Up-regulation of MDR1 function and expression by cisplatin in LLC-PK1 cells.
To examine whether cisplatin affects the multidrug transporter MDR1/P-glycoprotein in the kidneys, the effects of cisplatin on cell sensitivity to an anticancer drug, MDR1 function and expression were examined by assessing the growth inhibition by the MDR1 substrate paclitaxel, the uptake and efflux of the MDR1 substrate Rhodamine123 and the level of MDR1 mRNA, respectively. Porcine kidney epithelial LLC-PK1 cells were used, as they have a structure and function similar to those of renal proximal tubular cells and physiologically express low levels of MDR1. The growth inhibitory curve of LLC-PK1 cells by paclitaxel was shifted to a higher concentration range by pretreatment with 1 micro M cisplatin for 48 h. The uptake and efflux of Rhodamine123 were significantly reduced and enhanced, respectively, by pretreatment with 1 micro M cisplatin for 48 h. This enhanced efflux was suppressed by the representative MDR1 substrate/inhibitor ciclosporin. The expression of MDR1 mRNA was increased by the existence of cisplatin for 48 h. These observations taken together suggested that the transient exposure to cisplatin could cause the up-regulation of MDR1 in LLC-PK1 cells.
Takara
Kohji
K
Department of Hospital Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, Kyoto, Japan. takara@mb.kyoto-phu.ac.jp
Tsujimoto
Masayuki
M
Kokufu
Misato
M
Ohnishi
Noriaki
N
Yokoyama
Teruyoshi
T
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D000818:Animals; D002945:Cisplatin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D018374:LLC-PK1 Cells / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013552:Swine; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D012333:RNA, Messenger; D002945:Cisplatin