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Digoxin up-regulates multidrug resistance transporter (MDR1) mRNA and simultaneously down-regulates steroid
Kohji Takara1, Kentaro Takagi, Masayuki Tsujimoto
1Department 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
Abstract:
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.
Insights
Digoxin up-regulates MDR1 (multidrug resistance 1) mRNA expression in colon cells. This study shows steroid xenobiotic receptor (SXR) mRNA decreases as MDR1 increases, revealing an inverse relationship.
Area of Science:
- Pharmacology
- Molecular Biology
- Cell Biology
Background:
- The steroid xenobiotic receptor (SXR) is implicated in the induction of multidrug resistance 1 (MDR1)/P-glycoprotein.
- Previous studies demonstrated MDR1 up-regulation by digoxin in Caco-2 cells, but SXR's role remained unclear.
Purpose of the Study:
- To investigate the participation of SXR in digoxin-induced MDR1 up-regulation in human colon cell lines.
- To elucidate the relationship between SXR and MDR1 mRNA expression levels under digoxin exposure.
Main Methods:
- Utilized reverse transcription-polymerase chain reaction (RT-PCR) to quantify mRNA expression.
- Examined MDR1 and SXR mRNA levels in Caco-2, digoxin-tolerant Caco/DX, and LS180 cells.
- Assessed concentration-dependent effects of digoxin exposure.
Main Results:
- Digoxin exposure increased MDR1 mRNA expression in a concentration-dependent manner in Caco-2 and LS180 cells.
- SXR mRNA levels decreased concentration-dependently with digoxin exposure, showing antithetical changes to MDR1.
- Digoxin-tolerant Caco/DX cells exhibited higher MDR1 mRNA and lower SXR mRNA compared to Caco-2 cells.
Conclusions:
- Digoxin up-regulates MDR1 mRNA expression in human colon cells.
- Digoxin simultaneously down-regulates SXR mRNA expression, indicating an inverse relationship between the two.
- SXR plays a role in the regulation of MDR1 expression in response to digoxin.