TY - JOUR T1 - Multidrug Resistance Protein 1 (MRP1/<em>ABCC1</em>)-Mediated Cellular Protection and Transport of Methylated Arsenic Metabolites Differs between Human Cell Lines JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1096 LP - 1105 DO - 10.1124/dmd.117.079640 VL - 46 IS - 8 AU - Mayukh Banerjee AU - Gurnit Kaur AU - Brayden D. Whitlock AU - Michael W. Carew AU - X. Chris Le AU - Elaine M. Leslie Y1 - 2018/08/01 UR - http://dmd.aspetjournals.org/content/46/8/1096.abstract N2 - The ATP-binding cassette (ABC) transporter multidrug resistance protein 1 (MRP1/ABCC1) protects cells from arsenic (a proven human carcinogen) through the cellular efflux of arsenic triglutathione [As(GS)3] and the diglutathione conjugate of monomethylarsonous acid [MMA(GS)2]. Previously, differences in MRP1 phosphorylation (at Y920/S921) and N-glycosylation (at N19/N23) were associated with marked differences in As(GS)3 transport kinetics between HEK293 and HeLa cell lines. In the current study, cell line differences in MRP1-mediated cellular protection and transport of other arsenic metabolites were explored. MRP1 expressed in HEK293 cells reduced the toxicity of the major urinary arsenic metabolite dimethylarsinic acid (DMAV), and HEK-WT-MRP1-enriched vesicles transported DMAV with high apparent affinity and capacity (Km 0.19 µM, Vmax 342 pmol⋅mg−1protein⋅min−1). This is the first report that MRP1 is capable of exporting DMAV, critical for preventing highly toxic dimethylarsinous acid formation. In contrast, DMAV transport was not detected using HeLa-WT-MRP1 membrane vesicles. MMA(GS)2 transport by HeLa-WT-MRP1 vesicles had a greater than threefold higher Vmax compared with HEK-WT-MRP1 vesicles. Cell line differences in DMAV and MMA(GS)2 transport were not explained by differences in phosphorylation at Y920/S921. DMAV did not inhibit, whereas MMA(GS)2 was an uncompetitive inhibitor of As(GS)3 transport, suggesting that DMAV and MMA(GS)2 have nonidentical binding sites to As(GS)3 on MRP1. Efflux of different arsenic metabolites by MRP1 is likely influenced by multiple factors, including cell and tissue type. This could have implications for the impact of MRP1 on both tissue-specific susceptibility to arsenic-induced disease and tumor sensitivity to arsenic-based therapeutics. ER -