@article {797,
	title = {Do arsenosugars pose a risk to human health? The comparative toxicities of a trivalent and pentavalent arsenosugar},
	journal = {Environmental Science \& Technology},
	volume = {38},
	number = {15},
	year = {2004},
	note = {ISI Document Delivery No.: 842WOTimes Cited: 23Cited Reference Count: 54},
	month = {Aug},
	pages = {4140-4148},
	type = {Article},
	abstract = {Seafood frequently contains high concentrations of arsenic (similar to10-100 mg/kg dry weight). In marine algae (seaweed), this arsenic occurs predominantly as ribose derivatives known collectively as arsenosugars. Although it is clear that arsenosugars are not acutely toxic, there is a possibility of arsenosugars having slight chronic toxicity. In general, trivalent arsenicals are more toxic than their pentavalent counterparts, so in this work we examine the hypothesis that trivalent arsenosugars might be significantly more toxic than pentavalent arsenosugars in vitro. We compared the in vitro toxicity of (R)-2,3-dihydroxypropyl-5-deoxy-5-dimethylarsinoyl-beta-D-riboside, a pentavalent arsenosugar, to that of its trivalent counterpart, (R)-2,3-dihydroxypropyl-5-deoxy-5-dimethylarsino-beta-D- riboside. The trivalent arsenosugar nicked plasmid DNA, whereas the pentavalent arsenosugar did not. The trivalent arsenosugar was more cytotoxic (IC50 = 200 muM, 48 h exposure) than its pentavalent counterpart (IC50 > 6000 muM, 48 h exposure) in normal human epidermal keratinocytes in vitro as determined via the neutral red uptake assay. However, both the trivalent and the pentavalent arsenosugars were significantly less toxic than MMA(III), DMA(III), and arsenate. Neither the pentavalent arsenosugar nor the trivalent arsenosugar were mutagenic in Salmonella TA104. The trivalent arsenosugar was readily formed by reaction of the pentavalent arsenosugar with thiol compounds, including, cysteine, glutathione, and dithioerythritol. This work suggests that the reduction of pentavalent arsenosugars to trivalent arsenosugars in biology might have environmental consequences, especially because seaweed consumption is a significant environmental source for human exposure to arsenicals.},
	keywords = {DIMETHYLARSINIC ACID, DNA-DAMAGE, HUMAN-CELLS, IN-VITRO, INORGANIC ARSENICS, METABOLISM, METHYLATED ARSENICALS, MONOMETHYLARSONOUS ACID MMA(III), ORGANIC ARSENIC COMPOUNDS, SEAWEED},
	isbn = {0013-936X},
	url = {<Go to ISI>://000223035400022},
	author = {Andrewes, P. and Demarini, D. M. and Funasaka, K. and Wallace, K. and Lai, V. W. M. and Sun, H. S. and Cullen, W. R. and Kitchin, K. T.}
}
@article {929,
	title = {Evidence of hemoglobin binding to arsenic as a basis for the accumulation of arsenic in rat blood},
	journal = {Chemical Research in Toxicology},
	volume = {17},
	number = {12},
	year = {2004},
	note = {ISI Document Delivery No.: 881XKTimes Cited: 45Cited Reference Count: 74},
	month = {Dec},
	pages = {1733-1742},
	type = {Article},
	abstract = {Four trivalent arsenic species, inorganic arsenite (iAs(III)), monomethylarsonous acid (MMA(III)), dimethylarsinous acid (DMA(III)), and phenylarsine oxide ((PhAsO)-O-III), have shown increasing binding affinity with the hemoglobin (Hb) of rats and humans. The binding stoichiometry was consistent with the number of reactive cysteine residues in the alpha and beta chains of Hb. Comparing the binding affinity of rat Hb and human Hb for the same trivalent arsenic species, rat Hb was 3-16 times stronger than human Hb as demonstrated by their apparent binding constants. Comparative experiments involving incubation of human and rat red blood cells (RBC) with iAs(III), MMA(III), and