In vivo acute toxicity of detoxified Fuzi (lateral root of Aconitum carmichaeli) after a traditional detoxification process
Keywords:acute toxicity, Aconitum carmichaeli, aconitine, zebrafish, UPLC-MS
Many herbs of traditional Chinese medicine (TCM) possess not only therapeutic efficacy, but also toxicity towards normal tissues. The herbal toxicities occasionally cause serious adverse events or even fatal poisoning due to the erroneous use of TCM herbs. Fuzi (lateral root of Aconitum carmichaeli) is such an herb with its toxic ingredient, aconites. Aconitine, mesaconitine, and hypaconitine are the main toxic components of Fuzi, which are hydrolyzed into non-toxic derivatives by water decoction. Therefore, long-time decoction was commonly applied as a traditional way to detoxify Fuzi before use. Nevertheless, recent clinical trials presorted on adverse events induced by long-time decocted Fuzi, putting some doubt on the safety of Fuzi after the traditional detoxification procedure. To thoroughly determine whether or not long-time decocted Fuzi was safe, we conducted in vivo acute toxicity assays using both rodent and zebrafish models and performed chemoprofile analyses using HPLC and UPLC-MS. The HPLC analysis showed that toxic aconitine components were hydrolyzed into benzoyl derivatives with increasing time of decoction. These aconitines were undetected by HPLC in Fuzi after 2 h-decoction (FZ-120), indicating seemingly non-toxicity of FZ-120. Unlike the non-decocted Fuzi (FZ-0) and 60 min-decocted Fuzi (FZ-60) with lethal toxicity, FZ-120 at 130 g/kg did not cause any deaths or side effects in mice regarding body weight and biochemical parameters. This seems to confirm safety of Fuzi after long-time decoction. However, histopathological observations revealed an abnormal liver phenotype and a significant decrease of the liver index following FZ-120 treatment, indicating a potential hepatoxicity of FZ-120. By using a zebrafish model, we observed that FZ-120 at a dose range from 288 to 896 μg/ml caused considerable adverse events including arrhythmia, liver degeneration, yolk sac absorption delay, length decrease, and swim bladder loss, which clearly speak for acute toxicity on cardiovascular, digestive, development, and respiratory systems. The dose range of FZ-120 was lower than that used for clinical application in human beings. Moreover, UPLC-MS revealed that FZ-120 still contained toxic aconitines that were not detectable by HPLC, which might explain its acute toxicity in zebrafish. We concluded that Fuzi is not sufficiently safe even after long-time decoction. The zebrafish model combined with UPLC-MS assay may represent an appropriate test system to unravel aconitine-related acute toxicity.
How to Cite
Authors who publish in this journal agree to the following terms:
- The authors keep the copyright and grant the journal the right of first publication under the terms of the Creative Commons Attribution license, CC BY 4.0. This licencse permits unrestricted use, distribution and reproduction in any medium, provided that the original work is properly cited.
- The use of general descriptive names, trade names, trademarks, and so forth in this publication, even if not specifically identified, does not imply that these names are not protected by the relevant laws and regulations.
- Because the advice and information in this journal are believed to be true and accurate at the time of publication, neither the authors, the editors, nor the publisher accept any legal responsibility for any errors or omissions presented in the publication. The publisher makes no guarantee, express or implied, with respect to the material contained herein.
- The authors can enter into additional contracts for the non-exclusive distribution of the journal's published version by citing the initial publication in this journal (e.g. publishing in an institutional repository or in a book).