@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 {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 {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.}
}
@article {5144,
	title = {Methylated trivalent arsenic species are genotoxic},
	journal = {Chemical Research in Toxicology},
	volume = {14},
	number = {4},
	year = {2001},
	note = {ISI Document Delivery No.: 424XZTimes Cited: 253Cited Reference Count: 55},
	month = {Apr},
	pages = {355-361},
	type = {Article},
	abstract = {The reactivities of methyloxoarsine (MAsIII) and iododimethylarsine (DMAsIII), two methylated trivalent arsenicals, toward supercoiled phi X174 RFI DNA were assessed using a DNA nicking assay. The induction of DNA damage by these compounds in vitro in human peripheral lymphocytes was assessed using a single-cell gel (SCG, "comet") assay. Both methylated trivalent arsenicals were able to nick and/or completely degrade phi X174 DNA in vitro in 2 h incubations at 37 degreesC (pH 7.4) depending on concentration. MAsIII was effective at nicking phi X174 DNA at 30 mM; however, at 150 muM DMAsIII, nicking could be observed. Exposure of (phi X174 DNA to sodium arsenite (iAs(III); from 1 nM up to 300 mM), sodium arsenate (from 1 muM to 1 M), and the pentavalent arsenicals, monomethylarsonic acid (from 1 muM to 3 M) and dimethylarsinic acid (from 0.1 to 300 mM), did not nick or degrade phi X174 DNA under these conditions. In the SCG assay in human lymphocytes, methylated trivalent arsenicals were much more potent than any other arsenicals that were tested. On the basis of the slopes of the concentration-response curve for the tail moment in the SCG assay, MAsIII and DMAsIII were 77 and 386 times more potent than iAs(III), respectively. Because methylated trivalent arsenicals were the only arsenic compounds that were observed to damage naked DNA and required no exogenously added enzymatic or chemical activation systems, they are considered here to be direct-acting forms of arsenic that are genotoxic, though they are not, necessarily, the only genotoxic species of arsenic that could exist.},
	keywords = {CELLS, DIMETHYLARSINIC ACID, DRINKING-WATER, ENZYMATIC METHYLATION, FIBROBLASTS, GLUTATHIONE-REDUCTASE, HUMAN, HUMAN URINE, INHIBITION, MONOMETHYLARSONOUS ACID, SODIUM ARSENITE},
	isbn = {0893-228X},
	url = {<Go to ISI>://000168260400005},
	author = {Mass, M. J. and Tennant, A. and Roop, B. C. and Cullen, W. R. and Styblo, M. and Thomas, D. J. and Kligerman, A. D.}
}
@article {5083,
	title = {Unstable trivalent arsenic metabolites, monomethylarsonous acid and dimethylarsinous acid},
	journal = {Journal of Analytical Atomic Spectrometry},
	volume = {16},
	number = {12},
	year = {2001},
	note = {ISI Document Delivery No.: 498MYTimes Cited: 95Cited Reference Count: 52},
	pages = {1409-1413},
	type = {Article},
	abstract = {Two key arsenic metabolites, monomethylarsonous acid (MMA(III)) and dimethylarsinous acid (DMA(III)), have recently been detected in human urine. There is an increasing interest in the speciation of these metabolites in humans because of their demonstrated effects on cellular toxicity and DNA damage. However, there is no information on the oxidative stability of these arsenic species. It is not known whether and to what extent these trivalent metabolites are changed during sample handling and storage. The objective of this study was to demonstrate the oxidative conversion of these arsenic species during sample storage. We compared the effects of the storage temperature (25, 4, and -20 degreesC) and storage duration (up to 5 months) on the stability of MMA(III) and DMA(III) in de-ionized water and in human urine. We used HPLC with hydride generation atomic fluorescence detection for the speciation of arsenic. This method provided sub-mug L-1 to low-mug L-1 detection limits for each arsenic species. We found that the oxidation of MMA(III) and DMA(III) was matrix and temperature dependent. Low temperature conditions (4 and -20 degreesC) improved the stability of these arsenic species over the room temperature storage condition. MMA(III) in de-ionized water was relatively stable for almost 4 months, when stored at 4 or -20 degreesC with less than 10\% of MMA(III) oxidized to MMA(V). In contrast, most of MMA(III) ( 90\%) in urine was oxidized to MMA(V) over the 5 month period under the 4 or -20 degreesC storage condition. At 25 degreesC, MMA(III) in urine was completely oxidized to MMA(V) within a week. DMA(III) in deionized water was stable for only 2-3 days, being rapidly oxidized to DMA(V). DMA(III) in urine was completely oxidized to DMA(V) within a day at 4 or -20 degreesC. The conversion of DMA(III) to DMA(V) in urine at 25 degreesC was complete in 17 h. These results show that MMA(III) and DMA(III) are much less stable than other arsenic species, and their stability depends on sample matrix and temperature.},
