Multidrug resistance proteins and the renal elimination of inorganic mercury mediated by 2,3-dimercaptopropane-1-sulfonic acid and meso-2,3-dimercaptosuccinic acid.
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). After 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 i.v. with 0.5 mumol/kg HgCl(2) containing (203)Hg(2+). Twenty-four and 28 h later, rats were injected with saline, DMPS, or DMSA. Tissues were harvested 48 h after HgCl(2) 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 observations by demonstrating that DMPS- and DMSA-S-conjugates of Hg(2+) are transportable substrates of MRP2. Collectively, these data support a role for Mrp2 in the DMPS- and DMSA-mediated elimination of Hg(2+) from the kidney.
Bridges
Christy C
CC
Mercer University School of Medicine, Division of Basic Medical Sciences, 1550 College Street, Macon, GA 31207, USA. bridges_cc@mercer.edu
Joshee
Lucy
L
Zalups
Rudolfs K
RK
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002614:Chelating Agents / Q000494:pharmacology*; D005243:Feces / Q000737:chemistry; D007668:Kidney / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D008628:Mercury / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D051381:Rats; D017208:Rats, Wistar; D004113:Succimer / Q000494:pharmacology*; D014494:Unithiol / Q000494:pharmacology*
D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D002614:Chelating Agents; D014494:Unithiol; D004113:Succimer; D008628:Mercury