Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1260386 (GSH)
 38,102 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The uptake by rabbit erythrocytes of 0.4 mM arsenate, As(V), monomethylarsinate, MMA(V) and dimethylarsonate, DMA(V) were compared over 24 h. In membrane-free hemolysate, the distribution of As between proteins (10 kDa) and ultrafiltrate was determined by ultrafiltration and arsenic species in the ultrafiltrate were identified by thin layer chromatography methods. 1H spin-echo Fourier transform NMR was used to follow the binding of these arsenic species to glutathione (GSH). 31P-NMR was used to observe their effects on high-energy adenine nucleotide levels (ATP, ADP). These results demonstrate that As(III) readily accumulates in cells, reaches a quasi-plateau at 78% of the total As in the incubation after 1 h and 88% of the total As after 24 h. On average, 20% of the total erythrocyte As(III) burden is associated with the protein fraction, particularly with hemoglobin (Hb). About 68% of the erythrocyte As(III) burden is bound to GSH. As(III) has no effect on ATP levels during a 5-h incubation. By comparison, As(V) enters erythrocytes more slowly (53% of the total As after 5 h). Erythrocytes take up 81% of the As(V) in the reaction system after a 24 h incubation. Of the total As burden in As(V)-exposed erythrocytes, 22% was associated with the proteins (10 kDa) and possibly reduced to As(III) and 59% was in the ultrafiltrate (8% as As(III) and 51% as As(V)). This finding indicates that, over a 24 h incubation period, the reduction of As(V) to As(III) may account for 30% of the total As in rabbit erythrocytes. As(V) present in the erythrocytes enters the phosphate pool and depletes ATP. In comparison, about 65% of the total MMA(V) or about 44% of the total DMA(V) in the incubation system is taken up by rabbit erythrocytes during a 24 h incubation. Neither organoAs species perturbed the Hb signals observed by spin-echo Fourier transform NMR and the binding to GSH was minimal. Unlike As(V), MMA(V) and DMA(V) do not perturb phosphate metabolism, showing that, despite their pentavalent oxidation state, these arsenic species are not analogs for phosphate.
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PMID:Time dependence of accumulation and binding of inorganic and organic arsenic species in rabbit erythrocytes. 758 52

The toxicology of arsenic is complicated by its ability to convert between oxidation states and organometalloidal forms. These processes cause differences in the relative tissue-binding affinities of the various arsenic species, and they determine both the intoxication and the detoxification mechanisms. In this review, a chemical hypothesis of arsenic biomethylation is developed from an examination of data and observations presented by researchers who conducted numerous in vivo and in vitro experiments. It is likely that a combination of pathways is actually used during methylation of arsenic in vivo, and that the principal mechanism depends on various factors affecting the cellular environment. Despite these uncertainties, several observations can be made: (i) glutathione (GSH) is required for reduction of arsenic(V) to arsenic(III) species in preparation for enzyme-catalyzed oxidative methylation; (ii) GSH is not involved in monomethylation once arsenite is formed, but GSH is involved in dimethylation by reducing methylarsonic acid [MMA(V)] to methylarsonous acid [MMA(III)]; (iii) GSH is also required in the methylation of arsenic by stabilizing the reductive nature of the cell; (iv) a different methyltransferase is used in each methylation step; (v) dithiols (either a cofactor or the methyltransferases) are required for both mono- and dimethylation and (vi) where dithiols are involved, oxidative methylation reduces the stability of the arsenic-sulfur complex and permits dissociation of the arsenic species. This lower affinity of the pentavalent organoarsenic species for dithiols is part of the reason why methylation of arsenic can be a detoxification mechanism when the As(III) intermediates are not permitted to accumulate.
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PMID:A chemical hypothesis for arsenic methylation in mammals. 840 81

Both alpha-linolenic (ALA) and eicosapentaenoic acids (EPA) were toxic to SP 2/0 mouse myeloma cells in vitro. On the other hand, linoleic acid (LA), gamma-linolenic acid (GLA), di-homo-gamma linolenic acid (DGLA), arachidonic acid (AA), docosahexaenoic acid (DHA) and oleic acid (OA) were much less effective in their growth suppressive actions. Both nordihydroguaiaretic acid (NDGA) and Indomethacin (IM) could block the action of the fatty acids indicating a role for prostaglandins (PGs) and leukotrienes (LTs) in the growth suppressive action of ALA and EPA. Superoxide dismutase (SOD) completely blocked, while vitamin E and reduced glutathione (GSH) could prevent to a limited extent the anti-proliferative effects of ALA and EPA. Catalase, mannitol, chlorpromazine (CPZ) and trifluoperazine (TFP) did not block the cytotoxic actions of ALA and EPA. N(G)-mono-methyl L-arginine (N(G)MMA), an analogue of L-arginine, which inhibits nitric oxide synthase, was ineffective in preventing the cytotoxicity induced by ALA and EPA. Fatty acid analysis of the various lipid fractions of SP 2/0 cells treated with ALA and EPA showed significant incorporation of these fatty acids in the cell membrane lipid pools. These results suggest that ALA and EPA induced suppression of SP 2/0 cell proliferation is cyclo-oxygenase (CO), lipoxygenase (LO) and superoxide dependent. Lipid peroxidation has only a limited role in this process. Both calmodulin dependent process and L-arginine derived nitric oxide do not seem to have a role in the cytotoxic action of ALA and EPA in these cells.
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PMID:Cytotoxic action of alpha-linolenic and eicosapentaenoic acids on myeloma cells in vitro. 915 Mar 74