	keywords = {ATOMIC FLUORESCENCE DETECTION, BLACKFOOT DISEASE, chemical, DRINKING-WATER, ENZYMATIC, GLUTATHIONE-REDUCTASE, HUMAN HEPATOCYTES, HUMAN URINE, LIQUID-CHROMATOGRAPHY, METHYLATION, RABBIT LIVER, SPECIATION},
	isbn = {0267-9477},
	url = {<Go to ISI>://000172516100011},
	author = {Gong, Z. L. and Lu, X. F. and Cullen, W. R. and Le, X. C.}
}
@article {4584,
	title = {Immunochemical extraction and detection of LSD in whole blood},
	journal = {Journal of Immunological Methods},
	volume = {224},
	number = {1-2},
	year = {1999},
	note = {ISI Document Delivery No.: 195AQTimes Cited: 10Cited Reference Count: 19},
	month = {Apr},
	pages = {11-18},
	type = {Article},
	abstract = {Polyclonal antibodies raised against the hallucinogenic drug, lysergic acid diethylamide (LSD), were used to detect and extract drug from whole blood samples. An indirect ELISA was used to detect as little as 1 pg of total drug in 25 mu l blood. The limit of detection of the immunoassay, calculated from the mean - 3 SD was 39 pg/ml. The analytical recovery of LSD (2.5-0.2 ng/ml) from whole blood was 102-113\%. Within-run CVs for LSD spiked in blood at 1.25, 0.16 and 0.04 ng/ml were 5.6, 3.1, and 8.9\%, respectively (n = 4). There was an overall decrease in precision when whole blood was used in place of urine, due to the increased complexity of the matrix. However, using this technique LSD was calibrated in blood in the sub-ng/ml region of forensic interest. Immunoaffinity extraction was used to isolate LSD from blood and urine samples. The affinity support was prepared by covalently attaching anti-LSD antibodies to Protein A-coated agarose beads. No pre-treatment of the sample was required other than the addition of neutral buffer. Sub-ng/ml concentrations of LSD were routinely extracted from blood and urine samples with greater than 80\% recovery of drug. This technique, which could be used to extract LSD from blood and urine samples prior to confirmatory drug analysis, could be completed in about 10 min. (C) 1999 Elsevier Science B.V. All rights reserved.},
	keywords = {BLOOD, CHROMATOGRAPHY-MASS-SPECTROMETRY, CONFIRMATION, ELISA, HUMAN URINE, immunoaffinity extraction, IMMUNOASSAY, LSD, LYSERGIC-ACID DIETHYLAMIDE, N-DEMETHYL-LSD, RADIOIMMUNOASSAY, SERUM},
	isbn = {0022-1759},
	url = {<Go to ISI>://000080227300002},
	author = {Kerrigan, S. and Brooks, D. E.}
}
@article {3094,
	title = {EFFECT OF CYSTEINE ON THE SPECIATION OF ARSENIC BY USING HYDRIDE GENERATION ATOMIC-ABSORPTION SPECTROMETRY},
	journal = {Analytica Chimica Acta},
	volume = {285},
	number = {3},
	year = {1994},
	note = {ISI Document Delivery No.: MV474Times Cited: 61Cited Reference Count: 41},
	month = {Jan},
	pages = {277-285},
	type = {Article},
	abstract = {The use of hydride generation techniques for arsenic species is pH dependent. Identical responses can not be obtained from arsenite, arsenate, monomethylarsonic acid (MMAA) and dimethylarsinic acid (DMAA) when the same acid concentration is used. Thus some methods commonly used for the direct determination of total arsenic under compromised conditions are subject to error. This error is eliminated by the addition of 2\% cysteine to samples prior to hydride generation. In the presence of cysteine the optimum condition for the determination of these arsenic species is in the same range, and a single arsenic species can be used for calibration. This finding is applied to the determination of arsenic in human urine by using flow injection, hydride generation, and atomic absorption spectrometry methodology. The effect of cysteine and thioglycerol is reported in detail, and it is proposed that arsenate, MMAA and DMAA all in the As(V) state, are reduced to the As(III) state as organo-sulfur-arsenic(III) compounds through the reaction between the arsenic species and the thiol. These products, organosulfur derivatives of arsenic(III), easily react with tetrahydroborate(III) under similar conditions to afford the arsines without interference from cysteine. Non-thiol-containing amino acids such as methionine, glycine and histidine do not react with arsenic species in this way, and therefore they do not affect the pH dependence of the generation of arsenic hydride species.},
	keywords = {AMOUNTS, ANTIMONY, ARSENIC SPECIATION, ATOMIC ABSORPTION SPECTROMETRY, CHROMATOGRAPHY, CYSTEINE, EMISSION-SPECTROMETRY, ENVIRONMENT, FLOW INJECTION, HUMAN URINE, HYDRIDE GENERATION, INTERFERENCE REDUCTION, L-CYSTINE, NATURAL-WATERS, selenium, SPECTROSCOPY, TIN, TRACE},
	isbn = {0003-2670},
	url = {<Go to ISI>://A1994MV47400004},
	author = {Le, X. C. and Cullen, W. R. and Reimer, K. J.}
}
