RT Journal Article
SR Electronic
T1 A Novel Pathway for Arsenic Elimination: Human Multidrug Resistance Protein 4 (MRP4/<em>ABCC4</em>) Mediates Cellular Export of Dimethylarsinic Acid (DMA<sup>V</sup>) and the Diglutathione Conjugate of Monomethylarsonous Acid (MMA<sup>III</sup>)
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 168
OP 179
DO 10.1124/mol.113.091314
VO 86
IS 2
A1 Mayukh Banerjee
A1 Michael W. Carew
A1 Barbara A. Roggenbeck
A1 Brayden D. Whitlock
A1 Hua Naranmandura
A1 X. Chris Le
A1 Elaine M. Leslie
YR 2014
UL http://molpharm.aspetjournals.org/content/86/2/168.abstract
AB Hundreds of millions of people worldwide are exposed to unacceptable levels of arsenic in drinking water. This is a public health crisis because arsenic is a Group I (proven) human carcinogen. Human cells methylate arsenic to monomethylarsonous acid (MMAIII), monomethylarsonic acid (MMAV), dimethylarsinous acid (DMAIII), and dimethylarsinic acid (DMAV). Although the liver is the predominant site for arsenic methylation, elimination occurs mostly in urine. The protein(s) responsible for transport of arsenic from the liver (into blood), ultimately for urinary elimination, are unknown. Human multidrug resistance protein 1 (MRP1/ABCC1) and MRP2 (ABCC2) are established arsenic efflux pumps, but unlike the related MRP4 (ABCC4) are not present at the basolateral membrane of hepatocytes. MRP4 is also found at the apical membrane of renal proximal tubule cells, making it an ideal candidate for urinary arsenic elimination. In the current study, human MRP4 expressed in HEK293 cells reduced the cytotoxicity and cellular accumulation of arsenate, MMAIII, MMAV, DMAIII, and DMAV while two other hepatic basolateral MRPs (MRP3 and MRP5) did not. Transport studies with MRP4-enriched membrane vesicles revealed that the diglutathione conjugate of MMAIII, monomethylarsenic diglutathione [MMA(GS)2], and DMAV were the transported species. MMA(GS)2 and DMAV transport was osmotically sensitive, allosteric (Hill coefficients of 1.4 ± 0.2 and 2.9 ± 1.2, respectively), and high affinity (K0.5 of 0.70 ± 0.16 and 0.22 ± 0.15 μM, respectively). DMAV transport was pH-dependent, with highest affinity and capacity at pH 5.5. These results suggest that human MRP4 could be a major player in the elimination of arsenic.