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Query: UMLS:C0268318 (ICP)
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Selenium- (SE) organo compounds of pooled human milk (7th-14th d after delivery) were separated by centrifugation and subsequent size-exclusion chromatography (SEC) as described in ref. (1). The SEC fractions were used for Se determinations by electrothermal vaporization inductively coupled plasma mass spectrometry (ETV-ICP-MS) in parallel to identification procedures of the organic ligands by two different capillary zone electrophoresis (CZE) methods. Further, the combination of isotachophoresis- (ITP) CZE with ETV-ICP-MS was used for final identifications. Mass balances were carried out at each analytical step for quality assurance. Reinjection experiments were performed to check the stability of Se-organo compounds during the analytical procedure. These quality-control experiments showed that no species transformations took place during the analytical procedure, and the Se species were native in human milk. The identification and quantification of organic ligands were clear and resulted in values of 2 (+/- 0.2) mg/L GSH/GSeH, 2 (+/- 0.22) mg/L cystamine/Se-cystamine, 4 (+/- 0.4) mg/L cystine/ Se-cystine, and 1 (+/- 0.18) mg/L methionine/Se-methionine. Unfortunately, a differentiation between sulfur (S) and Se analogs was not possible with the applied CE methods. The Se values per organic ligand were determined as 2.5 (+/- 0.23) mg/L associated with GSH (as GSeH), 3.1 (+/- 0.31) mg/L associated with cystamine (as Se-cystamine), 5.2 (+/- 0.4) mg/L associated with cystine (as Se-cystine), and 1 (+/- 0.1) mg/L associated with methionine (as Se-methionine).
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PMID:Selenium speciation in human milk with special respect to quality control. 952 46

The aim of this experiment was to determine if buthionine sulfoximine (BSO), an inhibitor of glutathione (GSH) synthesis, enhances the ototoxicity of carboplatin. Osmotic pumps were used to infuse BSO into the right cochleas of 12 adult chinchillas for 14 days. The left cochleas served as controls. Animals were assigned to three groups: a drug control group that did not receive carboplatin, a group that received a single dose of carboplatin (25 mg/kg i.p.), and a group that received a double dose of carboplatin (25 mg/kg i.p. x 2), with 4 days between injections. Carboplatin was administered after three days of BSO pre-treatment. Ototoxicity was assessed with evoked potentials recorded from electrodes implanted in the inferior colliculi (ICPs), distortion product otoacoustic emissions (DPOAEs), and cochleograms. BSO infusion itself caused no long-term functional or morphological changes. One of four animals treated with it single dose of carboplatin showed a significant loss of inner hair cells (IHCs), with greater loss in the BSO-treated ear. All animals in the double-dose carboplatin group showed marked differences between BSO-treated and control ears. Average IHC losses were 59% in BSO-treated ears vs. 18% in control ears. Moreover, BSO-treated ears sustained significantly greater outer hair cell (OHC) losses than control ears (37% vs. 2%, respectively). ICP and DPOAE response amplitudes were reduced slightly in BSO-treated ears relative to control ears, consistent with their greater hair cell loss. The results clearly show that BSO can enhance carboplatin ototoxicity in the chinchilla, supporting a role of GSH and reactive oxygen species in platinum ototoxicity.
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PMID:Intracochlear infusion of buthionine sulfoximine potentiates carboplatin ototoxicity in the chinchilla. 1008 93

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

Coupled HPLC-ICP-MS has been used to quantitatively study the effects of GSSG and GSH on the ability of metallothionein (MTII) to donate essential and non-essential metals to apo-carbonic anhydrase. Stable isotopically labeled (67)Zn(3)Cd(4) MTII was used to enable Zn donated from MTII to be differentiated from extraneous sources of Zn. Transfer of both (67)Zn and Cd from MTII to apo-carbonic anhydrase was noted in the absence of either GSSG or GSH. GSSG increased the initial transfer of both Zn and Cd. Thereafter, a gradual increase in the (67)Zn content at the expense of Cd was noted over 24-h indicating continued interaction and exchange between MTII and the enzyme commensurate with the relative preferences shown by the proteins for these two metals. Although GSH also increased transfer of (67)Zn from MT it reduced the simultaneous transfer of Cd to the enzyme thereby conferring protection against Cd induced activation.
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PMID:Metal donation and apo-metalloenzyme activation by stable isotopically labeled metallothionein. 1517 55

