Glutathione-dependent interaction of heavy metal compounds with multidrug resistance proteins MRP1 and MRP2.

The interactions of three heavy metal-containing compounds, cisplatin (CDDP), arsenic trioxide (As(2)O(3)), and mercury dichloride (HgCl(2)), with the multidrug resistance transporters MRP1 and MRP2 and the involvement of glutathione (GSH)-related processes herein were investigated. In Madin-Darby canine kidney cells stably expressing MRP1 or MRP2, viability, GSH content, calcein efflux and polarized GSH efflux were measured as a function of exposure to CDDP, As(2)O(3) and HgCl(2). In isolated Sf9-MRP1 and Sf9-MRP2 membrane vesicles, the interaction with MRP-associated ATPase activity was measured. In the latter model system adduct formation with GSH is not an issue. The data show that (1) CDDP interacts with both MRP1 and MRP2, and GSH appears to play no major role in this process, (2) As(2)O(3) interacts with MRP1 and MRP2 in which process GSH seems to be essential, and (3) HgCl(2) interacts with MRP1 and MRP2, either alone and/or as a metal-GSH complex.