DMA(III) showed that 15-30-fold more arsenic species were bound to the Hb of rat RBC than that of human RBC. In vivo experiments using rats fed with an arsenic-supplemented diet showed that arsenic in RBC of the rats was predominantly found in the protein-bound form. Further characterization by nanoelectrospray mass spectrometry of the arsenic species in the RBC of these rats confirmed that most arsenic was bound to the alpha chain of Hb. Taken together, these results suggest that the stronger binding affinity of these arsenic species to rat Hb is responsible for the accumulation of arsenic in rat blood. The results provide a chemical basis to explain the previously observed intriguing difference in the retention of arsenic in the human and the rat. The techniques and approaches described can be applied to the studies of arsenic interactions with other functional proteins.},
	keywords = {ACUTE PROMYELOCYTIC LEUKEMIA, CULTURED HUMAN-CELLS, dimethylarsinous acid, DNA-DAMAGE, HUMAN URINE, METHYLATED METABOLITES, MONOMETHYLARSONOUS ACID MMA(III), TOXICITY, TRIOXIDE, TRIVALENT},
	isbn = {0893-228X},
	url = {<Go to ISI>://000225902600023},
	author = {Lu, M. L. and Wang, H. L. and Li, X. F. and Lu, X. F. and Cullen, W. R. and Arnold, L. L. and Cohen, S. M. and Le, X. C.}
}
@article {647,
	title = {Interaction of trivalent axsenicals with metallothionein},
	journal = {Chemical Research in Toxicology},
	volume = {16},
	number = {7},
	year = {2003},
	note = {ISI Document Delivery No.: 702UQTimes Cited: 53Cited Reference Count: 625th International Conference on Arsenic Exposure and Health EffectsJUL 14-18, 2002SAN DIEGO, CALIFORNIA},
	month = {Jul},
	pages = {873-880},
	type = {Proceedings Paper},
	abstract = {Arsenic is a human carcinogen, causing skin, bladder, and lung cancers. Although arsenic in drinking water affects millions of people worldwide, the mechanism(s) of action by which arsenic causes cancers is not known. Arsenic probably exerts some toxic effects by binding with proteins. However, few experimental data are available on arsenic-containing proteins in biological systems. This study reports on arsenic interaction with metallothionein and established binding stoichiometries between metallothionein and the recently discovered trivalent metabolites of arsenic metabolism. Size exclusion chromatography with inductively coupled plasma mass spectrometry analysis of reaction mixtures between trivalent arsenicals and metallothionein clearly demonstrated the formation of complexes of arsenic with metallothionein. Analysis of the complexes using electrospray quadrupole time-of-flight tandem mass spectrometry revealed the detailed binding stoichiometry between arsenic and the 20 Cys residues in the metallothionein molecule. Inorganic arsenite (As-III) and its two trivalent methylation metabolites, monomethylarsonous acid (MMA(III)) and dimethylarsinous acid (DMA(III)), readily bind with metallothionein. Each metallothionein molecule could bind with up to six As-III, 10 MMA(III), and 20 DMA(III) molecules, consistent with the coordination chemistry of these arsenicals. The findings on arsenic interaction with proteins are useful for a better understanding of arsenic health effects.},
	keywords = {ARSENIC METABOLITES, ENZYMATIC METHYLATION, GLUTATHIONE-REDUCTASE, HUMAN URINE, INORGANIC ARSENICALS, MONOMETHYLARSONOUS ACID MMA(III), PYRUVATE-DEHYDROGENASE, RABBIT LIVER, THIOREDOXIN REDUCTASE, TOXICITY},
	isbn = {0893-228X},
	url = {<Go to ISI>://000184243200009},
	author = {Jiang, G. F. and Gong, Z. L. and Li, X. F. and Cullen, W. R. and Le, X. C.}
}
@article {386,
