Effects of P-glycoprotein inhibitors on transepithelial transport of cadmium in cultured renal epithelial cells, LLC-PK1 and LLC-GA5-COL 150

The purpose of this study using LLC-PK1 cells and P-glycoprotein (P-gp) overexpressed LLC-PK1 cells (LLC-GA5-COL 150 cells) was to investigate the secretory transport of cadmium (Cd) via endogenous and overexpressed P-gp, respectively. Cell monolayers cultured on permeable membranes were incubated at 37 degreesC for 60 min with 1 muM CdCl2 from either the apical or the basolateral side. The basolateral-to-apical transport of Cd was 1.7 times higher than the apical-to-basolateral transport of Cd in LLC-GA5-COL 150 cells, while the transport from apical and basolateral sides was almost the same in LLC-PK1 cells. Treatment with a P-gp monoclonal antibody, UIC2, significantly decreased the basolateral-to-apical transport of Cd in LLC-PK1 and LLC-GA5-COL 150 cells, and significantly increased the apical-to-basolateral transport of Cd in both cells. The effects of UIC2 were more marked in LLC-GA5-COL 150 cells than in LLC-PK1 cells. Furthermore, typical P-gp inhibitors such as cyclosporin A, and doxorubicin decreased the basolateral-to-apical transport of Cd slightly in LLC-PK1 cells and significantly in LLC-GA5-COL 150 cells. These results suggest that Cd is extruded from the apical membrane of LLC-PK1 and LLC-GA5-COL 150 cells, probably depending on the level of P-gp expression. (C) 2004 Elsevier Ireland Ltd. All rights reserved.