MRP2 involvement in renal proximal tubular elimination of methylmercury mediated by DMPS or DMSA.
2, 3-Dimercaptopropane-1-sulfonic acid (DMPS) and meso-2, 3-Dimercaptosuccinic acid (DMSA) are dithiols used to treat humans exposed to methylmercury (CH(3)Hg(+)). After treatment, significant amounts of mercury are eliminated rapidly from the kidneys and are excreted in urine. In the present study, we extended our previous studies by testing the hypothesis that MRP2 mediates the secretion of DMPS or DMSA S-conjugates of CH(3)Hg(+). To test this hypothesis, the disposition of mercury was assessed in control and Mrp2-deficient (TR(-)) rats exposed intravenously to a 5.0-mg/kg dose of CH(3)HgCl. Twenty-four and 28 h after exposure, groups of four control and four TR(-) rats were injected with saline, DMPS, or DMSA. Tissues were harvested 48 h later. Renal and hepatic contents of mercury were greater in saline-injected TR(-) rats than in controls. In contrast, the amounts of mercury excreted in urine and feces by TR(-) rats were less than those by controls. DMPS and DMSA significantly reduced the renal and hepatic content of mercury in both groups of rats, with the greatest reduction in controls. A significant increase in urinary and fecal excretion of mercury (which was greater in the controls) was also observed. Our findings in inside-out membrane vesicles prepared from hMRP2-transfected Sf9 cells show that uptake of DMPS and DMSA S-conjugates of CH(3)Hg(+) was greater in the vesicles containing hMRP2 than in control vesicles. Overall, these dispositional findings indicate that MRP2 does play a role in DMPS- and DMSA-mediated elimination of mercury from the kidney.
Zalups
Rudolfs K
RK
Division of Basic Medical Sciences, Mercer University School of Medicine, 1550 College St., Macon, GA 31207, USA. Zalups_rk@mercer.edu
Bridges
Christy C
CC
D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D001923:Brain Chemistry; D002460:Cell Line; D005243:Feces / Q000737:chemistry; D005786:Gene Expression Regulation; D007313:Insecta; D007668:Kidney / Q000737:chemistry / Q000201:enzymology; D008099:Liver / Q000737:chemistry / Q000201:enzymology; D008297:Male; D008628:Mercury / Q000652:urine; D008767:Methylmercury Compounds / Q000378:metabolism* / Q000633:toxicity*; D000089762:Multidrug Resistance-Associated Protein 2; D051381:Rats; D017208:Rats, Wistar; D004113:Succimer / Q000008:administration & dosage*; D014494:Unithiol / Q000008:administration & dosage*
C000715087:ABCC2 protein, human; D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D008767:Methylmercury Compounds; D000089762:Multidrug Resistance-Associated Protein 2; D014494:Unithiol; D004113:Succimer; D008628:Mercury