MRP2 and the handling of mercuric ions in rats exposed acutely to inorganic and organic species of mercury

Abstract

Mercuric ions accumulate preferentially in renal tubular epithelial cells and bond with intracellular thiols. Certain metal-complexing agents have been shown to promote extraction of mercuric ions via the multidrug resistance-associated protein 2 (MRP2). Following exposure to a non-toxic dose of inorganic mercury (Hg 2+ ), in the absence of complexing agents, tubular cells are capable of exporting a small fraction of intracellular Hg 2+ through one or more undetermined mechanisms. We hypothesize that MRP2 plays a role in this export. To test this hypothesis, Wistar (control) and TR − rats were injected intravenously with a non-nephrotoxic dose of HgCl 2 (0.5 μmol/kg) or CH 3 HgCl (5 mg/kg), containing [ 203 Hg], in the presence or absence of cysteine (Cys; 1.25 μmol/ kg or 12.5 mg/kg, respectively). Animals were sacrificed 24 h after exposure to mercury and the content of [ 203 Hg] in blood, kidneys, liver, urine and feces was determined. In addition, uptake of Cys-S-conjugates of Hg 2+ and methylmercury (CH 3 Hg + ) was measured in inside-out membrane vesicles prepared from either control Sf9 cells or Sf9 cells transfected with human MRP2. The amount of mercury in the total renal mass and liver was significantly greater in TR − rats than in controls. In contrast, the amount of mercury in urine and feces was significantly lower in TR − rats than in controls. Data from membrane vesicles indicate that Cys-S-conjugates of Hg 2+ and CH 3 Hg + are transportable substrates of MRP2. Collectively, these data indicate that MRP2 plays a role in the physiological handling and elimination of mercuric ions from the kidney.

Amelioration of mercury nephrotoxicity after pharmacological manipulation of organic anion transporter 1 (Oat1) and multidrug resistance-associated protein 2 (Mrp2) with furosemide

“…Oat1 supports organic anion/α-ketoglutarate exchange 34,35 . Several recent studies have demonstrated that Mrp2 plays an important role in the cellular elimination and secretion of certain mercuric species 10,31,36 . Mrp2 is localized exclusively in the apical plasma membrane of proximal tubule epithelial cells.…”

Mechanisms involved in the transport of mercuric ions in target tissues

“…The export of mercuric species from within enterocytes, across the apical membrane, and into the intestinal lumen may be mediated by MRP2 ( ABCC2 ). MRP2 has been shown to be involved in the intestinal secretion of organic anions (Itagaki et al 2008) and has been implicated previously in the transport of mercuric ions (Bridges et al 2008a, b, 2011). Owing to the broad substrate specificity of MRP2 and MRP3, it is possible that they may be involved in the basolateral to apical movement of thiol S -conjugates of Hg 2+ across enterocytes.…”

“…A small fraction of mercuric ions are transported out of proximal tubular cells without the use of a chelating agent (Bridges et al 2011). However, the most efficient means of extracting mercuric ions from within target cells is through the use of a dithiol, metal chelator/complexing agent, such as 2,3-dimercapto-1-propanesulfonic acid (DMPS) or dimercaptosuccinic acid (DMSA; Fig.…”

“…Numerous in vivo studies in rats have shown that mercuric ions accumulate in hepatocytes following exposure to HgCl 2 (Bridges et al 2008a, b, 2011, 2014, 2015; Oliveira et al 2016, 2015; Zalups 1993a, b). When mercuric ions are presented to the sinusoidal membrane of hepatocytes, they are most likely bound to non-protein thiols and plasma proteins, such as albumin, ferritin, and γ-globulins.…”

Plausibility of toxicological interaction between lead and methylmercury

“…No corresponding study was located which considered Pb. The two chemicals are also likely transported across the brain barrier via different transporters, MeHg via the neutral amino acid carrier and possibly the p-glycoprotein MDR2 (Yin 2008;Bridges, Joshee, and Zalups 2011) and Pb via the DCT (Ballatori 2002), although research in this area is far from complete. There are also known BBB maturation differences between rodents and humans, which would complicate quantitative interpretation of results from animal experiments (Calabrese 1983).…”