Oxaliplatin up-regulated the function and expression of P-glycoprotein/MDR1 in porcine kidney epithelial LLC-PK cells

Abstract

The purpose of this study was to clarify the effects of oxaliplatin on the function and expression of the multidrug efflux transporter P-glycoprotein/MDR1 in a porcine kidney epithelial cell line, LLC-PK, as a renal tubular epithelial model. LLC-PK cells were pretreated with or without oxaliplatin for 48 h, and the growth inhibitory effects of a MDR1 substrate, paclitaxel, and the transport of a MDR1 substrate, Rhodamine123, were assessed. The level of MDR1 mRNA and protein was also examined in the cells treated with or without oxaliplatin for 48 h using RT-PCR and immunoblotting. In the present study, the pretreatment with oxaliplatin tended to suppress the growth inhibitory effects of paclitaxel in LLC-PK cells, presumably by accelerating the functions of MDR1. In addition, the uptake of Rhodamine123 was reduced significantly by pretreatment with oxaliplatin, and the efflux of Rhodamine123 from LLC-PK cells was enhanced significantly. These accelerated functions were supported by the suppression of Rhodamine123 s transport by a representative MDR1 substrate/inhibitor, ciclosporin, at 10 µM. The exposure to oxaliplatin for 48 h resulted in an increase in the expression of MDR1 in LLC-PK cells. These findings were similar to those obtained with cisplatin, a nephrotoxic drug. In conclusion, the present findings suggested that transient exposure for 48 h to oxaliplatin caused the up-regulation of MDR1 function and expression in LLC-PK cells, as was the case for cisplatin.