A Novel Pathway for Arsenic Elimination: Human Multidrug Resistance Protein 4 (MRP4/ABCC4) Mediates Cellular Export of Dimethylarsinic Acid (DMAV) and the Diglutathione Conjugate of Monomethylarsonous Acid (MMAIII)

• DOI: 10.1124/mol.113.091314
• Publication Date: 2014-05-29T02:45:59Z
• Authors: Mayukh Banerjee; Michael W. Carew; Barbara A. Roggen...; Brayden D. Whitlock; Hua Naranmandura; X. Chris Le; Elaine M. Leslie
• Keywords: 0303 health sciences; Biological Transport; Hydrogen-Ion Concentration; Glutathione; Arsenicals; Multidrug Resistance-Associated Protein 2; 6. Clean water; Arsenic; Cell Line; 3. Good health; 03 medical and health sciences; HEK293 Cells; Organometallic Compounds; Cacodylic Acid; Humans; Multidrug Resistance-Associated Proteins

Hundreds of millions people worldwide are exposed to unacceptable levels arsenic in drinking water. This is a public health crisis because Group I (proven) human carcinogen. Human cells methylate monomethylarsonous acid (MMA^III), monomethylarsonic (MMA^V), dimethylarsinous (DMA^III), and dimethylarsinic (DMA^V). Although the liver predominant site for methylation, elimination occurs mostly urine. The protein(s) responsible transport from (into blood), ultimately urinary elimination, unknown. multidrug resistance protein 1 (MRP1/<i>ABCC1</i>) MRP2 (<i>ABCC2</i>) established efflux pumps, but unlike related MRP4 (<i>ABCC4</i>) not present at basolateral membrane hepatocytes. also found apical renal proximal tubule cells, making it an ideal candidate elimination. In current study, expressed HEK293 reduced cytotoxicity cellular accumulation arsenate, MMA^III, MMA^V, DMA^III, DMA^V while two other hepatic MRPs (MRP3 MRP5) did not. Transport studies with MRP4-enriched vesicles revealed that diglutathione conjugate monomethylarsenic [MMA(GS)₂], were transported species. MMA(GS)₂ was osmotically sensitive, allosteric (Hill coefficients 1.4 ± 0.2 2.9 1.2, respectively), high affinity (<i>K</i>_0.5 0.70 0.16 0.22 0.15 <i>μ</i>M, respectively). pH-dependent, highest capacity pH 5.5. These results suggest could be major player arsenic.