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-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.
Kimura
Osamu
O
Clinical Toxicology and Metabolism, Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Kanazawa, 1757 Ishikari-Tobetsu, Hokkaido 061-0293, Japan.
Endo
Tetsuya
T
Hotta
Yohei
Y
Sakata
Masakatsu
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D002104:Cadmium / Q000493:pharmacokinetics*; D002106:Cadmium Radioisotopes; D002462:Cell Membrane / Q000378:metabolism*; D004317:Doxorubicin / Q000493:pharmacokinetics; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D018374:LLC-PK1 Cells; D027701:Organic Cation Transport Proteins / Q000378:metabolism; D014176:Protein Biosynthesis; D013552:Swine
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002106:Cadmium Radioisotopes; D027701:Organic Cation Transport Proteins; D002104:Cadmium; D004317:Doxorubicin