Glutathione Status and the Renal Elimination of Inorganic Mercury in the Mrp2−/− Mouse

Multidrug resistance-associated proteins (MRP) 2 and 4 are localized in proximal tubular epithelial cells and participate in the renal elimination of xenobiotics. MRP2 has also been implicated in the renal and hepatic elimination of mercury. The current study tested the hypothesis that MRP2 and MRP4 are involved in renal and hepatic handling of inorganic mercury (Hg(2+)). We examined the disposition of Hg(2+) in Mrp2(-/-) mice and assessed the transport of mercuric conjugates in inside-out membrane vesicles containing human MRP4. Since MRP2 has been shown to utilize glutathione (GSH) for transport of select substrates, we examined renal concentrations of GSH and cysteine and the expression of glutamate cysteine ligase (GCL) in Mrp2(-/-) and FVB mice. The effect of Hg(2+) exposure on renal GSH levels was also assessed in these mice. Our data suggest that MRP2, but not MRP4, is involved in proximal tubular export of Hg(2+). In addition, GSH levels are greater in Mrp2(-/-) mice and exposure to Hg(2+) reduced renal levels of GSH. Expression of GCL was also altered in Mrp2(-/-) mice under normal conditions and following exposure to HgCl2. This study provides important novel data regarding the transport of Hg(2+) and the effect of Hg(2+) exposure on GSH levels.