Safety evaluations of the processed lateral root of Aconitum carmichaelii Debx. And its hepatotoxicity mechanisms in rats

Xiaoyu Ji; Mengbi Yang; Guolin Shen; Ka Hang Or; Wan Sze Yim; Zhong Zuo

doi:10.1016/j.jep.2022.115801

Safety evaluations of the processed lateral root of Aconitum carmichaelii Debx. And its hepatotoxicity mechanisms in rats

J Ethnopharmacol. 2023 Jan 30:301:115801. doi: 10.1016/j.jep.2022.115801. Epub 2022 Oct 7.

Authors

Xiaoyu Ji¹, Mengbi Yang², Guolin Shen³, Ka Hang Or⁴, Wan Sze Yim⁴, Zhong Zuo⁵

Affiliations

¹ School of Pharmacy, The Chinese University of Hong Kong, Hong Kong SAR, PR China.
² School of Pharmacy, The Chinese University of Hong Kong, Hong Kong SAR, PR China; Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, PR China.
³ Institute of Chemicals Safety, Chinese Academy of Inspection and Quarantine, Beijing, PR China.
⁴ School of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China.
⁵ School of Pharmacy, The Chinese University of Hong Kong, Hong Kong SAR, PR China. Electronic address: joanzuo@cuhk.edu.hk.

PMID: 36216199
DOI: 10.1016/j.jep.2022.115801

Abstract

Ethnopharmacological relevance: The processed lateral root of Aconitum carmichaelii Debx. is known as Fuzi, an extensively used Traditional Chinese Medicine to treat cardiovascular diseases, rheumatism arthritis, bronchitis, pains, and hypothyroidism, etc. Although Chinese Pharmacopeia regulates the safe clinical dosage of Fuzi at 3-15 g/person/day, such recommendation not only lacks bench evidence but also does not differentiate Fuzi with different processing types, such as Heishunpian and Paofupian.

Aim of the study: The current study aimed to 1) determine No-Observed-Adverse-Effect-Levels of Heishunpian and Paofupian in rats and 2) investigate the related toxicity mechanisms for their safe clinical use.

Materials and methods: After giving clinically relevant dosing regimen of Heishunpian/Paofupian to rats, we conducted toxicity assessments including ECG monitoring, histopathological changes and serum biomarkers to detect organ injury. Metabolomic study in the liver revealed changes in endogenous metabolite levels after two-week treatment of Fuzi preparations or its corresponding six toxic alkaloids mixtures.

Results: The NOAEL for both bolus and two-week treatments of Heishunpian and Paofupian in rats was designated to be 7.5 g/kg and 15 g/kg, respectively. Corresponding recommended doses in humans were 7.5-25 g/person/day for Heishunpian and 15-50 g/person/day for Paofupian. Metabolic profiles revealed more significant alterations in endogenous substances from rats receiving the two Fuzi preparations than their corresponding toxic alkaloids mixtures. Upregulation of bile acid pathway could be responsible for Fuzi induced liver injury.

Conclusions: Compared to the current maximum recommended dose, our suggested upper limit of guided dose for Heishunpian was comparable, whereas that for Paofupian could be further elevated. Both C₁₉-diterpenoid alkaloids and co-occurring components in Fuzi preparations contributed to their hepatotoxicity via upregulation of bile acid pathway.

Keywords: Diterpenoid alkaloids; Liver injury; Metabolic profiling; NOAEL; The processed lateral root of Aconitum carmichaelii Debx.

MeSH terms

Aconitum* / toxicity
Alkaloids* / metabolism
Animals
Bile Acids and Salts / metabolism
Chemical and Drug Induced Liver Injury* / etiology
Diterpenes* / metabolism
Drugs, Chinese Herbal* / pharmacology
Humans
Medicine, Chinese Traditional / adverse effects
Plant Roots / toxicity
Rats

Substances

Drugs, Chinese Herbal
Alkaloids
Diterpenes
Bile Acids and Salts