The MRP2/cMOAT Transporter and Arsenic-Glutathione Complex Formation Are Required for Biliary Excretion of Arsenic

Abstract

Worldwide, millions of people are exposed to arsenic in drinking water that exceeds the World Health Organization standard of 10 g/liter by as much as 50 -300-fold, yet little is known about the molecular basis for arsenic excretion. Here we show that transport of arsenic into bile depends on the MRP2/cMOAT transporter and that glutathione is obligatory for such transport. Using reversed phase liquid chromatography/mass spectrometry, we demonstrate that two arsenic-glutathione complexes not previously identified in vivo, arsenic triglutathione and methylarsenic diglutathione, account for most of the arsenic in the bile. The structure of the compounds was also confirmed by nuclear magnetic resonance spectroscopy. Our findings may help explain the increased susceptibility of malnourished human populations to arsenic.

Transcriptional expression analysis of ABC efflux transporters and xenobiotic-metabolizing enzymes in the Chinese rare minnow

“…Furthermore, some of the phase I metabolites (e.g., B[a]P-7,8-diol-9,10-epoxide, the activated form of BaP) are suitable substrates for the GSTs (Stegeman and Lech, 1991;Christine Paetzold et al, 2009), and phase I and II metabolism makes many substances more suitable for export via the ABC transporters (Leslie et al, 2005). For example, arsenic-glutathione complex formation is required for the MRP2-mediated transport of arsenic into the bile (Kala et al, 2000), and sulfate conjugation of benzo[a]pyrene generates suitable ABCG2 substrates (Ebert et al, 2005). Therefore, the function of the ABC transporters and biotransformation enzymes could be complementary (Christine Paetzold et al, 2009).…”

Organic anion transporting polypeptide-C mediates arsenic uptake in HEK-293 cells

“…In the presence of reduced GSH, arsenite conjugates with three molecules of glutathione to form ATG. The monomethyl metabolite of arsenic conjugates with two equivalents of glutathione to form methylarsenic diglutathione (MADG) [27,39]. The dimethyl metabolite of arsenic conjugates with one equivalent of glutathione to form dimethylarsenic glutathione (DMAG) [39,40].…”

“…The dimethyl metabolite of arsenic conjugates with one equivalent of glutathione to form dimethylarsenic glutathione (DMAG) [39,40]. Previous study showed that ATG and MADG, but not DMAG, is transported out of hepatocytes via the MRP2/ cMOAT transporter [27]. MRP1 is known to pump out inorganic arsenic as a tri-GSH conjugate at the basolateral membrane [25,26].…”

“…Arsenic triglutathione (ATG) was prepared as described previously by Kala et al [27] with modifications. ATG was prepared by dissolving sodium arsenite (0.0129 g; 0.1 mmol) and GSH (0.0921 g; 0.3 mmol) in 1 ml MQ; the reaction was carried out for 12 h at room temperature.…”

“…Both transporters are members of the ABC (ATPbinding cassette) family [23,24]. In eukaryotic organisms, both MRP1 [25,26] and MRP2 [27] can transport a complex of arsenite and glutathione (GSH). Arsenite and glutathione can form an As(GS) 3 complex, in which arsenite is excreted.…”