Abstract
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 (Hg2+). We examined the disposition of Hg2+ 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 Hg2+ 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 Hg2+. In addition, GSH levels are greater in Mrp2−/− mice and exposure to Hg2+ 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 Hg2+ and the effect of Hg2+ exposure on GSH levels.
Highlights
The multidrug resistance-associated protein 2 (Mrp2) has been implicated in the cellular export of various endobiotics and xenobiotics, including chemotherapeutic agents and heavy metals such as arsenic [1,2], platinum [2,3], cadmium [4,5], and mercury [2,6,7,8]
In kidneys of Mrp22/2 mice, the amount of Hg2+ in the renal cortex was twofold greater than that in the outer stripe of the outer medulla. This finding is likely due to preferential accumulation of mercuric ions in S1 and S2 proximal tubular segments [11], which are the primary sites of Mrp2 expression and localization [24]
Urinary excretion of mercuric ions was lower in Mrp22/2 mice than in control mice, which supports the idea that, in the absence of Mrp2, mercuric ions are retained within proximal tubular epithelial cells and are not excreted in urine
Summary
The multidrug resistance-associated protein 2 (Mrp2) has been implicated in the cellular export of various endobiotics and xenobiotics, including chemotherapeutic agents and heavy metals such as arsenic [1,2], platinum [2,3], cadmium [4,5], and mercury [2,6,7,8]. The purpose of the current study was to: 1) test the hypothesis that Mrp is involved in the transport of mercuric species; 2) test the hypothesis that GSH status and biosynthesis is altered by exposure to mercury. These studies will be carried out in a manner similar to that used in our previous studies, the current studies using Mrp22/2 mice are novel and offer several advantages over the use of TR2 rats. A portion of data obtained from the current study tends to confirm our previous findings from TR2 rats, the use of Mrp22/2 mice to study the disposition and handling of Hg2+ is novel and significant
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