A unique enzyme, MMA(V) reductase, has been partially purified from rabbit liver by using DEAE-cellulose, carboxymethylcellulose, and red dye ligand chromatography. The enzyme is unique since it is the rate-limiting enzyme in the biotransformation of inorganic arsenite in rabbit liver. The K(m) and V(max) values were 2.16 x 10(-)(3) M and 10.3 micromol h(-)(1) (mg of protein)(-)(1). When DMA(V) or arsenate was tested as a substrate, the K(m) was 20.9 x 10(-)(3) or 109 x 10(-)(3) M, respectively. The enzyme has an absolute requirement for GSH. Other thiols such as DTT or L-cysteine were inactive alone. At a pH below the physiological pH, GSH carried out this reduction, but this GSH reduction in the absence of the enzyme had little if any value at pH 7.4. When the K(m) values of rabbit liver arsenite methyltransferase (5.5 x 10(-)(6) M) and MMA(III) methyltransferase (9.2 x 10(-)(6)) were compared to that of MMA(V) reductase (2.16 x 10(-)(3) M), it can be concluded that MMA(V) reductase was the rate-limiting enzyme of inorganic arsenite biotransformation. MMA(V) reductase was also present in surgically removed human liver.
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PMID:Enzymatic reduction of arsenic compounds in mammalian systems: the rate-limiting enzyme of rabbit liver arsenic biotransformation is MMA(V) reductase. 1060 79

A speciation technique for arsenic has been developed using an anion-exchange high-performance liquid chromatography/inductively coupled argon plasma mass spectrometer (HPLC/ICP MS). Under optimized conditions, eight arsenic species [arsenocholine, arsenobetaine, dimethylarsinic acid (DMA(V)), dimethylarsinous acid (DMA(III)), monomethylarsonic acid (MMA(V)), monomethylarsonous acid (MMA(III)), arsenite (As(III)), and arsenate (As(V))] can be separated with isocratic elution within 10 min. The detection limit of arsenic compounds was 0.14-0.33 microg/L. To validate the method, Standard Reference Material in freeze-dried urine, SRM-2670, containing both normal and elevated levels of arsenic was analyzed. The method was applied to determine arsenic species in urine samples from three arsenic-affected districts of West Bengal, India. Both DMA(III) and MMA(III) were detected directly (i.e., without any prechemical treatment) for the first time in the urine of some humans exposed to inorganic arsenic through their drinking water. Of 428 subjects, MMA(III) was found in 48% and DMA(III) in 72%. Our results indicate the following. (1) Since MMA(III) and DMA(III) are more toxic than inorganic arsenic, it is essential to re-evaluate the hypothesis that methylation is the detoxification pathway for inorganic arsenic. (2) Since MMA(V) reductase with glutathione (GSH) is responsible for conversion of MMA(V) to MMA(III) in vivo, is DMA(V) reductase with GSH responsible for conversion of DMA(V) to DMA(III) in vivo? (3) Since DMA(III) forms iron-dependent reactive oxygen species (ROS) which causes DNA damage in vivo, DMA(III) may be responsible for arsenic carcinogenesis in human.
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PMID:Identification of dimethylarsinous and monomethylarsonous acids in human urine of the arsenic-affected areas in West Bengal, India. 1130 25

