Exploring the in vitro formation of trimethylarsine sulfide from dimethylthioarsinic acid in anaerobic microflora of mouse cecum using HPLC-ICP-MS and HPLC-ESI-MS
- US EPA, ORD, NERL, Microbiological and Chemical Exposure, Assessment Research Division, Cincinnati, OH 45268 (United States)
- US EPA, ORD, NHEERL, Environmental Carcinogenesis Division, Research Triangle Park, NC 27711 (United States)
- US EPA, ORD, NHEERL, Experimental Toxicology Division, Research Triangle Park, NC 27711 (United States)
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 {sup 34}S labeled dimethylthioarsinic acid ({sup 34}S-DMTA{sup 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 {sup 34}S-DMTA{sup V} made it possible to differentiate among potential metabolic pathways for production of the trimethylarsine sulfide (TMAS{sup V}). Upon in vitro incubation in an assay containing anaerobic microflora of mouse cecum, {sup 34}S-DMTA{sup V} underwent several transformations. Labile {sup 34}S was exchanged with more abundant {sup 32}S to produce {sup 32}S-DMTA{sup V}, a thiol group was added to yield DMDTA{sup V}, and a methyl group was added to yield {sup 34}S-TMAS{sup V}. Because incubation of {sup 34}S-DMTA{sup V} resulted in the formation of {sup 34}S-TMAS{sup V}, the pathway for its formation must preserve the arsenic-sulfur bond. The alternative metabolic pathway postulated for formation of TMAS{sup V} from dimethylarsinic acid (DMA{sup V}) would proceed via a dimethylarsinous acid (DMA{sup III}) intermediate and would necessitate the loss of {sup 34}S label. Structural confirmation of the metabolic product was achieved using HPLC-ESI-MS/MS. The data presented support the direct methylation of DMTA{sup V} to TMAS{sup V}. Additionally, the detection of isotopically pure {sup 34}S-TMAS{sup V} raises questions about the sulfur exchange properties of TMAS{sup V} in the cecum material. Therefore, {sup 34}S-TMAS{sup V} was incubated and the exchange was monitored with respect to time. The data suggest that the As-S bond associated with TMAS{sup V} is less labile than the As-S bond associated with DMTA{sup V}.
- OSTI ID:
- 21272636
- Journal Information:
- Toxicology and Applied Pharmacology, Vol. 239, Issue 2; Conference: Valencia Spain arsenic meeting: From nature to humans, Valencia (Spain), 21-23 May 2008; Other Information: DOI: 10.1016/j.taap.2008.12.008; PII: S0041-008X(08)00521-8; Copyright (c) 2008 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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