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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 (DMA V ), and HEK-WT-MRP1-enriched vesicles transported DMA V with high apparent affinity and capacity ( K  m 0.19 µ M, V  max 342 pmol⋅mg -1 protein⋅min -1 ). This is the first report that MRP1 is capable of exporting DMA V , critical for preventing highly toxic dimethylarsinous acid formation. In contrast, DMA V 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 V  max compared with HEK-WT-MRP1 vesicles. Cell line differences in DMA V and MMA(GS) 2 transport were not explained by differences in phosphorylation at Y920/S921. DMA V did not inhibit, whereas MMA(GS) 2 was an uncompetitive inhibitor of As(GS) 3 transport, suggesting that DMA V 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.

drug metabolism and disposition/dmd online

Multidrug Resistance Protein 1 (MRP1/<i>ABCC1</i>)-Mediated Cellular Protection and Transport of Methylated Arsenic Metabolites Differs between Human Cell Lines

Multidrug Resistance Protein 1 (MRP1/ABCC1)-Mediated Cellular Protection and Transport of Methylated Arsenic Metabolites Differs between Human Cell Lines