Study on the difference and correlation between the contents and toxicity of aristolochic acid analogues in Aristolochia plants

Jingzhuo Tian; Chenyue Liu; Lianmei Wang; Zhong Xian; Yong Zhao; Shasha Qin; Yan Yi; Chunying Li; Jiayin Han; Chen Pan; Yushi Zhang; Suyan Liu; Jing Meng; Xuan Tang; Fang Wang; Meiting Liu; Aihua Liang

doi:10.1016/j.jep.2023.116568

Study on the difference and correlation between the contents and toxicity of aristolochic acid analogues in Aristolochia plants

J Ethnopharmacol. 2023 Oct 28:315:116568. doi: 10.1016/j.jep.2023.116568. Epub 2023 May 20.

Authors

Jingzhuo Tian¹, Chenyue Liu¹, Lianmei Wang¹, Zhong Xian¹, Yong Zhao¹, Shasha Qin¹, Yan Yi¹, Chunying Li¹, Jiayin Han¹, Chen Pan¹, Yushi Zhang¹, Suyan Liu¹, Jing Meng¹, Xuan Tang¹, Fang Wang¹, Meiting Liu¹, Aihua Liang²

Affiliations

¹ Key Laboratory of Beijing for Identification and Safety Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, China.
² Key Laboratory of Beijing for Identification and Safety Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, China. Electronic address: ahliang@icmm.ac.cn.

PMID: 37217154
DOI: 10.1016/j.jep.2023.116568

Abstract

Ethnopharmacological relevance: The nephrotoxicity and carcinogenicity induced by traditional Chinese medicines (TCMs) containing aristolochic acids (AAs) and related compound preparations have greatly limited their clinical application. While the toxicity of AA-I and AA-II is relatively clear, there are marked differences in the toxic effects of different types of aristolochic acid analogues (AAAs). Thus, the toxicity of TCMs containing AAAs cannot be evaluated based on the toxicity of a single compound.

Aim of the study: To systematically investigate the toxicity induced by Zhushalian (ZSL), Madouling (MDL) and Tianxianteng (TXT) as representative TCMs derived from Aristolochia.

Materials and methods: AAA contents in ZSL, MDL and TXT were determined using HPLC. Subsequently, mice were treated for 2 weeks with high (H) and low (L) dosages of TCMs containing total AAA contents of 3 mg/kg and 1.5 mg/kg, respectively. Toxicity was evaluated using biochemical and pathological examination and was based on organ indices. Correlations between AAA contents and induced toxicity were analysed using multiple methods.

Results: Of the total AAA content, ZSL contained mainly AA-I and AA-II (>90%, of which AA-I accounted for 49.55%). AA-I accounted for 35.45% in MDL. TXT mainly contained AA-IVa (76.84%) and other AAAs accounted for <10%. Short-term toxicity tests indicated that ZSL and high-dose MDL induced obvious renal interstitial fibrosis and gastric injury, whereas TXT (high and low dosages) caused only slight toxicity. Correlation analysis suggested that AA-I might be the critical hazard factor for toxicity.

Conclusions: The toxicity of TCMs containing AAAs cannot be generalised. The toxicity of TXT is relatively low compared with those of ZSL and MDL. The toxicity of Aristolochia depends mainly on the AA-I content; therefore, control of AA-I levels in TCMs and related compound preparations is required to reduce the risk of toxicity associated with the use of Aristolochia herbs in clinical settings.

Keywords: AA-I; Aristolochic acid analogues (AAAs); Content; Difference and correlation; Renal/gastric toxicity.

MeSH terms

Animals
Aristolochia* / chemistry
Aristolochic Acids* / toxicity
Chromatography, High Pressure Liquid / methods
Drugs, Chinese Herbal* / chemistry
Kidney Diseases* / chemically induced
Mice

Substances

aristolochic acid I
Aristolochic Acids
Drugs, Chinese Herbal