Induction of P-glycoprotein expression and activity by Aconitum alkaloids: Implication for clinical drug-drug interactions.

Fangyuan Li,Shugui He,Yuanfeng Zhu,Na Li,Zhongqiu Liu,Linlin Lu,Jinjun Wu,Lizhi Feng,Na Lin,Rilan Ou,Liang Liu,Guiyu Zhang,Shuqiang Liu

doi:10.1038/srep25343

Abstract

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.

Highlights

Aconitine (AC) is one of the main bioactive Aconitum alkaloids present in the Aconitum species (Ranunculaceae family), and is widely used in China and other Asian countries to treat rheumatoid arthritis, cardiovascular diseases, and tumors[1,2]
P-gp expression and activity are frequently changed by its own substrates, potentially affecting its pharmacokinetics, bioavailability, toxicity, and therapeutic response, which is recognized by authorities as one of the most important causes of drug-drug interactions (DDIs) among P-gp substrates[14,15,16]
AC treatment (50 μ M, 6 days) significantly increased the MDR1 mRNA levels in LS174T (Fig. 1F) and Caco-2 (Fig. 1G) cells in the order AC > BAC > aconine, which was consistent with our results showing increased P-gp protein levels under these conditions

Summary

Introduction

Aconitine (AC) is one of the main bioactive Aconitum alkaloids present in the Aconitum species (Ranunculaceae family), and is widely used in China and other Asian countries to treat rheumatoid arthritis, cardiovascular diseases, and tumors[1,2]. Any effect of the Aconitum alkaloids on P-gp expression and/or activity might cause DDIs, thereby resulting in undesirable variation in the plasma concentrations of co-administered substrate drugs, with treatment failure or toxicologically unsafe consequences. A thorough assessment of DDI risk with co-administration of Aconitum alkaloids and P-gp substrates drugs is essential and urgent For this purpose, we first evaluated the effects of AC, BAC, and aconine on the expression of P-gp in LS174T and Caco-2 cells. We first evaluated the effects of AC, BAC, and aconine on the expression of P-gp in LS174T and Caco-2 cells These two cell lines are suitable in vitro models to study P-gp induction, localization, and function by xenobiotic drugs[21,36,37,38,39]. Our findings have important implications for the correct clinical application of Aconitum alkaloids

Methods

Results

Conclusion