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Monomethylarsenic Diglutathione [MMAIII(GS)2] Transport by the Human Multidrug Resistance Protein 1 (MRP1/ABCC1).
MedLine Citation:
PMID:  21918036     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
The ATP-binding cassette (ABC) transporter protein 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 than empty vector control (HeLa-vector) cells to MMA(III), and this resistance was dependent on glutathione (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 non-reducing GSH analogue, 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:
Michael W Carew; Hua Naranmandura; Caley B Shukalek; X C Le; Elaine M Leslie
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-9-14
Journal Detail:
Title:  Drug metabolism and disposition: the biological fate of chemicals     Volume:  -     ISSN:  1521-009X     ISO Abbreviation:  -     Publication Date:  2011 Sep 
Date Detail:
Created Date:  2011-9-15     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
University of Alberta.
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