Journal
TOXICOLOGY AND APPLIED PHARMACOLOGY
Volume 239, Issue 2, Pages 137-143Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.taap.2008.12.008
Keywords
Dimethylthioarsinic acid; Trimethylarsine sulfide; 34-S labeled arsenicals; Speciation; Mouse cecum intestinal microflora
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Funding
- The United States Environmental Protection Agency through its Office of Research and Development
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Although metabolism of arsenicals to form methylated oxoarsenical species has been extensively studied. less is known about the formation of thiolated arsenical species that have recently been detected as urinary metabolites. Indeed, their presence suggests that the metabolism of ingested arsenic is more complex than previously thought. Recent reports have shown that thiolated arsenicals can be produced by the anaerobic microflora of the mouse cecum, suggesting that metabolism prior to systemic absorption may be a significant determinant of the pattern and extent of exposure to various arsenic-containing species. Here, we examined the metabolism of S-34 labeled dimethylthioarsinic acid (S-34-DMTA(V)) by the anaerobic microflora of the mouse cecum using HPLC-ICP-MS and HPLC-ESI-MS/MS to monitor for the presence of various oxo- and thioarsenicals. The use of isotopically enriched S-34-DMTA(V) made it possible to differentiate among potential metabolic pathways for production of the trimethylarsine sulfide (TMAS(V)). Upon in vitro incubation in an assay containing anaerobic microflora of mouse cecum, S-34-DMTA(V) underwent several transformations. Labile S-34 was exchanged with more abundant S-34 to produce S-34-DMTA(V), a thiol group was added to yield DMDTA(V), and a methyl group was added to yield S-34-TMAS(V). Because incubation of S-34-DMTA(V) resulted in the formation of S-34-TMAS(V), the pathway for its formation must preserve the arsenic-sulfur bond. The alternative metabolic pathway postulated for formation of TMAS(V) from dimethylarsinic acid (DMA(V)) would proceed via a dimethylarsinous acid (DMA(III)) intermediate and would necessitate the loss of S-34 label. Structural confirmation of the metabolic product was achieved using HPLC-ESI-MS/MS. The data presented support the direct methylation of DMTA(V) to TMAS(V). Additionally, the detection of isotopically pure S-34-TMAS(V) raises questions about the sulfur exchange properties of TMAS(V) in the cecum material. Therefore, S-34-TMAS(V) was incubated and the exchange was monitored with respect to time. The data suggest that the As-S bond associated with TMAS(V) is less labile than the As-S bond associated with DMTA(V). Published by Elsevier Inc.
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