MRP2 and the Transport Kinetics of Cysteine Conjugates of Inorganic Mercury
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Human exposure to mercuric species occurs regularly throughout the world. Mercuric ions may accumulate in target cells and subsequently lead to cellular intoxication and death. Therefore, it is important to have a thorough understanding of how transportable species of mercury are handled by specific membrane transporters. The purpose of the current study was to characterize the transport kinetics of cysteine (Cys)-S-conjugates of inorganic mercury (Cys-S-Hg-S-Cys) at the site of the multidrug resistance-associated transporter 2 (MRP2). In order to estimate the maximum velocity (V max) and Michaelis constant (K m) for the uptake of Cys-S-Hg-S-Cys mediated by MRP2, in vitro studies were carried out using radioactive Cys-S-Hg-S-Cys (5 μM) and inside-out membrane vesicles made from Sf9 cells transfected with MRP2. The V max was estimated to be 74.3 ± 10.1 nmol mg protein−1 30 s−1 while the K m was calculated to be 63.4 ± 27.3 μM. In addition, in vivo studies were utilized to measure the disposition of inorganic mercury (administered dose 0.5 μmol kg−1 in 2 mL normal saline) over time in Wistar and TR¯ (Mrp2-deficient) rats. These studies measured the disposition of mercuric ions in the kidney, liver, and blood. In general, the data suggest that the initial uptake of mercuric conjugates into select target cells is rapid followed by a period of slower uptake and accumulation. Overall, the data indicate that MRP2 transports Cys-S-Hg-S-Cys in a manner that is similar to that of other MRP2 substrates.
KeywordsMercury Multidrug resistance-associated protein 2 Kidney Transport
This work was supported by grants awarded by the National Institutes of Health (National Institute of Environmental Health Sciences) [ES019991 to CCB] and Navicent Health Foundation (awarded to CCB).
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