Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q8NB91 (FAB)
 3,573 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Microcystins LR, YR, and RR, cyclic heptapeptide hepatotoxins produced by cyanobacteria, were synthetically converted into glutathione (GSH) and cysteine (Cys) conjugates. Fast atom bombardment mass spectra showed [M + H]+ ions corresponding to GSH and Cys conjugates of microcystins LR, YR, and RR for the obtained compounds. 1H NMR spectral analyses revealed that two singlet signals of olefinic protons of N-methyldehydroalanine (Mdha) in microcystins disappeared in the conjugates, confirming that thiols of GSH and Cys added nucleophilically to the alpha, beta-unsaturated carbonyl of the Mdha moiety. On examination of the 50% lethal dose (LD50) with intravenous injection using mice, both GSH and Cys conjugates showed reduction in toxicity compared with microcystins, but their toxicity still remained. Microcystin LR and its GSH conjugate were separated and identified in a standard mixture by using a frit-fast atom bombardment liquid chromatography/mass spectrometry (Frit-FAB LC/MS) method. Obtained conjugates in the present study would be important compounds as the standard samples for study of metabolism of microcystins, and the Frit-FAB LC/MS method would be applicable to mass spectrometric identification of metabolites of microcystins.
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PMID:Formation, characterization, and toxicity of the glutathione and cysteine conjugates of toxic heptapeptide microcystins. 144 98

1. p-Aminophenol, a minor metabolite of phenacetin, is a potent nephrotoxic agent. 2. We have examined the binding of p-aminophenol to glutathione (GSH), a model amino acid, in the presence of horseradish peroxidase, which catalyses one electron oxidation. 3. The reaction product was purified by preparative h.p.l.c., and its structure was determined by FAB mass spectrometry and 1H-n.m.r. to be a p-aminophenol-GSH conjugate. The conjugate was formed between the ortho carbon of the amino group of p-aminophenol and the SH group of GSH. 4. It was confirmed by h.p.l.c. and 1H-n.m.r. that formation of the conjugate was catalysed in vitro by rat liver microsomes and cumene hydroperoxide.
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PMID:Studies of paracetamol/phenacetin toxicity: isolation and characterization of p-aminophenol-glutathione conjugate. 194 9

Using two peroxidative systems (prostaglandin H synthase/arachidonic acid and horseradish peroxidase/H2O2) we observed GSH conjugate formation with a number of compounds including polycyclic aromatic hydrocarbon-diols (PAH-diols), insecticides, and steroids. Several of the conjugates were characterized by chromatography, uv-vis spectrophotometry, and FAB mass spectroscopy. Conjugate formation is dependent upon a functioning peroxidase, GSH, and is markedly enhanced (3- to 10-fold) by the inclusion of a number of reducing cosubstrates including phenol, uric acid, phenylbutazone, and acetaminophen. The mechanism of conjugate formation appears to involve addition of thiyl radical to alkene bonds conjugated to an electron releasing group probably by resonance stabilization of the carbon-centered radical intermediate. Thiyl radicals are formed either directly by GSH reduction of the peroxidase or indirectly by GSH reduction of radicals formed from reducing cosubstrates. The nitrone spin trap, 5,5-dimethyl-1-pyrroline N-oxide, which traps thiyl radicals, totally inhibits production of GSH conjugates in both peroxidative systems. Conjugation of PAH-diols, some of which are penultimate carcinogens, would prevent their metabolism to the diol-epoxides, an ultimate carcinogenic species of PAH. Conjugation by peroxidases appears to be a general pathway for glutathione conjugate formation that may lead to potential detoxification of chemicals.
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PMID:Peroxidase-mediated formation of glutathione conjugates from polycyclic aromatic dihydrodiols and insecticides. 249 94

3'-Hydroxyacetanilide (AMAP) is a nonhepatotoxic regioisomer of acetaminophen (APAP) that nonetheless does form reactive metabolites which bind to hepatic proteins. Because differences in the nature of reactive metabolites formed from AMAP and APAP may explain differences in their propensity to cause hepatotoxicity, characterization of the reactive metabolites of AMAP was undertaken. The naturally occurring sulfhydryl-containing tripeptide glutathione (GSH) was used to trap the reactive metabolites. Four mono-GSH conjugates and one di-GSH conjugate of oxidative AMAP metabolites were characterized by 1H NMR and soft ionization (LSIMS or FAB) mass spectral techniques, as well as by comparison of liquid chromatographic and spectral characteristics with synthetic standards. Two isomeric mono-GSH conjugates of 2-acetamidohydroquinone (2-AcHQ) are formed as well as a bis-GSH conjugate. A mono-GSH conjugate of 3',4'-dihydroxyacetanilide (3-OH-APAP) also was formed. Thus, these GSH conjugates most likely arise by reaction of GSH with 2-acetamido-p-benzoquinone (2-APBQ) and 4-acetamido-o-benzoquinone (4-AOBQ), respectively, as oxidation products of the known AMAP metabolites 2-AcHQ and 3-OH-APAP. Finally, a GSH conjugate of 3'-methoxy-4'-hydroxy-acetanilide (3-OMe-APAP) was detected in bile of mice administered AMAP. This conjugate probably arises by oxidation of 3-OMe-APAP, another known metabolite of AMAP. The presumed oxidation product, N-acetyl-3-methoxy-p-benzoquinone imine (MAPQI), was synthesized and found to react with GSH to give the same GSH conjugate as that detected in bile and in incubations of 3-OMe-APAP with mouse liver microsomes plus GSH.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of glutathione conjugates of reactive metabolites of 3'-hydroxyacetanilide, a nonhepatotoxic positional isomer of acetaminophen. 251 30

