Humans continue to be exposed to organic (CH3Hg+) and inorganic (Hg2+) forms of mercury. These environmental toxicants affect numerous organ systems, but a major target for their accumulation and toxicity is the kidney, specifically the proximal tubule. Numerous studies have shown that CH3Hg+ and Hg2+ can be removed from proximal tubules by treatment with the metal chelators, 2,3-dimercapto-1-propanesulfonic acid (DMPS) and meso-2,3-dimercaptosuccinic acid (DMSA). This removal appears to involve a conjugation step wherein intracellular mercuric ions form strong bonds with one of these chelators, and a subsequent export step where these mercury-chelator complexes are secreted into the tubular lumen. The actual mechanisms involved in this secretion, however, remain undefined. Yet based on the characteristics of the multidrug resistance proteins (MRP), it is likely that one or more of these proteins are involved in the DMPS- and DMSA- mediated export of mercuric ions. Therefore, the purpose of the current proposal is to test the hypothesis that MRP2, and/or MPR4, play a role in the DMPS- and DMSA-mediated elimination of CH3Hg+ and Hg2+ from the kidney. To test this hypothesis, we will use TR- rats, which do not express the Mrp2 protein, and Madin-Darby canine kidney (MDCK) cells stably transfected with OAT1 and MRP2 or MRP4. We will first examine the effect of DMPS and DMSA on the handling and disposition of CH3Hg+ and Hg2+ in control and TR- rats. As an alternative model, the transfected MDCK cells will be used to study the roles of MRP2 and MRP4 in the export of various species of mercury. The use of these cells allows for the separation of MRP2 and MRP4 activities and enables a more accurate characterization of the role of each protein in the transport of mercuric species. Collectively, these studies will determine whether MRP2 and/or MRP4 play(s) a role in the DMPS- and DMSA- mediated secretion of CH3Hg+ and Hg2+ from proximal tubular cells. The data obtained from these experiments will serve as the basis for a more expanded set of studies. The current and future studies will be important to human health in that they will serve as the basis for the development of additional therapeutic regimes for mercury poisoning. Mercury is a prevalent environmental toxicant to which humans are exposed frequently. The data obtained from the proposed studies will provide important information related to the way in which mercury is eliminated from the body. These data will serve as the basis for the development of additional treatments for mercury poisoning. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Small Research Grants (R03)
Project #
5R03ES015511-02
Application #
7409598
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Maull, Elizabeth A
Project Start
2007-04-20
Project End
2011-03-31
Budget Start
2008-04-01
Budget End
2011-03-31
Support Year
2
Fiscal Year
2008
Total Cost
$71,643
Indirect Cost
Name
Mercer University Macon
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
065365041
City
Macon
State
GA
Country
United States
Zip Code
31207
Bridges, Christy C; Zalups, Rudolfs K (2017) Mechanisms involved in the transport of mercuric ions in target tissues. Arch Toxicol 91:63-81
Bridges, Christy C; Joshee, Lucy; van den Heuvel, Jeroen J M W et al. (2013) Glutathione status and the renal elimination of inorganic mercury in the Mrp2(-/-) mouse. PLoS One 8:e73559
Bridges, Christy C; Joshee, Lucy; Zalups, Rudolfs K (2012) Placental and fetal disposition of mercuric ions in rats exposed to methylmercury: role of Mrp2. Reprod Toxicol 34:628-34
Zalups, Rudolfs K; Bridges, Christy C (2012) Relationships between the renal handling of DMPS and DMSA and the renal handling of mercury. Chem Res Toxicol 25:1825-38
Bridges, Christy C; Krasnikov, Boris F; Joshee, Lucy et al. (2012) New insights into the metabolism of organomercury compounds: mercury-containing cysteine S-conjugates are substrates of human glutamine transaminase K and potent inactivators of cystathionine ?-lyase. Arch Biochem Biophys 517:20-9
Bridges, Christy C; Joshee, Lucy; Zalups, Rudolfs K (2011) MRP2 and the handling of mercuric ions in rats exposed acutely to inorganic and organic species of mercury. Toxicol Appl Pharmacol 251:50-8
Zalups, Rudolfs K; Bridges, Christy C (2010) Seventy-five percent nephrectomy and the disposition of inorganic mercury in 2,3-dimercaptopropanesulfonic acid-treated rats lacking functional multidrug-resistance protein 2. J Pharmacol Exp Ther 332:866-75
Bridges, Christy C; Zalups, Rudolfs K (2010) Transport of inorganic mercury and methylmercury in target tissues and organs. J Toxicol Environ Health B Crit Rev 13:385-410
Zalups, Rudolfs K; Bridges, Christy C (2009) MRP2 involvement in renal proximal tubular elimination of methylmercury mediated by DMPS or DMSA. Toxicol Appl Pharmacol 235:10-7
Bridges, C C; Joshee, L; Zalups, R K (2009) Effect of DMPS and DMSA on the placental and fetal disposition of methylmercury. Placenta 30:800-5

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