Citation:

DROBNA, Z., A. HERNANDEZ-ZAVALA, V. DEVESA I PEREZ, D. J. THOMAS, AND M. STYBLO. THE ROLE OF MEMBRANE TRANSPORTERS IN THE CELLULAR METABOLISM OF ARSENIC. Presented at Society of Toxicology Annual Meeting, Charlotte, NC, March 25 - 29, 2007.

Description:

Arsenic (+3 oxidation state) methyltransferase (AS3MT) catalyzes methylation of inorganic arsenic (iAs) in humans. In this pathway iAs is converted to mono- (MAs) and dimethylated (DMAs) metabolites containing either As^III or As^V. Because toxicities and metabolic fates of these metabolites differ, the overall toxicity associated with exposure to iAs depends on the pattern and extent of its conversion to metabolites. In a clonal human urothelial cell line expressing rat AS3MT (UROtsa/F35) iAs^III is more cytotoxic than in parental UROtsa cells that neither express AS3MT nor methylate iAs. Increased cytotoxicity of iAs^III in UROtsa/F35 cells has been associated with production and retention of MAs. Here, we examined the roles of membrane transporters, multidrug resistance associated proteins (MRPs), and P-glycoprotein (P-gp), in production and retention of iAs metabolites in UROtsa and UROtsa/F35 cells. Retention and methylation of arsenicals were examined in cells in which MRPs or P-gp were inhibited or in untreated cells after exposure to 1 µM iAs^III, MAs^III, or DMAs^III for 2 or 24 h.. After 2-h exposure, Inhibition of MRP or P-gp significantly increased MAs^III accumulation in either cell line and slightly increased DMAs production in MAs^III-treated UROtsa/F35 cells. MRP and P-gp inhibition also increased MAs^III accumulation in UROtsa cells after 24-h exposure. Neither cellular retention nor methylation rate was affected in UROtsa/F35 cells which converted MAs^III to DMAs. Retention and methylation rates were unaffected in UROtsa or UROtsa/F35 cells exposed to iAs^III or DMAs^III for 2 or 24 h. Hence, MRPs or P-gp may play a key role in efflux of MAs^III, a toxic intermediate in iAs metabolism, cells with limited capacity to convert MAs^III to DMAs. (This abstract does not reflect EPA policy.)

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