The metabolic pathways for arsenic were precisely studied by determining the metabolic balance and chemical species of arsenic to gain an insight into the mechanisms underlying the animal species difference in the metabolism and preferential accumulation of arsenic in red blood cells (RBCs) in rats. Male Wistar rats were injected intravenously with a single dose of arsenite (iAs(III)) at 2.0 mg of As/kg of body weight, and then the time-dependent changes in the concentrations of arsenic in organs and body fluids were determined. Furthermore, arsenic in the bile was analyzed on anion and cation exchange columns by high-performance liquid chromatography-inductively coupled argon plasma mass spectrometry (HPLC-ICP MS). The metabolic balance and speciation studies revealed that arsenic is potentially transferred to the hepato-enteric circulation through excretion from the liver in a form conjugated with glutathione (GSH). iAs(III) is methylated to mono (MMA)- and dimethylated (DMA) arsenics in the liver during circulation in the conjugated form [iAs(III)(GS)(3)], and a part of MMA is excreted into the bile in the forms of MMA(III) and MMA(V), the former being mostly in the conjugated form [CH(3)As(III)(GS)(2)], and the latter being in the nonconjugated free form. DMA(III) and DMA(V) were not detected in the bile. In the urine, arsenic was detected in the forms of iAs(III), arsenate, MMA(V), and DMA(V), iAs(III) being the major arsenic in the first 6-h-urine, and DMA(V) being increased in the second 6-h-urine. The present metabolic balance and speciation study suggests that iAs(III) is methylated in the liver during its hepato-enteric circulation through the formation of the GSH-cojugated form [iAs(III)(GS)(3)], and MMA(III) and MMA(V) are partly excreted into the bile, the former being in the conjugated form [CH(3)As(III)(GS)(2)]. DMA is not excreted into the bile but into the bloodstream, accumulating in RBCs, and then excreted into the urine mostly in the form of DMA(V) in rats.
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PMID:Glutathione-conjugated arsenics in the potential hepato-enteric circulation in rats. 1174 43

Excess intake of arsenic is known to cause vascular diseases as well as skin lesions and cancer in humans. Recent reports suggest that trivalent methylated arsenicals, which are intermediate metabolites in the methylation process of inorganic arsenic, are responsible for the toxicity and carcinogenicity of environmental arsenic. We investigated acute toxicity and accumulation of monomethylarsonic acid (MMA(V)), dimethylarsinic acid (DMA(V)), trimethylarsine oxide (TMAO), and monomethylarsonous acid diglutathione (MMA(III) (GS)(2)) in rat heart microvessel endothelial (RHMVE) cells. MMA(V) (LC(50) = 36.6 mM) and DMA(V) (LC(50) = 2.54 mM) were less toxic than inorganic arsenicals (cf. LC(50) values for inorganic arsenite (iAs(III)), and inorganic arsenate (iAs(V)) was reported to be 36 and 220 microM, respectively, in RHMVE cells. TMAO was essentially not toxic. However, MMA(III) (GS)(2) was highly toxic (LC(50) = 4.1 microM). The order of cellular arsenic accumulation of those four organic arsenic compounds was MMA(III) (GS)(2) >> MMA(V) > DMA(V) > TMAO. MMA(III) (GS)(2) was efficiently taken up by the cells and cellular arsenic content increased with the concentration of MMA(III) (GS)(2) in culture medium. N-acetyl-l-cysteine (NAC) reduced cellular arsenic content in DMA(V)-exposed cells and also decreased the cytotoxicity of DMA(V), whereas it changed neither cellular arsenic content nor the viability in MMA(V)-exposed cells. mRNA levels of heme oxygenase-1 (HO-1) were decreased by NAC in DMA(V)-exposed, but MMA(V)-exposed cells. Buthionine sulfoximine (BSO), a cellular glutathione (GSH) depleting agent, enhanced the cytotoxicity of MMA(V). However, BSO reduced, rather than enhanced, the cytotoxicity of DMA(V). These results suggest that intracellular GSH modulated the toxic effects of arsenic in opposite ways for MMA(V) and DMA(V). Even though intracellular GSH decreased the cytotoxicity of MMA(V), extracellularly added GSH enhanced the cytotoxicity of MMA(V). The use of high-performance liquid chromatography (HPLC)-inductively coupled plasma mass spectrometric analyses suggested that a small amount of MMA(V) was converted to MMA(III) (GS)(2) in the presence of GSH. These results suggest that MMA(III) (GS)(2) is highly toxic compared to other arsenic compounds because of faster accumulation of this species by cells, in addition to having the toxic nature of methylated trivalent organic arsenics.
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PMID:The accumulation and toxicity of methylated arsenicals in endothelial cells: important roles of thiol compounds. 1527 27

