@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 {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 {4942,
	title = {Comparative toxicity of trivalent and pentavalent inorganic and methylated arsenicals in rat and human cells},
	journal = {Archives of Toxicology},
	volume = {74},
	number = {6},
	year = {2000},
	note = {ISI Document Delivery No.: 349ZATimes Cited: 358Cited Reference Count: 37},
	month = {Aug},
	pages = {289-299},
	type = {Article},
	abstract = {Biomethylation is considered a major detoxification pathway for inorganic arsenicals (iAs). According to the postulated metabolic scheme, the methylation of iAs yields methylated metabolites in which arsenic is present in both pentavalent and trivalent forms. Pentavalent mono- and dimethylated arsenicals are less acutely toxic than iAs. However, little is known about the toxicity of trivalent methylated species. In the work reported here the toxicities of iAs and trivalent and pentavalent methylated arsenicals were examined in cultured human cells derived from tissues that are considered a major site for iAs methylation (liver) or targets for carcinogenic effects associated with exposure to iAs (skin, urinary bladder, and lung). To characterize the role of methylation in the protection against toxicity of arsenicals, the capacities of cells to produce methylated metabolites were also examined. In addition to human cells, primary rat hepatocytes were used as methylating controls. Among the arsenicals examined, trivalent monomethylated species were the most cytotoxic in all cell types. Trivalent dimethylated arsenicals were at least as cytotoxic as trivalent iAs (arsenite) for most cell types. Pentavalent arsenicals were significantly less cytotoxic than their trivalent analogs. Among the cell types examined, primary rat hepatocytes exhibited the greatest methylation capacity for iAs followed by primary human hepatocytes, epidermal keratinocytes, and bronchial epithelial cells. Cells derived from human bladder did not methylate iAs. There was no apparent correlation between susceptibility of cells to arsenic toxicity and their capacity to methylate iAs. These results suggest that (1) trivalent methylated arsenicals, intermediary products of arsenic methylation, may significantly contribute to the adverse effects associated with exposure to iAs, and (2) high methylation capacity does not protect cells from the acute toxicity of trivalent arsenicals.},
	keywords = {ARSENATE, arsenic, ARSENITE, BINDING, bladder, cell culture, CELLULAR UPTAKE, DIMETHYLARSINIC ACID, dimethylarsinous acid, DRINKING-WATER, ENZYMATIC METHYLATION, GLUTATHIONE, HEPATOCYTES, HUMAN, IN-VITRO METHYLATION, LIVER, lung, METABOLISM, methylarsonic acid, methylarsonous acid, METHYLATION, RABBIT LIVER, SKIN, TOXICITY},
	isbn = {0340-5761},
	url = {<Go to ISI>://000089074500001},
	author = {Styblo, M. and Del Razo, L. M. and Vega, L. and Germolec, D. R. and LeCluyse, E. L. and Hamilton, G. A. and Reed, W. and Wang, C. and Cullen, W. R. and Thomas, D. J.}
}
@article {4862,
	title = {Determination of monomethylarsonous acid, a key arsenic methylation intermediate, in human urine},
	journal = {Environmental Health Perspectives},
	volume = {108},
	number = {11},
	year = {2000},
	note = {ISI Document Delivery No.: 373XPTimes Cited: 101Cited Reference Count: 48},
	month = {Nov},
	pages = {1015-1018},
	type = {Article},
