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

The ATP-binding cassette (ABC) transporter Multidrug Resistance Protein 1 (MRP1/ABCC1) is known to protect cells from the proven human carcinogen arsenic through the cellular efflux of arsenic triglutathione [As(GS)3], and the diglutathione conjugate of the highly toxic monomethylarsonous acid (MMAIII) [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. The objectives of the current study were to determine if differences in MRP1-mediated cellular protection and transport of other arsenic metabolites exist between HEK293 and HeLa cells. MRP1 expressed in HEK293 cells conferred protection against the major urinary arsenic metabolite dimethylarsinic acid (DMAV) through high apparent affinity and capacity transport (Km 0.19 μM, Vmax 342 pmol mg-1 protein min-1). In contrast, DMAV transport was not detected using HeLa-WT-MRP1 membrane vesicles. MMA(GS)2 transport by HeLa-WT-MRP1 vesicles had a similar apparent Km, but a greater than 3-fold higher Vmax, compared to 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, while MMA(GS)2 was an uncompetitive inhibitor of As(GS)3 transport, suggesting that DMAV and MMA(GS)2 have non-identical binding sites to As(GS)3 on MRP1. Detoxification of different arsenic metabolites by MRP1 is likely influenced by multiple factors including cell and tissue type. This could have implications for the influence of MRP1 on both tissue specific susceptibility to arsenic-induced disease, and tumour sensitivity to arsenic-based therapeutics.