Takara Kohji, Tsujimoto Masayuki, Ohnishi Noriaki, Yokoyama Teruyoshi
Department of Hospital Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan.
Biochem Biophys Res Commun. 2002 Mar 22;292(1):190-4. doi: 10.1006/bbrc.2002.6619.
Because MDR1 (P-glycoprotein) plays an important role in pharmacokinetics such as absorption and excretion of xenobiotics and multidrug resistance, an understanding of the factors regulating its function and expression is important. Here, the effects of digoxin on cell sensitivity to an anticancer drug, MDR1 function, and expression were examined by assessing the growth inhibition by paclitaxel, the transport characteristics of the MDR1 substrate Rhodamine123, and the level of MDR1 mRNA, respectively, using human colon carcinoma Caco-2 cells, which are widely used as a model of intestinal epithelial cells. The sensitivity to paclitaxel, an MDR1 substrate, in Caco-2 cells pretreated with digoxin was lower than that in non-treated cells. The accumulation of Rhodamine123 was reduced by pretreatment with digoxin and its efflux was enhanced. The level of MDR1 mRNA in Caco-2 cells was increased in a digoxin concentration-dependent manner. These results taken together suggested that digoxin up-regulates MDR1 in Caco-2 cells.
由于多药耐药蛋白1（P-糖蛋白）在诸如异生物的吸收和排泄等药代动力学以及多药耐药中发挥着重要作用，因此了解调节其功能和表达的因素非常重要。在此，分别使用广泛用作肠上皮细胞模型的人结肠癌Caco-2细胞，通过评估紫杉醇的生长抑制、MDR1底物罗丹明123的转运特性以及MDR1 mRNA水平，研究了地高辛对细胞对抗癌药物的敏感性、MDR1功能和表达的影响。用洋地黄毒苷预处理的Caco-2细胞对MDR1底物紫杉醇的敏感性低于未处理的细胞。用洋地黄毒苷预处理可减少罗丹明123的积累并增强其外排。Caco-2细胞中MDR1 mRNA的水平以洋地黄毒苷浓度依赖性方式增加。这些结果综合表明，地高辛上调Caco-2细胞中的MDR1。
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