Inorganic arsenicals such as arsenite (iAs(III)) and arsenate (iAs(V)) are well-known human carcinogens. Arsenic is metabolized by repetitive reduction and oxidative methylation, and is excreted mainly in urine as monomethylated arsenicals (MMAs) and dimethylated arsenicals (DMAs). Recently, it has been shown that iAs(III) administered intravenously or orally is excreted into bile as arsenic-glutathione (As-GSH) complexes such as arsenic triglutathione [As(GS)(3)] and methylarsenic diglutathione [CH(3)As(GS)(2)]. In order to carry out the speciation of As-GSH complexes, it is important to understand their stability. The present study was designed to clarify the stability of As-GSH complexes in rat bile, and the role of GSH in stabilizing these complexes. Arsenic species were separated on an anion-exchange column and were analyzed by high-performance liquid chromatography-inductively coupled argon plasma mass spectrometry (HPLC-ICP MS). As(GS)(3) and CH(3)As(GS)(2) were unstable in bile and were hydrolyzed to iAs(III) and monomethylarsonous acid (MMA(III)) in the absence of GSH. As(GS)(3) appeared to be stable in the presence of 10mM GSH. Exogenously added GSH also stabilized CH(3)As(GS)(2) in bile at the concentrations of 5mM or higher. It has been suggested that trivalent arsenicals, especially MMA(III), are more toxic than corresponding pentavalent ones. These results suggest that GSH plays an important role in preventing hydrolysis of As-GSH complexes and the generation of well-known toxic trivalent arsenicals.
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PMID:Stability of arsenic metabolites, arsenic triglutathione [As(GS)3] and methylarsenic diglutathione [CH3As(GS)2], in rat bile. 1586 54

Epidemiological studies have demonstrated a variety of potential environmental factors that may alter susceptibility to chronic pancreatitis (CP) through oxidative/xenobiotic stress; however, a direct causal and mechanistic role has not been established. We aimed (1) to determine the prevalence of functional genetic polymorphisms in the antioxidant enzymes, glutathione S-transferase GSTM-1, GSTP-1, and GSTT-1, manganese superoxide dismutase, and catalase in CP and (2) to reveal evidence of oxidative stress in patients with CP by measuring whole-blood glutathione redox status. In total, 122 patients with CP (75 alcohol-induced [A1CP], 33 idiopathic [ICP], and 13 hereditary) and 245 age- and sex-matched controls were recruited. The prevalence of the functional GSTT-1 genotype (GSTT-1*A) was significantly higher in CP (88.5%) compared to healthy controls (76%; chi2 = 7.26, P = 0.007). Stratification to disease etiology demonstrated that the GSTT-1*A genotype was also significantly more prevalent among patients with ICP (94%; P = 0.02; 95% CI, 0.04-9.16) but not in those with A1CP. In 22 patients with stable CP, the whole-blood glutathione concentration (median [IQR]: 72 micromol/L [21-181 micromol/L]) and the glutathione redox ratio (GSH/GSSG) (median [IQR]: 9 (3-77]) were significantly reduced compared to those in 20 healthy volunteers (median [IQR]: 815 micromol/L [679-1148 micromol/L], P < 0.001, and 96 [52-347], P = 0.005, respectively). We conclude that the GSTT-1 functional genotype is associated with ICP. Evidence of altered glutathione redox status suggests that this disease modification may be a consequence of oxidative stress or the bioactivation of xenobiotics.
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PMID:Genetic polymorphisms of GSTT1, GSTM1, GSTP1, MnSOD, and catalase in nonhereditary chronic pancreatitis: evidence of xenobiotic stress and impaired antioxidant capacity. 1604 90

The aim of the study was to determine the time-dependent formation of arsenic-phytochelatin (As-PC) complexes in the roots, stems and leaves of an arsenic-nontolerant plant (Helianthus annuus) during exposure to 66 mol l(-1) arsenite (As(III)) or arsenate (As(V)). We used our previously developed method of simultaneous element-specific (inductively coupled plasma mass spectrometry, ICP-MS) and molecular-specific (electrospray-ionization mass spectrometry, ES-MS) detection systems interfaced with a suitable chromatographic column and eluent conditions, which enabled us to identify and quantify As-PC complexes directly. Roots of As-exposed H. annuus contained up to 14 different arsenic species, including the complex of arsenite with two (gamma-Glu-Cys)(2)-Gly molecules [As((III))-(PC(2))(2)], the newly identified monomethylarsonic phytochelatin-2 or (gamma-Glu-Cys)(2)-Gly CH(3)As (MA((III))-PC(2)) and at least eight not yet identified species. The complex of arsenite with (gamma-Glu-Cys)(3)-Gly (As((III))-PC(3)) and the complex of arsenite with glutathione (GSH) and (gamma-Glu-Cys)(2)-Gly (GS-As((III))-PC(2)) were present in all samples (roots, stems and leaves) taken from plants exposed to As. The GS-As((III))-PC(2) complex was the dominant complex after 1 h of exposure. As((III))-PC(3) became the predominant As-PC complex after 3 h, binding up to 40% of the As present in the exposed plants. No As-PC complexes were found in sap (mainly xylem sap from the root system), in contrast to roots, stems and leaves, which is unequivocal evidence that As-PC complexes are not involved in the translocation of As from root to leaves of H. annuus.
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PMID:Uptake, translocation and transformation of arsenate and arsenite in sunflower (Helianthus annuus): formation of arsenic-phytochelatin complexes during exposure to high arsenic concentrations. 1631 33

