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

• Published in: Toxicology (Amsterdam) 2005-03, Vol.208 (1), p.123-132
• Main Authors: KIMURA, Osamu, ENDO, Tetsuya, HOTTA, Yohei, SAKATA, Masakatsu
• Format: Article
• Language: English
• Subjects: Animals; ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Biological and medical sciences; Biological Transport; Cadmium - pharmacokinetics; Cadmium Radioisotopes; Cell Membrane - metabolism; Chemical and industrial products toxicology. Toxic occupational diseases; Doxorubicin - pharmacokinetics; Epithelial Cells - drug effects; Epithelial Cells - metabolism; LLC-PK1 Cells; Medical sciences; Metals and various inorganic compounds; Organic Cation Transport Proteins - metabolism; Protein Biosynthesis; Swine; Toxicology
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2004.11.015

The purpose of this study using LLC-PK(1) cells and P-glycoprotein (P-gp) overexpressed LLC-PK(1) 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 degrees C for 60 min with 1 microM CdCl(2) 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-PK(1) cells. Treatment with a P-gp monoclonal antibody, UIC2, significantly decreased the basolateral-to-apical transport of Cd in LLC-PK(1) 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-PK(1) cells. Furthermore, typical P-gp inhibitors such as cyclosporin A, and doxorubicin decreased the basolateral-to-apical transport of Cd slightly in LLC-PK(1) cells and significantly in LLC-GA5-COL 150 cells. These results suggest that Cd is extruded from the apical membrane of LLC-PK(1) and LLC-GA5-COL 150 cells, probably depending on the level of P-gp expression.