The metabolism of arsenic is generally accepted to proceed by repetitive reduction and oxidative methylation; the latter is mediated by arsenic methyltransferase (Cyt19). In human urine, the major metabolites of inorganic arsenicals such as arsenite (iAsIII) and arsenate (iAsV) are monomethylarsonic acid (MMA(V)) and dimethylarsinic acid (DMA(V)). On the other hand, in rat bile, the major metabolites of iAsIII have been reported to be arsenic-glutathione (As-GSH) complexes. In the present study we investigate whether these As-GSH complexes are substrates for arsenic methyltransferase by using human recombinant Cyt19. Analyses by high-performance liquid chromatography-inductively coupled plasma mass spectrometry suggested that arsenic triglutathione (ATG) was generated nonenzymatically from iAsIII when GSH was present at concentrations 2 mM or higher. Human recombinant Cyt19 catalyzed transfer of a methyl group from S-adenosyl-L-methionine to arsenic and produced monomethyl and dimethyl arsenicals. The methylation of arsenic was catalyzed by Cyt19 only when ATG was present in the reaction mixture. Moreover, monomethylarsonic diglutathione (MADG) was a substrate of Cyt19 for further methylation to dimethylarsinic glutathione (DMAG). On the other hand, monomethylarsonous acid (MMA(III)), a hydrolysis product of MADG, was not methylated to dimethyl arsenical by Cyt19. These results suggest that As-GSH complexes such as ATG and MADG were converted by Cyt19 to MADG and DMAG, respectively. Both MADG and DMAG were unstable in solution when the GSH concentration was lower than 1 mM, and were hydrolyzed and oxidized to MMA(V) and DMA(V), respectively. Metabolism of iAsIII to methylated arsenicals by Cyt19 was via ATG and MADG rather than by oxidative methylation of iAsIII and MMA(III).
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PMID:A new metabolic pathway of arsenite: arsenic-glutathione complexes are substrates for human arsenic methyltransferase Cyt19. 1552 90

Human monomethylarsenate reductase [MMA(V) reductase] and human glutathione S-transferase omega 1-1 (hGSTO1-1) [because MMA(V) reductase and hGSTO1-1 are identical proteins, the authors will utilize the designation "hGSTO1-1"] are identical proteins that catalyze the reduction of arsenate, monomethylarsenate [MMA(V)], and dimethylarsenate [DMA(V)]. Sodium selenite (selenite) inhibited the reduction of each of these substrates by the enzyme in a concentration-dependent manner. The kinetics indicated a noncompetitive inhibition of the MMA(V), DMA(V), or arsenate reducing activity of hGSTO1-1. The inhibition of the MMA(V) reducting activity of hGSTO1-1 by selenite was reversed by 1 mM DL-dithiothreitol (DTT) but not by reduced glutathione (GSH), which is a required substrate for the enzyme. Neither superoxide anion nor hydrogen peroxide was involved in the selenite inhibition of hGSTO1-1. MALDI-TOF and MS/MS analysis demonstrated that five molecules of GSH were bound to one monomer of hGSTO1-1. Four of the five cysteines of the monomer were glutathionylated. Cys-32 in the active center, however, exists mostly in the sulfhydryl form since it was alkylated consistently by iodoacetamide. MALDI-TOF mass spectra analysis of hGSTO1-1 after reaction with GSH and sodium selenite indicated that selenium was integrated into hGSTO1-1 molecules. Three selenium were found to be covalently bonded to the monomer of hGSTO1-1 with three molecules of GSH. It is proposed that the reaction products of the reduction of selenite inhibited the activity of hGSTO1-1 by reacting with disulfides of glutathionylated cysteines to form bis (S-cysteinyl)selenide and S-selanylcysteine and had little or no interaction with the sulfhydryl of Cys-32 in the active site of the enzyme.
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PMID:Interactions of sodium selenite, glutathione, arsenic species, and omega class human glutathione transferase. 1609 2

Arsenic is an established human carcinogen. The role of aquaglyroporins (AQPs) in arsenic disposition was recently identified. In order to examine whether organic anion transporting polypeptide-C (OATP-C) also plays a role in arsenic transport, OATP-C cDNA was transfected into cells of a human embryonic kidney cell line (HEK-293). Transfection increased uptake of the model OATP-C substrate, estradiol-17beta-D-glucuronide, by 10-fold. In addition, we measured uptake and cytotoxicity of arsenate, arsenite, monomethylarsonate(MMA(V)), and dimethylarsinate (DMA(V)). Transfection of OATP-C increased uptake and cytotoxicity of arsenate and arsenite, but not of MMA(V) or DMA(V). Rifampin and taurocholic acid (a substrate of OATP-C) reversed the increased toxicity of arsenate and arsenite seen in OATP-C-transfected cells. The increase in uptake of inorganic arsenic was not as great as that of estradiol-17beta-D-glucuronide. Our results suggest that OATP-C can transport inorganic arsenic in a (GSH)-dependent manner. However, this may not be the major pathway for arsenic transport.
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PMID:Organic anion transporting polypeptide-C mediates arsenic uptake in HEK-293 cells. 1647 12


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