Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, Liaoning, PR China.
Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, Liaoning, PR China; Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian, Liaoning, PR China.
Toxicol Appl Pharmacol. 2014 Jun 1;277(2):146-54. doi: 10.1016/j.taap.2014.03.013. Epub 2014 Mar 26.
The purpose of this study was to investigate the enhancing effect of dioscin on the absorption of methotrexate (MTX) and clarify the molecular mechanism involved in vivo and in vitro. Dioscin increased MTX chemosensitivity and transepithelial flux in the absorptive direction, significantly inhibiting multidrug resistance 1 (MDR1) mRNA and protein expression and MDR1 promoter and nuclear factor κ-B (NF-κB) activities in Caco-2 cells. Moreover, inhibitor κB-α (IκB-α) degradation was inhibited by dioscin. Dioscin enhanced the intracellular concentration of MTX by down-regulating MDR1 expression through a mechanism that involves NF-κB signaling pathway inhibition in Caco-2 cells. Dioscin strengthened MTX absorption by inhibiting MDR1 expression in rat intestine. In addition, even though MTX is absorbed into the enterocytes, there was no increase in toxicity observed, and that, in fact, decreased toxicity was seen.
本研究旨在探讨薯蓣皂苷元对甲氨蝶呤（MTX）吸收的增强作用，并阐明其体内和体外涉及的分子机制。薯蓣皂苷元可增加 MTX 的化疗敏感性和吸收方向的跨上皮通量，显著抑制 Caco-2 细胞中多药耐药基因 1（MDR1）mRNA 和蛋白表达，以及 MDR1 启动子和核因子 κ-B（NF-κB）活性。此外，薯蓣皂苷元还可抑制抑制剂 κB-α（IκB-α）降解。薯蓣皂苷元通过抑制 Caco-2 细胞中 NF-κB 信号通路，下调 MDR1 表达，从而增强 MTX 的细胞内浓度。薯蓣皂苷元在大鼠肠道中通过抑制 MDR1 表达来增强 MTX 的吸收。此外，即使 MTX 被肠细胞吸收，也没有观察到毒性增加，反而观察到毒性降低。