The accumulation of As and Cd in Brassica juncea plants and the formation of complexes of these elements with bioligands such as glutathione and/or phytochelatins (PCs) is studied. The genetic manipulation of these plants to induce higher As and Cd accumulation has been achieved by overexpressing the genes encoding for gamma-glutamyl cysteine synthetase (gamma-ECS) and glutathione synthetase (GS). These two enzymes are responsible for glutathione (GSH) formation in plants, which is the first step in the production of PCs. The biomass produced in both the wild type and the genetically modified plants, has been evaluated. Additionally, the total Cd and As concentration accumulated in the plant tissues was measured by inductively coupled plasma mass spectrometry (ICP-MS) after extraction. Speciation studies on the extracts were conducted using size exclusion liquid chromatography (SEC) coupled online with ICP-MS to monitor As, Cd and S. For further purification of the As fractions, reversed phase high performance liquid chromatography (RP-HPLC) was used. Structural elucidation of the PCs and other thiols, as well as their complexes with As and Cd, was performed by electrospray-quadrupole-time-of-flight (ESI-Q-TOF). In both the Cd and As exposed plants it was possible to observe the presence of oxidized PC2 ([M + H]+, m/z 538), GS-PC2(-Glu) ([M + H]+, m/z 716) as well as reduced GSH ([M + H]+, m/z 308) and oxidized glutathione (GSSG) ([M + H]+, m/z 613). However, only the GS plants exhibited the presence of As(GS)3 complex ([M + H]+, m/z 994) that was further confirmed by MS/MS. This species is reported for the first time in B. juncea plant tissues.
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PMID:Study of phytochelatins and other related thiols as complexing biomolecules of As and Cd in wild type and genetically modified Brassica juncea plants. 1642 78

In addition to its superoxide dismutase (SOD) activity, Cu,Zn-superoxide dismutase (CuZnSOD) catalyzes the reductive decomposition of S-nitroso-L-glutathione (GSNO) in the presence of thiols such as L-glutathione (GSH). The GSNO-reductase activity but not the superoxide dismutase (SOD) activity of CuZnSOD is inhibited by the commonly used polyaminocarboxylate metal ion chelators, EDTA and DTPA. The basis for this selective inhibition is systematically investigated here. Incubation with EDTA or DTPA caused a time-dependent decrease in the 680 nm d-d absorption of Cu(II)ZnSOD but no loss in SOD activity or in the level of metal loading of the enzyme as determined by ICP-MS. The chelators also protected the SOD activity against inhibition by the arginine-specific reagent, phenylglyoxal. Measurements of both the time course of SNO absorption decay at 333 nm and oxymyoglobin scavenging of the NO that is released confirmed that the chelators inhibit CuZnSOD catalysis of GSNO reductive decomposition by GSH. The decreased GSNO-reductase activity is correlated with decreased rates of Cu(II)ZnSOD reduction by GSH in the presence of the chelators as monitored spectrophotometrically at 680 nm. The aggregate data suggest binding of the chelators to CuZnSOD, which was detected by isothermal titration calorimetry (ITC). Dissociation constants of 0.08 +/- 0.02 and 8.3 +/- 0.2 microM were calculated from the ITC thermograms for the binding of a single EDTA and DTPA, respectively, to the CuZnSOD homodimer. No association was detected under the same conditions with the metal-free enzyme (EESOD). Thus, EDTA and DTPA must bind to the solvent-exposed active-site copper of one subunit without removing the metal. This induces a conformational change at the second active site that inhibits the GSNO-reductase but not the SOD activity of the enzyme.
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PMID:Binding of polyaminocarboxylate chelators to the active-site copper inhibits the GSNO-reductase activity but not the superoxide dismutase activity of Cu,Zn-superoxide dismutase. 1704 90


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