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TOXICOLOGY

Multidrug Resistance Proteins and the Renal Elimination of Inorganic Mercury Mediated by 2,3-Dimercaptopropane-1-Sulfonic Acid and Meso-2,3-dimercaptosuccinic Acid

Division of Basic Medical Sciences, Mercer University School of Medicine, Macon, Georgia

Current therapies for inorganic mercury (Hg²⁺) intoxication include administration of a metal chelator, either 2,3-dimercaptopropane-1-sulfonic acid (DMPS) or meso-2,3-dimercaptosuccinic acid (DMSA). After exposure to either chelator, Hg²⁺ 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 Hg²⁺ from proximal tubular cells. To test this hypothesis, the disposition of Hg²⁺ was examined in control and Mrp2-deficient TR^- rats. Rats were injected i.v. with 0.5 µmol/kg HgCl₂ containing ²⁰³Hg²⁺. Twenty-four and 28 h later, rats were injected with saline, DMPS, or DMSA. Tissues were harvested 48 h after HgCl₂ exposure. The renal and hepatic burden of Hg²⁺ in the saline-injected TR^- rats was greater than that of controls. In contrast, the amount of Hg²⁺ 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 Hg²⁺ in both groups of rats, with the greatest reduction in controls. A significant increase in urinary and fecal excretion of Hg²⁺, which was greater in the controls, was also observed following DMPS treatment. Experiments utilizing inside-out membrane vesicles expressing MRP2 support these observations by demonstrating that DMPS- and DMSA-S-conjugates of Hg²⁺ are transportable substrates of MRP2. Collectively, these data support a role for Mrp2 in the DMPS- and DMSA-mediated elimination of Hg²⁺ from the kidney.

Address correspondence to: Dr. Christy C. Bridges, Mercer University School of Medicine, Division of Basic Medical Sciences, 1550 College Street, Macon, GA 31207. E-mail: bridges_cc{at}mercer.edu

This article has been cited by other articles:

				C. C. Bridges, L. Joshee, and R. K. Zalups MRP2 and the DMPS- and DMSA-Mediated Elimination of Mercury in TR- and Control Rats Exposed to Thiol S-Conjugates of Inorganic Mercury Toxicol. Sci., September 1, 2008; 105(1): 211 - 220. [Abstract] [Full Text] [PDF]