	title = {Determination of arsenic metabolic complex excreted in human urine after administration of sodium 2,3-dimercapto-1-propane sulfonate},
	journal = {Chemical Research in Toxicology},
	volume = {15},
	number = {10},
	year = {2002},
	note = {ISI Document Delivery No.: 607TXTimes Cited: 15Cited Reference Count: 42},
	month = {Oct},
	pages = {1318-1323},
	type = {Article},
	abstract = {Sodium 2,3-dimercapto-1-propane sulfonate (DMPS) has been used to treat acute arsenic poisoning. Presumably DMPS functions by chelating some arsenic species to increase the excretion of arsenic from the body. However, the excreted complex of DMPS with arsenic has not been detected. Here we describe a DMPS complex with monomethylarsonous acid (MMA(III)), a key trivalent arsenic in the arsenic methylation process, and show the presence of the DMPS-MMA(III) complex in human urine after the administration of DMPS. The DMPS-MMA(III) complex was characterized using electrospray tandem mass spectrometry and determined by using HPLC separation with hydride generation atomic fluorescence detection (HGAFD). The DMPS-MMAIII complex did not form a volatile hydride with borohydride treatment. On-line digestion with 0.1 M sodium hydroxide following HPLC separation decomposed the DMPS-MMA(III) complex and allowed for the subsequent quantification by hydride generation atomic fluorescence. Arsenite (As-III), arsenate (As-V), monomethylarsonic, acid (MMA(V)), dimethylarsinic acid (DMA(V)), MMA(III), and DMPS-MMA(III) complex were analyzed in urine samples from human subjects collected after the ingestion of 300 mg of DMPS. The administration of DMPS resulted in a decrease of the DMA(V) concentration and an increase of the MMA(V) concentration excreted in the urine, confirming the previous results. The finding of the DMPS-MMA(III) complex in human urine after DMPS treatment provides an explanation for the inhibition of arsenic methylation by DMPS. Because MMA(III) is the substrate for the biomethylation of arsenic from MMA(V) to DMA(V), the formation of DMPS-MMA(III) complex would reduce the availability of MMA(III) for the subsequent biomethylation.},
	keywords = {ARSENICALS, CHALLENGE TEST, DRINKING-WATER, ENZYMATIC, GLUTATHIONE-REDUCTASE, HUMAN HEPATOCYTES, IN-VITRO INHIBITION, LIVER, METHYLATED, METHYLATION, MONOMETHYLARSONOUS ACID MMA(III), RABBIT, THIOREDOXIN REDUCTASE},
	isbn = {0893-228X},
	url = {<Go to ISI>://000178807800016},
	author = {Gong, Z. and Jiang, G. F. and Cullen, W. R. and Aposhian, H. V. and Le, X. C.}
}
@article {465,
	title = {DNA damage induced by methylated trivalent arsenicals is mediated by reactive oxygen species},
	journal = {Chemical Research in Toxicology},
	volume = {15},
	number = {12},
	year = {2002},
	note = {ISI Document Delivery No.: 627VUTimes Cited: 104Cited Reference Count: 48},
	month = {Dec},
	pages = {1627-1634},
	type = {Article},
	abstract = {Arsenic is a human carcinogen; however, the mechanisms of arsenic{\textquoteright}s induction of carcinogenic effects have not been identified clearly. We have shown previously that monomethylarsonous acid (MMA(III)) and dimethylarsinous acid (DMA(III)) are genotoxic and can damage supercoiled phiX174 DNA and the DNA in peripheral human lymphocytes in culture. These trivalent arsenicals are biomethylated forms of inorganic arsenic and have been detected in the urine of subjects exposed to arsenite and arsenate. We show here by molecular, chemical, and physical methods that reactive oxygen species (ROS) are intermediates in the DNA-damaging activities of MMA(III) and DMA(III). Using the phiX174 DNA nicking assay we found that the ROS inhibitors Tiron, melatonin, and the vitamin