MULTIDRUG RESISTANCE PROTEINS AND THE RENAL ELIMINATION OF INORGANIC MERCURY MEDIATED BY DMPS OR DMSA.
Mercer University School of Medicine.
Current therapies for inorganic mercury (Hg(2+)) intoxication include administration of a metal chelator, either 2, 3-dimercaptopropane-1-sulfonic acid (DMPS) or meso-2, 3-dimercaptosuccinic acid (DMSA). Following exposure to either chelator, Hg(2+) is rapidly eliminated from the kidneys and excreted in the urine, presumably as an S-conjugate of DMPS or DMSA. The multidrug resistance protein 2 (Mrp2) has been implicated in this process. We hypothesize that Mrp2 mediates the secretion of DMPS- or DMSA-S-conjugates of Hg(2+) from proximal tubular cells. To test this hypothesis, the disposition of Hg(2+) was examined in control and Mrp2-deficient TR(-) rats. Rats were injected intravenously with 0.5 micromol/kg HgCl2 containing (203)Hg(2+). Twenty-four and 28 hours later, rats were injected with saline, DMPS, or DMSA. Tissues were harvested 48 hours after HgCl2 exposure. The renal and hepatic burden of Hg(2+) in the saline-injected TR(-) rats was greater than that of controls. In contrast, the amount of Hg(2+) excreted in urine and feces of TR(-) rats was less than that of controls. DMPS, but not DMSA, significantly reduced the renal and hepatic content of Hg(2+) in both groups of rats, with the greatest reduction in controls. A significant increase in urinary and fecal excretion of Hg(2+), which was greater in the controls, was also observed following DMPS treatment. Experiments utilizing inside-out membrane vesicles expressing MRP2 support these conclusions by demonstrating that DMPS- and DMSA-S-conjugates of Hg(2+) are transportable substrates of MRP2. Collectively, these data suggest that Mrp2 plays a role in the DMPS- and DMSA-mediated elimination of Hg(2+) from the kidney.
PMID: 17940195 [PubMed - as supplied by publisher]
