Digoxin up-regulates multidrug resistance transporter (MDR1) mRNA and simultaneously down-regulates steroid xenobiotic receptor mRNA.
A steroid xenobiotic receptor (SXR) is involved in the induction of MDR1/P-glycoprotein. MDR1 up-regulation by digoxin was previously demonstrated in human colon adenocarcinoma Caco-2 cells, but the participation of SXR remains unclear. Herein, the participation of SXR in MDR1 up-regulation was examined using reverse transcription-polymerase chain reaction in Caco-2 cells, and digoxin-tolerant cells (Caco/DX) as well as human colon carcinoma LS180 cells, which expressed SXR. MDR1 mRNA expression in Caco-2 or LS180 cells was increased by exposure to 1 microM digoxin for 24h, in a concentration-dependent manner, but SXR mRNA decreased concentration-dependently and was undetectable or significantly lower at 1 microM digoxin, indicating antithetical changes in MDR1 and SXR mRNA expression. Moreover, the MDR1 mRNA level was higher in Caco/DX cells than Caco-2 cells, whereas the SXR mRNA level was lower in Caco/DX cells. Consequently, digoxin was demonstrated to up-regulate MDR1 mRNA and simultaneously down-regulate SXR mRNA expression.
Takara
Kohji
K
Department of Hospital Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, 607-8414, Kyoto, Japan. takara@mb.kyoto-phu.ac.jp
Takagi
Kentaro
K
Tsujimoto
Masayuki
M
Ohnishi
Noriaki
N
Yokoyama
Teruyoshi
T
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism; D018938:Caco-2 Cells; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism; D004077:Digoxin / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D019450:Genes, MDR / Q000187:drug effects*; D006801:Humans; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism*; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects
D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011987:Receptors, Steroid; D004077:Digoxin