E analogue Trolox inhibited the DNA-nicking activities of both MMA(III) and DMA(III) at low micromolar concentrations. The spin trap agent 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) also was effective at preventing the DNA nicking induced by MMA(III) and DMA(III.) ESR spectroscopy studies using DMPO identified a radical as a ROS intermediate in the DNA incubations with DMA(III). This radical adduct was assigned to the DMPO-hydroxyl free radical adduct on the basis of comparison of the observed hyperfine splitting constants and line widths with those reported in the literature. The formation of the DMPO-hydroxyl free radical adduct was dependent on time and the presence of DMA(III) and was completely inhibited by Tiron and Trolox and partially inhibited by DMSO. Using electrospray mass spectrometry, micromolar concentrations of DMA(v) were detected in the DNA incubation mixtures with DMA(III). These data are consistent with the conclusions that the DNA-damaging activity of DMA(III) is an indirect genotoxic effect mediated by ROS-formed concomitantly with the oxidation of DMA(III) to DMA(v).},
	keywords = {DIMETHYLARSINIC ACID, DRINKING-WATER, ENZYMATIC METHYLATION, FREE-RADICALS, HEPATOCYTES, HUMAN, HUMAN URINE, MALE F344 RATS, MONOMETHYLARSONOUS ACID MMA(III), ORAL-EXPOSURE, RAT-LIVER CYTOSOL},
	isbn = {0893-228X},
	url = {<Go to ISI>://000179957500017},
	author = {Nesnow, S. and Roop, B. C. and Lambert, G. and Kadiiska, M. and Mason, R. P. and Cullen, W. R. and Mass, M. J.}
}
@article {5130,
	title = {Arsenicals inhibit thioredoxin reductase in cultured rat hepatocytes},
	journal = {Chemical Research in Toxicology},
	volume = {14},
	number = {3},
	year = {2001},
	note = {ISI Document Delivery No.: 415LTTimes Cited: 86Cited Reference Count: 46},
	month = {Mar},
	pages = {305-311},
	type = {Article},
	abstract = {Thioredoxin reductase (TR), an NADPH-dependent flavoenzyme that catalyzes the reduction of many disulfide-containing substrates, plays an important role in the cellular response to oxidative stress. Trivalent arsenicals, especially methyl As that contains trivalent arsenic (MAsIII), are potent noncompetitive inhibitors of TR purified from mouse liver. Because MAsIII is produced in the biomethylation of As, it was postulated that the extent of inhibition of TR in cultured rat hepatocytes would correlate with the intracellular concentration of methyl As. Exposure of cultured hepatocytes to inorganic As-III (iAs(III)), MAsIII, or aurothioglucose (ATG, a competitive inhibitor of TR activity) for 30 min caused a concentration-dependent reduction in TR activity. The estimated IC50 was much greater than 100 muM for iAS(III), similar to 10 muM for ATG, and similar to3 muM for MAsIII. In hepatocytes exposed to 1 muM MAsIII for up to 24 h, the inhibition of TR activity was maximal (similar to 40\%) after exposure for 15 min. After exposure for 3 h [when most MAsIII has been converted to dimethyl As (DMAs)], TR activity in these cells had returned to control levels. Notably, exposure of the cell to 50 muM DMAsIII did not affect TR activity. In hepatocytes exposed to 10 muM iAs(III) for up to 24 h, the inhibition of TR activity was progressive; at 24 h, activity was reduced similar to 35\%. Following exposure to iAsIII or MAsIII, the extent of inhibition of TR activity correlated strongly with the intracellular concentration of MAs. Taken together, these results suggest that arsenicals formed in the course of cellular metabolism of As are potent inhibitors of TR activity. In particular, MAsIII, an intermediate in the metabolic pathway, is an especially potent inhibitor of TR. Hence, the capacity of cells to produce or consume the intermediates in the pathway for As methylation may be an important determinant of susceptibility to the toxic effects of As.},
