In vitro toxicological characterisation of the S-containing arsenic metabolites thio-dimethylarsinic acid and dimethylarsinic glutathione

Leffers, Larissa; Unterberg, Marlies; Bartel, Marc; Hoppe, Cornelia; Pieper, Imke; Stertmann, Julia; Ebert, Franziska; Humpf, Hans‐Ulrich; Schwerdtle, Tanja

doi:10.1016/j.tox.2013.01.007

Cited by 41 publications

(27 citation statements)

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“…98,99 The cytotoxicities of DMMTA V and DMA III (GS) are similar (IC 70 21 μM and 6 μM, respectively) in A549 human lung adenocarcinoma epithelial cells. 100 Taken together, these results show DMMTA V , a dimethylated thioarsenical containing pentavalent arsenic, to be nearly as cytotoxic as an inorganic oxoarsenical (iAs III ) or a dimethylated oxoarsenical that contains trivalent arsenic (DMA III and DMA III (GS)). Comparable cytotoxic potencies of DMMTA V and DMA III reflect similar kinetics for cellular accumulation of these compounds.…”

Section: Introductionmentioning

confidence: 72%

Importance of Being Thiomethylated: Formation, Fate, and Effects of Methylated Thioarsenicals

Wang

Thomas

Naranmandura³

2015

Chem. Res. Toxicol.

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Although inorganic arsenic has long been recognized as a potent toxicant and carcinogen in humans, recent evidence shows that at least some of its effects are mediated by methylated metabolites. Elucidating the conversion of inorganic arsenic to mono-, di-, and trimethylated species has provided insights into the enzymology of this pathway and identified genetic and environmental factors that influence the susceptibility of individuals to this metalloid's adverse health effects. Notably, almost all work on the formation, fate, and effects of methylated arsenicals has focused on oxoarsenicals in which arsenic is bound to one or more oxygen atoms. However, thioarsenicals are a class of arsenicals in which a sulfur atom has replaced one or more oxygens that are bound to arsenic. Thioarsenicals have been identified as urinary metabolites in humans and other animals following exposure to inorganic arsenic. Studies find that methylated thioarsenicals exhibit kinetic behavior and toxicological properties that distinguish them from methylated oxoarsenicals. This perspective considers that formation, fate, and effects of methylated thioarsenicals with an emphasis on examining the linkages between the molecular processes that underlie both methylation and thiolation reactions. Integrating this information will provide a more comprehensive view of the relationship between the metabolism of arsenic and the risk posed by chronic exposure to this environmental contaminant.

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Section: Introductionmentioning

confidence: 72%

Importance of Being Thiomethylated: Formation, Fate, and Effects of Methylated Thioarsenicals

Wang

Thomas

Naranmandura³

2015

Chem. Res. Toxicol.

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“…Comparative permeability, bioaccessability and effect on cell number for As species are summarized from previously published data (Ebert et al; Leffers et al, 2013a, 2013b; Meyer et al, 2014, 2015). A) Permeability of As species (apical to basolateral) after 48 hour apical incubation with Caco-2 cells.…”

Section: Figmentioning

confidence: 99%

Human exposure to organic arsenic species from seafood

Taylor

Goodale

Raab

et al. 2017

Science of The Total Environment

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256

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Seafood, including finfish, shellfish, and seaweed, is the largest contributor to arsenic (As) exposure in many human populations. In contrast to the predominance of inorganic As in water and many terrestrial foods, As in marine-derived foods is present primarily in the form of organic compounds. To date, human exposure and toxicological assessments have focused on inorganic As, while organic As has generally been considered to be non-toxic. However, the high concentrations of organic As in seafood, as well as the often complex As speciation, can lead to complications in assessing As exposure from diet. In this report, we evaluate the presence and distribution of organic As species in seafood, and combined with consumption data, address the current capabilities and needs for determining human exposure to these compounds. The analytical approaches and shortcomings for assessing these compounds are reviewed, with a focus on the best practices for characterization and quantitation. Metabolic pathways and toxicology of two important classes of organic arsenicals, arsenolipids and arsenosugars, are examined, as well as individual variability in absorption of these compounds. Although determining health outcomes or assessing a need for regulatory policies for organic As exposure is premature, the extensive consumption of seafood globally, along with the preliminary toxicological profiles of these compounds and their confounding effect on assessing exposure to inorganic As, suggests further investigations and process-level studies on organic As are needed to fill the current gaps in knowledge.