One of the conjugates of melphalan, characterized following incubation with glutathione (GSH) and immobilized microsomal glutathione-S-transferases, has been identified as 4-(glutathionyl)-phenylalanine. This conjugate is formed by displacement of the mustard moiety. The structure was confirmed by reaction of the corresponding 4-halophenylalanines with GSH as well as by TLC, HPLC, and FAB mass spectrometry. Evidence is presented here to support the hypothesis that this novel reaction occurs via a cyclic aziridinium ion. To test this proposed mechanism, N,N-dimethyl-p-toluidine and its corresponding quaternary ammonium iodide salt were incubated with GSH in the presence of immobilized glutathione-S-transferases at 37 degrees C for 1 hr at pH 7.4. The tertiary amine did not react, whereas the quaternary compound produced 4-(glutathionyl)toluene. The effect of ring substituent requirements for the reaction was evaluated. The formation of GSH adducts of alkylating agents may be a factor in the development of resistance to these drugs.
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PMID:Conversion of melphalan to 4-(glutathionyl)phenylalanine. A novel mechanism for conjugation by glutathione-S-transferases. 288 77

Three glutathione conjugates of acetaminophen were characterized by fast atom bombardment/mass spectrometry (FAB/MS) and fast atom bombardment/mass spectrometry/mass spectrometry (FAB/MS/MS). The conjugates, 3-(glutathion-S-yl)acetaminophen, 3-(glutathion-S-yl)diacetaminophen and 3-(diglutathion-S-yl)diacetaminophen showed intense [MH]+ ions at m/z 457, 606 and 911, respectively. Only 3-(glutathion-S-yl)acetaminophen showed any fragmentation by FAB/MS. Structurally characteristic fragmentation was observed with all three conjugates when the [MH]+ ions were collisionally activated. The loss of the glycine (GLY) and glutamic acid (GLU) moieties indicated the presence of at least one glutathione (GSH) group. Multiple losses, some of which could only occur via cleavages in both GSH moieties, were observed with the diglutathione conjugate.
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PMID:Fast atom bombardment mass spectrometry and fast atom bombardment mass spectrometry/mass spectrometry of three glutathione conjugates of acetaminophen. 296 Mar 98

Red cell pyruvate kinase (PK), pyrimidine 5'nucleotidase (P5N) and reduced glutathione content (GSH) were studied in 126 untreated patients with acute leukaemia (AL, 80 cases), chronic lymphocytic leukaemia (B-CLL, 38 cases) and B-cell lymphoma with leukaemic expression (LSCL, eight cases). Acute leukaemias were classified into lymphoblastic (ALL) and non-lymphoblastic (ANLL), the latter have been further sub-divided into four different variants according to FAB morphological criteria (1976). A significant decrease of PK activity was observed only in the ANLL group, leading to a clear-cut difference with the ALL group where a normal value was obtained. The decrease of P5N activity was similar in all the morphological variants of ANLL and no abnormalities in the low PEP assay system or after fructose 1,6-bisphosphate (Fru 1,6-P2) activation were observed. P5N activity was found to be significantly decreased in all groups of patients except in B-CLL, where it was normal. In regards to the different morphological groups of ANLL, a striking decrease of P5N activity was observed in the M3 variant. Although red cell GSH content was significantly increased in all groups of patients, no correlation was demonstrated between the raised GSH levels and the decreased P5N activities.
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PMID:Characteristics of red cell pyruvate kinase (PK) and pyrimidine 5'nucleotidase (P5N) abnormalities in acute leukaemia and chronic lymphoid diseases with leukaemic expression. 303 59

