Mercury is a group IIB transition metal that is a significant environmental and occupational contaminant and hazard in the United States (and other countries). One of the primary target sites where mercuric ions accumulate and induce significant toxic effects is in the kidney. Within the kidneys, mercuric ions accumulate mainly along the three segments of the proximal tubule, although distal segments of the nephron have not been excluded as secondary targets where mercuric ions may be handled. Inorganic mercury appears to be taken up along the three segments of the proximal tubule in a heterogeneous manner. Moreover, at least two distinct sets of mechanisms are involved in the uptake of mercury along the proximal tubule. One of these sets of mechanisms is localized on the luminal membrane and the other is localized on the basolateral membrane. Based on the research we have carried out to date, we have come up with the following central hypothesis: Mercuric conjugates of biologically relevant endogenous thiol-containing molecules (or their metabolites), are 1) the primary transportable species of inorganic mercury in the kidneys, and 2) are taken up by proximal tubular epithelial cells at both the luminal and basolateral membranes by known transporters of other molecules, such as those involved in the transport of amino acids and organic anions, presumably through mechanisms involving molecular homology or """"""""mimicry' One technology we will use to test this hypothesis will include the in vitro stable transfection of a distal-tubular, renal-epithelial, cell-line with the genetic code(s) for specific luminal and basolateral transporters presumed to be involved in the transport of mercury. Expression of a transporter in a cell that normally does contain it will permit us to determine if there is a gain of function. More specifically, we will be able to document if transport (and inhibition of transport) of specific mercuric conjugates occurs. The other technology we propose to use is the isolated perfused tubule, which is the only in vitro technique that allows one to access, perfuse, and bathe virtually any intact segment of the nephron to study the characteristics of particular transport systems under biophysical conditions similar to those found in vivo. With these techniques, we will be able to provide the most detailed and comprehensive assessment, to date, of the mechanisms involved in the uptake of inorganic mercuric ions along pars recta segments of the proximal tubule, which are the segments of the nephron most vulnerable to the nephrotoxic effects of mercury

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National Institute of Environmental Health Sciences (NIEHS)
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Alcohol and Toxicology Subcommittee 4 (ALTX)
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Maull, Elizabeth A
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Mercer University Macon
Other Basic Sciences
Schools of Medicine
United States
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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; Barfuss, Delon W; Joshee, Lucy et al. (2016) Compensatory Renal Hypertrophy and the Uptake of Cysteine S-Conjugates of Hg2+ in Isolated S2 Proximal Tubular Segments. Toxicol Sci 154:278-288
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
Wang, Yanhua; Zalups, Rudolfs K; Barfuss, Delon W (2012) Luminal transport of thiol S-conjugates of methylmercury in isolated perfused rabbit renal proximal tubules. Toxicol Lett 213:203-10
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
Wang, Yanhua; Zalups, Rudolfs K; Barfuss, Delon W (2010) Potential mechanisms involved in the absorptive transport of cadmium in isolated perfused rabbit renal proximal tubules. Toxicol Lett 193:61-8
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

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