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“…Anyway, so far nobody has resolved a phenomenon, that equal amounts of arsenic in the form of NP realgar and soluble ATO have comparable cytotoxicity, despite the fact that only a part of arsenic atoms is accessible for chemical reaction in the nanoparticles of about 100 nm in diameter. One of possible explanation can be found in the article of T. Schwerdtle et al [46] about S(ulphur)-containing arsenic metabolites that modulated total cellular glutathione amount at picomolar concentrations. Recently it was shown that sodium arsenite treatment of normal cells induces prolonged activation of Nrf2 through autophagy dysfunction [29].…”

Section: Realgar Nanoparticlesmentioning

confidence: 99%

Realgar (As4S4) nanoparticles and arsenic trioxide (As2O3) induced autophagy and apoptosis in human melanoma cells in vitro

Pastorek¹,

Gronesova²,

Cholujová³

et al. 2014

neo

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The aim of the present study was to compare the effect of realgar nanoparticles and arsenic trioxide (ATO) on viability, DNA damage, proliferation, autophagy and apoptosis in the human melanoma cell lines BOWES and A375. The application of various flow cytometric methods for measurements cell viability, DNA cell cycle, mitochondrial potential, lysosomal activity, and intracellular content of glutathione was used. In addition, quantitative PCR, western blotting and multiplex bead array analyses were applied for evaluation of redox stress, autophagic flux, and cell signaling alterations.The results showed that realgar treatment of studied cells caused modulation of cell proliferation, induced a block in G2/M phase of the cell cycle and altered phosphorylation of IκB, Akt, ERK1/2, p38, and JNK kinases, as well as decreased mitochondrial membrane potential. Additionally, it appeared that induction of cell death by both realgar and ATO was dose-dependent, when lower (0.3 µM) dosage increased lysosomal activity and induced autophagy and higher (1.25 µM) concentration resulted in the appearance of apoptosis, while pan-caspase inhibitor attenuated more efficiently realgar-than ATO-induced cell death. Furthermore, low concentrations of ATO and realgar nanoparticles increased the content of intracellular glutathione and elevated γ-H2AX expression confirmed DNA damage preferentially at higher concentrations of both drugs used. Further analysis revealed slight differences in time-dependent phosphorylation pattern due to both realgar and ATO treatments, while significant differences were noticed between cell lines.In conclusion, realgar nanoparticles and ATO treatment induced dose-dependent activation of autophagy and apoptosis in both melanoma cell lines, when autophagy flux was determined at lower drug concentrations and the switch to apoptosis occurred at higher concentrations of both arsenic forms.Key words : realgar, autophagy, cell cycle, DNA damage, Nrf2, chloroquine, glutathione Arsenic has been accepted to be a poison for years and it is generally considered as an extremely effective environmental co-carcinogen for some human malignancies, especially for skin and lung cancer [1]. The toxicity of arsenicals depends on their chemical states, exposure dose, the biological species, age and gender, as well as on individual susceptibilities, genetic and nutritional factors [2]. Largely, to living organisms methylated trivalent arsenicals are more toxic and pentavalent metabolites are less toxic than arsenite (iAs III ) [3,4]. In 2002, a pilot clinical study of pure realgar in treatment of patients with APL was conducted in China, and impressive responses were achieved and reported [5]. Realgar is a mineral composed mainly of tetra-arsenic tetra-sulfide (As 4 S 4 ), which is also called red arsenic due to its a deep red color (Xionghuang in Chinese). Low solubility of arsenic in realgar, using water as a solvent (0.4%), can be increased to approximately 1.5% by leaching in artificial body fluid [6]. Higher proportion of...

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In vitro toxicological characterisation of the S-containing arsenic metabolites thio-dimethylarsinic acid and dimethylarsinic glutathione

Cited by 41 publications

References 73 publications

Importance of Being Thiomethylated: Formation, Fate, and Effects of Methylated Thioarsenicals

Importance of Being Thiomethylated: Formation, Fate, and Effects of Methylated Thioarsenicals

Human exposure to organic arsenic species from seafood

Realgar (As4S4) nanoparticles and arsenic trioxide (As2O3) induced autophagy and apoptosis in human melanoma cells in vitro

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