Fotemustine is a chemotherapeutic drug for the treatment of melanoma. In this study, we investigated the metabolic and chemical stability of fotemustine with 31P-NMR and FAB-MS. In the absence of GSH, 95% of fotemustine decomposed rapidly into a reactive diethyl ethylphosphonate (DEP) isocyanate, both in rat liver S9 fraction and in HEPES buffer (pH = 7.4). DEP-isocyanate in turn hydrolyzed rapidly into diethyl (1-aminoethyl)phosphonate, which reacted subsequently with the parent DEP-isocyanate. The remaining 5% of fotemustine was shown to decompose via dechlorination into diethyl [1-(3-nitroso-2-oxoimidazolidin-1-yl)ethyl]-phosphonate. In the presence of GSH, hydrolysis of DEP-isocyanate was blocked, and a glutathione conjugate (DEP-SG) was formed instead. DEP-SG was relatively stable at 37 degrees C in HEPES buffer. Only two minor and as yet unidentified decomposition products were formed. Addition of N-acetyl-L-cysteine (NAC) to DEP-SG in HEPES buffer converted DEP-SG rapidly into the corresponding NAC conjugate of DEP-isocyanate (DEP-NAC). The formation of DEP-SG from DEP-isocyanate and GSH appeared to be spontaneous. The extent of formation of DEP-SG from fotemustine and GSH was equal in both enzymatically active and inactive rat liver S9 fractions. In the presence and in the absence of GSH, the half-lives of decomposition (t1/2) of fotemustine were 33 +/- 6 and 27 +/- 3 min, respectively. The formation of the DEP-isocyanate and 2-chloroethanediazohydroxide intermediates from fotemustine appeared to be rate limiting, and not the hydrolysis of the DEP-isocyanate nor its conjugation to GSH. Active or inactive rat liver S9 fractions accelerated the decomposition of fotemustine slightly; i.e., the t1/2 of fotemustine decreased from 39 +/- 3 to 29 +/- 1 min. Further knowledge of the metabolic and chemical stability of fotemustine and DEP-isocyanate will contribute to a better understanding of fotemustine-related cytostatic effects and toxic side effects and to the design of chemoprotection against undesired toxic side effects.
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PMID:Chemical and glutathione conjugation-related degradation of fotemustine: formation and characterization of a glutathione conjugate of diethyl (1-isocyanatoethyl)phosphonate, a reactive metabolite of fotemustine. 807 70

Arsenic is metabolized by living systems using oxidation-reduction and methylation reactions, and reduced glutathione (GSH) has been shown to be important in that metabolism. In this study, the solution reactions between GSH and arsenate, arsenite, and their methylated metabolites, monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA), were characterized using 1H and 13C NMR under a nitrogen atmosphere. Binding to GSH through the thiol group was primarily followed by shifts in the carbon atom bonded to the sulfhydryl group of the cysteinyl residue, i.e., the CH2 carbon atom and the protons bonded to it. The methylated metabolites also showed shifts in the methyl groups attached to the arsenic atom after reaction with GSH. Sodium arsenite, As(III), bound to GSH to form an As(SG)3 complex in solution as indicated by NMR spectra. The identity of the complex was confirmed by FAB-MS after isolation of the compound. Mixtures of sodium arsenate, As(V), and GSH showed that arsenate oxidized GSH in D2O solutions at pH 7 to form oxidized glutathione (GSSG). When the molar ratio of As:GSH exceeded 1:2, evidence for the formation of As(SG)3 was observed. MMA and DMA are both As(V) species, and mixtures with GSH showed oxidation to GSSG initially followed by formation of CH3.As(SG)2 and (CH3)2.As.SG, respectively. The effects of GSH on arsenic metabolism may result from direct reactions between the two compounds.
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PMID:Reactions of arsenic(III) and arsenic(V) species with glutathione. 844 39

1,3-Butadiene (BD) is a carcinogen in rats and mice. Previous in vitro studies showed that mouse liver microsomes formed 1,2-epoxy-3-butene (BMO) from BD and 1,2:3,4-diepoxybutane (BDE) from BMO at much higher rates than rat or human microsomes. Blood and tissue levels of BDE were significantly lower in rats than in mice following exposure to BD. Since mice are much more susceptible to cancer induced by BD than rats, these findings suggest a key role for BDE in BD-induced carcinogenicity. The aim of this study was to characterize the glutathione (GSH) conjugation of BDE by cytosol from human liver and mouse and rat liver and lung in vitro. BDE and radiolabeled GSH were incubated with cytosol. Conjugates were identified by 13C-NMR and FAB mass spectroscopy and quantitated by HPLC. The enzyme kinetics for the conjugation of BDE with GSH suggest that the higher BDE blood concentrations in mice compared with rats following inhalation exposure to BD are not due to differences in GSH conjugation of BDE.
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PMID:Hepatic and pulmonary glutathione conjugation of 1,2:3,4-diepoxybutane in human, rat, and mouse in vitro. 890 12


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