline, a hepatocarcinogen, mutates bacterial tester strains in the presence of rat liver microsomal enzymes and induces GST-P (placental glutathione S-transferase)-positive foci in a medium-term bioassay system for hepatocarcinogenesis. On the other hand, 3-fluorinated quinoline (3-FQ) was neither mutagenic nor carcinogenic in the same assay system, whereas 5-fluoroquinoline (5-FQ) was mutagenic and carcinogenic. Quinoline, 3-FQ, and 5-FQ were also tested in an in vivo mutagenicity assay system using a lacZ-transgenic mouse (Muta Mouse). Mutation was induced by quinoline and 5-FQ only in the liver, the target organ of carcinogenesis by quinoline, but not in the other organs examined. 3-FQ was non-mutagenic in all of the organs. The results strongly indicate that fluorine-substitution at the position-3 of quinoline could be an anti-genotoxic structural modification of quinoline in a wide range of its genotoxic end-points. Additionally, seventeen mono- and di-fluorinated derivatives of 1,7-phenanthroline, 1,10-phenanthroline, benzo[h]quinoline, and benzo[f]quinoline were subjected to analysis of their structure-mutagenicity relationship. The results support that the enamine epoxide structure of the pyridine moiety, as well as the bay-region epoxide structure, is responsible for mutagenicity. These results suggest that the introduction of a fluorine atom to the molecule in question may be a useful tool to modify their mutagenic potency and to better understand the mechanism of mutation.
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PMID:[Anti-carcinogenic structural modification by fluorine-substitution in aza-polycyclic aromatic hydrocarbons]. 1119 86

Data concerning the pathophysiological role of the interaction of circulating S100 proteins, a multigenic family of Ca(2+)-modulated proteins, with the receptor for advanced glycation endproducts (RAGE) in cardiovascular diseases, inflammatory processes, and tumorigenesis in vivo are scarce. One reason is the shortage of suitable radiotracer methods. We report a novel methodology using recombinant human S100A1, S100B, and S100A12 as potential probes for molecular imaging of this interaction. Therefore, human S100 proteins were cloned as GST fusion proteins in the bacterial expression vector pGEX-6P-1 and expressed in E. coli strain BL21. Purified recombinant human S100 proteins were radiolabeled with the positron emitter fluorine-18 ((18)F) by conjugation with N-succinimidyl-4-[(18)F]fluorobenzoate ([(18)F]SFB). The radiolabeled recombinant S100 proteins ((18)F-S100) were used in biodistribution experiments and small animal positron emission tomography (PET) studies in rats. The tissue-specific distribution of (18)F-S100 proteins in vivo correlated well with the anatomical localization of RAGE, e.g., in lungs and in the vascular system. These findings indicate circulating S100A1, S100B, and S100A12 proteins to be ligands for RAGE in rats in vivo. The approach allows the use of small animal PET and provides novel probes to delineate functional expression of RAGE under normal and pathophysiological conditions in rodent models of disease.
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PMID:Expression, purification and fluorine-18 radiolabeling of recombinant S100 proteins--potential probes for molecular imaging of receptor for advanced glycation endproducts (RAGE) in vivo. 1803 81

The cytosolic human carbonic anhydrase (hCA, EC 4.2.1.1) isozyme III (hCA III) has been cloned and purified by the GST-fusion protein method. Recombinant pure hCA III had the following kinetic parameters for the CO(2) hydration reaction at 20 degrees C and pH 7.5: k(cat) of 1.3 x 10(4) s(- 1) and k(cat)/K(M) of 2.5.10(5) M(- 1) s(- 1). The first detailed inhibition study of this enzyme with anions is reported. Inhibition data of the cytosolic isozymes hCA I - hCA III with a large number of anions (halides, pseudohalides, bicarbonate, carbonate, nitrate, nitrite, hydrosulfide, sulfate, sulfamic acid, sulfamide, etc.), were determined and these values are comparatively discussed for these three cytosolic isoforms. Fluoride, nitrate, nitrite, phenylboronic acid and phenylarsonic acid (as anions) were weak hCA III inhibitors (K(I)s of 21-78.5 mM), whereas bicarbonate, chloride, bromide, sulfate and several other simple anions showed K(I)s around 1 mM. The best hCA III inhibitors were carbonate, cyanide, thiocyanate, azide and hydrogensulfide, which showed K(I)s in the range of 10-90 microM. It is difficult to explain the inhibitory activity of carbonate (K(I) of 10 microM) against hCA III, also considering the fact that this ion has an affinity of 15-73 mM for hCA I and II and is in equilibrium with one of the substrates of this enzyme, i.e., bicarbonate, which is a much weaker inhibitor (K(I) of 0.74 mM against hCA III, of 12 mM against hCA I and of 85 mM against hCA II).
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PMID:Carbonic anhydrase inhibitors. Cloning, characterization and inhibition studies of the cytosolic isozyme III with anions. 1861 22


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