title: Monomethylarsenic diglutathione transport by the human multidrug resistance protein 1 (MRP1/ABCC1).
abstract: The ATP-binding cassette (ABC) transporter protein multidrug resistance protein 1 (MRP1; ABCC1) plays an important role in the cellular efflux of the high-priority environmental carcinogen arsenic as a triglutathione conjugate [As(GS)(3)]. Most mammalian cells can methylate arsenic to monomethylarsonous acid (MMA(III)), monomethylarsonic acid (MMA(V)), dimethylarsinous acid (DMA(III)), and dimethylarsinic acid (DMA(V)). The trivalent forms MMA(III) and DMA(III) are more reactive and toxic than their inorganic precursors, arsenite (As(III)) and arsenate (As(V)). The ability of MRP1 to transport methylated arsenicals is unknown and was the focus of the current study. HeLa cells expressing MRP1 (HeLa-MRP1) were found to confer a 2.6-fold higher level of resistance to MMA(III) than empty vector control (HeLa-vector) cells, and this resistance was dependent on GSH. In contrast, MRP1 did not confer resistance to DMA(III), MMA(V), or DMA(V). HeLa-MRP1 cells accumulated 4.5-fold less MMA(III) than HeLa-vector cells. Experiments using MRP1-enriched membrane vesicles showed that transport of MMA(III) was GSH-dependent but not supported by the nonreducing GSH analog, ophthalmic acid, suggesting that MMA(III)(GS)(2) was the transported form. MMA(III)(GS)(2) was a high-affinity, high-capacity substrate for MRP1 with apparent K(m) and V(max) values of 11 μM and 11 nmol mg(-1)min(-1), respectively. MMA(III)(GS)(2) transport was osmotically sensitive and inhibited by several MRP1 substrates, including 17β-estradiol 17-(β-D-glucuronide) (E(2)17βG). MMA(III)(GS)(2) competitively inhibited the transport of E(2)17βG with a K(i) value of 16 μM, indicating that these two substrates have overlapping binding sites. These results suggest that MRP1 is an important cellular protective pathway for the highly toxic MMA(III) and have implications for environmental and clinical exposure to arsenic.
authors.affiliation: Department of Physiology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Carew
authors.forename: Hua
authors.initials: H
authors.lastname: Naranmandura
authors.forename: Caley B
authors.initials: CB
authors.lastname: Shukalek
authors.forename: X Chris
authors.initials: XC
authors.lastname: Le
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Leslie
mesh_terms: D001152:Arsenicals / Q000493:pharmacokinetics*; D005978:Glutathione / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006367:HeLa Cells; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*
chemical_list: D001152:Arsenicals; D005978:Glutathione; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C571174:methylarsenic diglutathione; C421109:multidrug resistance-associated protein 1