	keywords = {apoptosis, ENZYMATIC REDUCTION, IN-VITRO METHYLATION, LIVER, MAMMALIAN SYSTEMS, MONOMETHYLARSONOUS ACID MMA(III), NF-KAPPA-B, RABBIT ERYTHROCYTES, REDOX, REGULATION, SUBSTRATE},
	isbn = {0893-228X},
	url = {<Go to ISI>://000167723600007},
	author = {Lin, S. and Del Razo, L. M. and Styblo, M. and Wang, C. Q. and Cullen, W. R. and Thomas, D. J.}
}
@article {5045,
	title = {Determination of trivalent methylated arsenicals in biological matrices},
	journal = {Toxicology and Applied Pharmacology},
	volume = {174},
	number = {3},
	year = {2001},
	note = {ISI Document Delivery No.: 464KTTimes Cited: 129Cited Reference Count: 67},
	month = {Aug},
	pages = {282-293},
	type = {Article},
	abstract = {The enzymatically catalyzed oxidative methylation of As yields methylated arsenicals that contain pentavalent As (As-V). Because trivalent As (As-III) is the favored substrate for this methyltransferase, methylated arsenicals containing As-V are reduced to trivalency in cells. Methylated arsenicals that contain As-III are extremely potent inhibitors of NADPH-dependent flavoprotein oxidoreductases and potent cytotoxins in many cell types. Therefore, the formation of methylated arsenicals that contain As-III may be properly regarded as an activation step, rather than a means of detoxification. Recognition of the role of methylated arsenicals that contain As-III in the toxicity and metabolism of As emphasizes the need for analytical methods to detect and quantify these species in biological samples. Hence, a method was developed to exploit pH-dependent differences in the generation of arsines from inorganic and methylated arsenicals that contain either As-V or As-III. Reduction with borohydride at pH 6 generated arsines from inorganic As-III, methyl As-III, and dimethyl As-III, but not from inorganic As-V, methyl As-V, and dimethyl As-V. Reduction with borohydride at pH 2 or lower generated arsines from arsenicals that contained either As-V or As-III. Arsines are trapped in a liquid nitrogen-cooled gas chromatographic trap, which is subsequently warmed to allow separation of the hydrides by their boiling points. Atomic absorption spectrophotometry is used to detect and quantify the arsines. The detection limits (ng As ml(-1)) for inorganic As-III, methyl As-III, and dimethyl As-III are 1.1, 1.2, and 6.5, respectively. This method has been applied to the analysis of arsenicals in water, human urine, and cultured cells. Both methyl As-III. and dimethyl As-III are detected in urine samples from individuals who chronically consumed inorganic As-contaminated water and in human cells exposed in vitro to inorganic As-III. The reliable quantitation of inorganic and methylated arsenicals that contain As-III. in biological samples will aid the study of the toxicity of these species and may provide a new biomarker of the effects of chronic exposure to As. (C) 2001 Academic Press.},
	keywords = {analysis, arsenic, atomic absorption spectrophotometry, biological matrices, CANCER MORTALITY, DIABETES-MELLITUS, DIMETHYLARSINIC ACID, DOSE-RESPONSE RELATIONSHIP, DRINKING-WATER, ENZYMATIC, HUMAN URINE, HYDRIDE GENERATION, MAMMALIAN SYSTEMS, MASS-SPECTROMETRY, METABOLISM, methylated arsenic, METHYLATION, MONOMETHYLARSONOUS ACID MMA(III), pentavalent arsenic, STABILITY, TOXICITY, trivalent arsenic},
	isbn = {0041-008X},
	url = {<Go to ISI>://000170532300010},
	author = {Del Razo, L. M. and Styblo, M. and Cullen, W. R. and Thomas, D. J.}
}