	abstract = {In this study we report on the finding of monomethylarsonous acid [MMA(III)I in human urine. This newly identified arsenic species is a key intermediate in the metabolic pathway of arsenic biomethylation, which involves stepwise reduction of pentavalent to trivalent arsenic species followed by oxidative addition of a methyl group. Arsenic speciation was carried out using ion-pair chromatographic separation of arsenic compounds with hydride generation atomic fluorescence spectrometry detection. Speciation of the inorganic arsenite [As(III)], inorganic arsenate [As(V)], monomethylarsonic acid [MMA(V)], dimethylarsinic acid [DMA(V)], and MMA(III) in a urine sample was complete in 5 min. Urine samples collected from humans before and after a single oral administration of 300 mg sodium 2,3-dimercapto-1-propane sulfonate (DMPS) were analyzed for arsenic species. MMA(III) was found in 51 out of 123 urine samples collected from 41 people in inner Mongolia 0-6 hr after the administration of DMPS. MMA(III)in urine samples did not arise from the reduction of MMA(V) by DMPS. DMPS probably assisted the release of MMA(III) that was formed in the body. Along with the presence of MMA(III), there was an increase in the relative concentration of MMA(V) and a decrease in DMA(V) in the urine samples collected after the DMPS ingestion.},
	keywords = {3-dimercapto-1-propane sulfonate, ARSENIC SPECIATION, BIOMARKERS, CARCINOGENESIS, CHEMICAL FORMS, DIMETHYLARSINIC ACID, ENZYMATIC METHYLATION, EXCRETION, EXPOSURE, GLUTATHIONE-REDUCTASE, INGESTION, METABOLISM, METABOLITES, METHYLATION, MONOMETHYLARSONOUS ACID, sodium 2, SPECIATION, trivalent methylarsenic species, urine metabolites},
	isbn = {0091-6765},
	url = {<Go to ISI>://000165315600019},
	author = {Le, X. C. and Ma, M. S. and Lu, X. F. and Cullen, W. R. and Aposhian, H. V. and Zheng, B. S.}
}
@article {4901,
	title = {Monomethylarsonous acid (MMA(III)) is more toxic than arsenite in Chang human hepatocytes},
	journal = {Toxicology and Applied Pharmacology},
	volume = {163},
	number = {2},
	year = {2000},
	note = {ISI Document Delivery No.: 295TBTimes Cited: 294Cited Reference Count: 28},
	month = {Mar},
	pages = {203-207},
	type = {Article},
	abstract = {Methylation has been considered to be the primary detoxication pathway of inorganic arsenic. Inorganic arsenic is methylated by many, but not all animal species, to monomethylarsonic acid (MMA(V)), monomethylarsonous acid (MMA(III)), and dimethylarsinic acid (DMA(V)). The As-V derivatives have been assumed to produce low toxicity, but the relative toxicity of MMA(III) remains unknown. In vitro toxicities of arsenate, arsenite, MMA(V), MMA(III) and DMA(V) were determined in Chang human hepatocytes, Leakage of lactate dehydrogenase (LDH) and intracellular potassium (K+) and mitochondrial metabolism of the tetrazolium salt XTT were used to assess cytotoxicity due to arsenic exposure. The mean LC50 based on LDH assays in phosphate media was 6 mu M for MMA(III) and 68 mu M for arsenite. Using the assay for K+ leakage in phosphate media, the mean LC50 was 6.3 mu M for MMA(III) and 19.8 mu M for arsenite. The mean LC50 based on the XTT assay in phosphate media was 13.6 mu M for MMA(III) and 164 mu M for arsenite. The results of the three cytotoxicity assays (LDH, K+, and XTT) reveal the following order of toxicity in Chang human hepatocytes: MMA(III) > arsenite > arsenate > MMA(V) = DMA(V). Data demonstrate that MMA(III) an intermediate in inorganic arsenic methylation, is highly toxic and again raises the question as to whether methylation of inorganic arsenic is a detoxication process. (C) 2000 Academic Press.},
	keywords = {ARSENATE, ARSENITE, ASSAY, CELLS, Chang human hepatocytes, DIMETHYLARSINIC ACID, DMA, DMA(V), DMPS, ENZYMATIC METHYLATION, LDH, LIVER, MICE, MMA(III), MMA(V), monomethylarsonic acid, MONOMETHYLARSONOUS ACID, POTASSIUM, VIABILITY, XTT},
	isbn = {0041-008X},
	url = {<Go to ISI>://000085983000013},
	author = {Petrick, J. S. and Ayala-Fierro, F. and Cullen, W. R. and Carter, D. E. and Aposhian, H. V.}
}
@article {4673,
	title = {Metabolism of arsenic in primary cultures of human and rat hepatocytes},
	journal = {Chemical Research in Toxicology},
	volume = {12},
	number = {7},
	year = {1999},
	note = {ISI Document Delivery No.: 219JCTimes Cited: 81Cited Reference Count: 26},
	month = {Jul},
	pages = {560-565},
