Ethnopharmacological communicationThe significant inhibition on CYP3A caused by radix Aconiti single herb is not observed in the Wutou decoction: The necessity of combination therapy of radix Aconiti
Graphical abstract
Introduction
Wutou (WT), the mother root of Aconitum carmichaelii Debx., is widely used in China and other Asian countries to treat rheumatoid arthritis, cardiovascular diseases, and tumors (Singhuber et al., 2009). However, WT is also a representative toxic herbal medicine that can cause adverse clinical reactions, such as severe arrhythmia and neurotoxicity if improperly used (Lu et al., 2010). Notably, diester diterpene alkaloids, including aconitine, mesaconitine (MA), and hypaconitine, are the foremost highly toxic pharmacological compounds in WT, and these compounds have a narrow therapeutic index (Bao et al., 2011). According to the theory of TCM and clinical practice, processed WT (PWT) is more often used and prepared as a decoction in combination with other herbs to achieve maximum benefits with minimal side effects. In our previous study, we also found that PWT single herb could strikingly inhibit CYP3A, implying that potential risks exist in the application of PWT alone (Wu et al., 2014). More scientific evidence must be obtained to support the reasonability and necessity of PWT combination therapy.
Wutou decoction (WTD) is one of the most classic traditional prescriptions containing PWT and is well recognized for its therapeutic effect on rheumatoid arthritis. WTD consists of five medicinal herbs, Radix Aconiti, Herba Ephedrae, Radix Paeoniae Alba, Radix Astragali, and Radix Glycyrrhizae. Given that WTD is widely used in Chinese clinics and is a representative prescription containing PWT, we have chosen WTD as a typical example to illuminate the reasonability and necessity of using PWT combinations.
In the current study, we chose testosterone (Tes) and buspirone (BP), which are sensitive CYP3A substrates (according to the US Food and Drug Administration), to examine the CYP3A activity ex vivo and in vivo, respectively. Tes is primarily metabolized by CYP3A into 6β-hydroxytestosterone (6β-OH-Tes) (Shou et al., 2000). The CYP3A-mediated metabolism of BP primarily produces metabolites 1-(2-pyrimidinyl) piperazine (1-PP) and 6′-hydroxybuspirone (6′-OH-BP) (Zhu et al., 2013). SKF-525A HCl was chosen as a positive control for CYP3A inhibition (Jajoo et al., 1990). The CYP3A protein and mRNA expression levels were also detected to explore the underlying mechanism of the changes in CYP3A activity.
Section snippets
Chemicals and reagents
Testosterone (Tes, purity>98%), 6β-hydroxytestosterone (6β-OH-Tes, purity>98%), Gemfibrozil (used as internal standard substance, purity>98%), buspirone HCl (BP·HCl) were obtained from Sigma-Aldrich (St. Louis, MO, USA). SKF-525A HCl (used as positive control drug), 1-(2-pyrimidinyl) piperazine (1-PP), 6′-hydroxybuspirone (6′-OH-BP) were purchased from Toronto Research Chemicals Inc. (Toronto, CA). NADPH regenerating system was purchased from BD Gentest Corp. (Woburn, MA, USA). Acetonitrile was
Results and discussion
Combination therapy between Chinese herbs and synthetic drugs has become increasingly popular. Consequently, potential DDIs have become a common clinical problem. The ex vivo results showed that the formation rates of 6β-OH-Tes from Tes significantly (P<0.05) decreased in a dose-dependent manner after pretreatment of rats with PWT for 7 d compared with the control group (Fig. 1(A)). Formation rates decreased gradually with the increasing doses of PWT. CYP3A protein (Fig. 1(B)) and mRNA (Fig. 1
Conflict of interest
The authors declare that there are no conflicts of interest.
Acknowledgments
This project was supported partly by the National Basic Research Program of China (973 Program) (2011CB505305) and the Grant of National Natural Science Foundation of China (81473410).
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These authors contributed equally to this work.