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

Abstract

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 (MMA . 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. V were the transported species. MMA(GS) 2 and DMA V transport was osmotically sensitive, allosteric (Hill coefficients of 1.4 6 0.2 and 2.9 6 1.2, respectively), and high affinity (K 0.5 of 0.70 6 0.16 and 0.22 6 0.15 mM, respectively). DMA V 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.

Nrf2 activation ameliorates cytotoxic effects of arsenic trioxide in acute promyelocytic leukemia cells through increased glutathione levels and arsenic efflux from cells

“…Recent study has reported that MRP4 is associated with the efflux of arsenic (Banerjee et al, 2014). Although no changes in MRP1, MRP2, and MRP4 expression were observed after CA treatment (Fig.…”

The Pharmacological and Physiological Role of Multidrug-Resistant Protein 4

“…In addition to the cotransport feature of this modulator, it is also likely to stimulate substrate transport by GSH conjugates. The GSH conjugate of monomethylarsonous acid, MMA(GS)2, was transported by MPR4 MVs, and its concentration-velocity curve fit exactly to that for an allosteric interaction (Banerjee et al, 2014). Interestingly, the MRP4 MV transported monomethylarsonous acid in the presence of GSH at a similar speed (Banerjee et al, 2014).…”

“…The GSH conjugate of monomethylarsonous acid, MMA(GS)2, was transported by MPR4 MVs, and its concentration-velocity curve fit exactly to that for an allosteric interaction (Banerjee et al, 2014). Interestingly, the MRP4 MV transported monomethylarsonous acid in the presence of GSH at a similar speed (Banerjee et al, 2014). Although some evidence noted the allosteric modulation of MRP4, the exact mechanism including the binding sites, conformation changes, and modulator specificity is largely unknown.…”

“…MRP4 expressed at physiologic barriers is vital for the pharmacokinetics, pharmacodynamics, tissue accumulation, and toxicities of its substrates. Recently, it was found that MRP4 mediated the transport of toxic arsenic metabolites into hepatic sinusoidal blood (Banerjee et al, 2014). The fact that arsenic elimination occurs predominantly in urine (60%-80%) (Loffredo et al, 2003) also suggests that renal MRP4 mediates the excretion of these exogenous compounds.…”

Arsenic Triglutathione [As(GS)3] Transport by Multidrug Resistance Protein 1 (MRP1/ABCC1) Is Selectively Modified by Phosphorylation of Tyr920/Ser921 and Glycosylation of Asn19/Asn23

“…The multidrug resistance proteins MRP1, MRP2, and MRP4 (gene symbols ABCC1, ABCC2, and ABCC4, respectively) are ATP-binding cassette (ABC) transporter proteins with established roles as arsenic efflux pumps (Kala et al, 2000;Leslie et al, 2004;Carew and Leslie, 2010;Banerjee et al, 2014).…”