Induction of P-glycoprotein expression and activity by Aconitum alkaloids: Implication for clinical drug-drug interactions.
Induction of P-glycoprotein expression and activity by Aconitum alkaloids: Implication for clinical drug-drug interactions.
复制标题
乌头生物碱诱导 P-糖蛋白表达和活性：对临床药物相互作用的影响
DOI：
10.1038/srep25343
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发表时间：
2016-05-03
影响因子：
4.6
通讯作者：
Lu L
中科院分区：
文献类型：
--
作者：
Wu J;Lin N;Li F;Zhang G;He S;Zhu Y;Ou R;Li N;Liu S;Feng L;Liu L;Liu Z;Lu L
甘草主要含有生物活性的甘草生物碱，临床上常与其他草药或化学药物合用。必须评估联合使用苦参碱和其他药物对特定靶点（如P-糖蛋白（P-gp））产生的药物相互作用（DDI）的潜在风险。本研究主要探讨乌头碱（AC）、苯甲酰乌头碱（BAC）和乌头碱对P-gp表达和活性的影响。结果表明，乌头生物碱对LS 174 T和Caco-2细胞P-gp表达的影响顺序为AC > BAC >乌头碱。核受体参与P-gp的诱导。AC和BAC可增加P-gp转运活性。引人注目的是，细胞内ATP水平和线粒体质量也增加。此外，暴露于AC降低长春新碱和阿霉素对细胞的毒性。在体内，AC显著上调FVB小鼠空肠、回肠和结肠中的P-gp蛋白水平，并保护它们免受急性AC毒性。总之，我们的体外和体内实验结果表明，AC可以诱导P-gp表达，AC与P-gp底物药物联合给药可能会导致DDI。我们的研究结果对临床上的抗肿瘤治疗有重要意义。
The Aconitum species, which mainly contain bioactive Aconitum alkaloids, are frequently administered concomitantly with other herbal medicines or chemical drugs in clinics. The potential risk of drug–drug interactions (DDIs) arising from co-administration of Aconitum alkaloids and other drugs against specific targets such as P-glycoprotein (P-gp) must be evaluated. This study focused on the effects of three representative Aconitum alkaloids: aconitine (AC), benzoylaconine (BAC), and aconine, on the expression and activity of P-gp. We observed that Aconitum alkaloids increased P-gp expression in LS174T and Caco-2 cells in the order AC > BAC > aconine. Nuclear receptors were involved in the induction of P-gp. AC and BAC increased the P-gp transport activity. Strikingly, intracellular ATP levels and mitochondrial mass also increased. Furthermore, exposure to AC decreased the toxicity of vincristine and doxorubicin towards the cells. In vivo, AC significantly up-regulated the P-gp protein levels in the jejunum, ileum, and colon of FVB mice, and protected them against acute AC toxicity. Taken together, the findings of our in vitro and in vivo experiments indicate that AC can induce P-gp expression, and that co-administration of AC with P-gp substrate drugs may cause DDIs. Our findings have important implications for Aconitum therapy in clinics.