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

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Mayukh BanerjeeElaine M Leslie

Abstract

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...Continue Reading

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