	type = {Article},
	abstract = {The liver is considered a major site for methylation of inorganic arsenic (iAs). However, there is Little data on the capacity of human liver to methylate iAs. This work examined the metabolism of arsenite (iAs(III)), arsenate (iAs(v)), methylarsine oxide ((MAsO)-O-III), methylarsonic acid (MAsv), dimethylarsinous acid (DMAsIII), and dimethylarsinic acid (DMAsV) in primary cultures of normal human hepatocytes. Primary rat hepatocytes were used as methylating controls, iAs(III) and (MAsO)-O-III were metabolized more extensively than iAs(v) and MAsv by either cell type. Neither human nor rat hepatocytes metabolized DMAsIII or DMAsV. Methylation of iAs(III) by human hepatocytes yielded methylarsenic (MAs) and dimethylarsenic (DMAs) species; (MAsO)-O-III was converted to DMAs. The total methylation yield (MAs and DMAs) increased over the range of 0.1 to 4 mu M iAs(III). However, DMAs production was inhibited by iAs(III) in a concentration-dependent manner, and the DMAs/MAs ratio decreased. iAs(III) (10 and 20 mu M) inhibited both methylation reactions. Inhibition of DMAs synthesis resulted in accumulation of iAs and MAs in human hepatocytes, suggesting that dimethylation is required for iAs clearance from cells. Methylation capacities of human hepatocytes obtained from four donors ranged from 3.1 to 35.7 pmol of iAs(III) per 10(6) cells per hour and were substantially lower than the methylation capacity of rat hepatocytes (387 pmol of iAs(III) per 10(6) cells per hour). The maximal methylation rates for either rat or human hepatocytes were attained between 0.4 and 4 mu M iAs(III). In summary, (i) human hepatocytes methylate iAs, (ii) the capacities for iAs methylation vary among individuals and are saturable, and (iii) moderate concentrations of iAs inhibit DMAs synthesis, resulting in an accumulation of iAs and MAs in cells.},
	keywords = {ASSAY, ENZYMATIC METHYLATION, IN-VITRO, INGESTION, LIVER, PURIFICATION, TOXICITY, URINARY-EXCRETION},
	isbn = {0893-228X},
	url = {<Go to ISI>://000081603300003},
	author = {Styblo, M. and Del Razo, L. M. and LeCluyse, E. L. and Hamilton, G. A. and Wang, C. Q. and Cullen, W. R. and Thomas, D. J.}
}
@article {4552,
	title = {The separation of dimethylarsinic acid, methylarsonous acid, methylarsonic acid, arsenate and dimethylarsinous acid on the Hamilton PRP-X100 anion-exchange column},
	journal = {Applied Organometallic Chemistry},
	volume = {13},
	number = {11},
	year = {1999},
	note = {ISI Document Delivery No.: 255DLTimes Cited: 24Cited Reference Count: 29},
	month = {Nov},
	pages = {837-843},
	type = {Article},
	abstract = {In order to separate the potential arsenite metabolites methylarsonous acid and dimethylarsinous acid from arsenite, arsenate, methylarsonic acid and dimethylarsinic acid, the pH-dependent retention behaviour of all six arsenic compounds was studied on a Hamilton PRP-X100 anion-exchange column with 30 mM phosphate buffers (pH 5, 6, 7, 8 and 9) containing 20\% (v/v) methanol as mobile phase and employing an inductively coupled plasma atomic emission spectrometer (ICP-AES) as the arsenic-specific detector. Baseline separation of dimethylarsinic acid, methylarsonous acid, methylarsonic acid, arsenate and dimethylarsinous acid was achieved with a 30 mmol dm(-3) phosphate buffer (pH 5)-methanol mixture (80:20, v/v) in 25 min. Arsenite is not baseline-separated from dimethylarsinic acid under these conditions, Copyright (C) 1999 John Wiley \& Sons, Ltd.},
	keywords = {ARSENATE, ARSENITE, BEHAVIOR, DIMETHYLARSINIC ACID, dimethylarsinous acid, ENVIRONMENT, ENZYMATIC METHYLATION, GLUTATHIONE, HPLC-ICP-AES, LAKE-BIWA, METABOLISM, METHYLARSENICALS, methylarsonic acid, methylarsonous acid, SPECIATION, SPECTROMETRY},
	isbn = {0268-2605},
	url = {<Go to ISI>://000083654200005},
	author = {Gailer, J. and Madden, S. and Cullen, W. R. and Denton, M. B.}
}
