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  2. Clinical poisoning events involving yunaconitine may be highly correlated with metabolism-based interactions: A critical role of CYP3A4

Clinical poisoning events involving yunaconitine may be highly correlated with metabolism-based interactions: A critical role of CYP3A4

  • Food Chem Toxicol. 2023 Aug 22;113989. doi: 10.1016/j.fct.2023.113989.
Xiaocui Li 1 Yu Fu 1 Huawei Qiu 1 Xueyu Xu 1 Tingting Lin 1 Weiqing Hou 1 Weiying Chen 2 Rong Zhang 1 Zhongqiu Liu 1 Lijun Zhu 3
Affiliations

Affiliations

  • 1 Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
  • 2 The Second Clinical Medicial College, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
  • 3 Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China. Electronic address: zhulijun@gzucm.edu.cn.
Abstract

Clinical poisoning events involving yunaconitine (YAC), a toxic Aconitum alkaloid, occur more and more frequently, and whether the mechanism is correlated with metabolism-based interactions remains unknown. This study aimed to reveal the presumable mechanism by clarifying the metabolic profiles and kinetic-based mechanism of YAC. YAC could be oxidized into 20 metabolites by human liver microsomes, while CYP3A4 have a critical metabolic superiority. Sixteen of the metabolites were primary generated by CYP3A4, and 4 of them were generated only by CYP3A4. The presence of CYP3A inhibitor ketoconazole (KCZ) significantly suppressed the generation of all the 20 metabolites, with 9 of them being suppressed completely (P < 0.05). The plasma exposure (Cmax and AUC0-t values), cardiotoxicity and neurotoxicity of YAC enhanced remarkably in mice when Cyp3a were inhibited (P < 0.05). Moreover, the CYP3A4-based kinetics of YAC is an example of substrate inhibition, and the inhibitory manner of YAC on CYP3A4 was competitive, with Ki value being 1.76 μmol/L. Overall, YAC was a sensitive substrate and moderately competitive inhibitor of CYP3A4. The inhibition on CYP3A4 could sharply increase the in vivo exposure and toxicity of YAC. Thus, clinical poisoning events involving YAC may be highly correlated with CYP3A4-mediated interactions.

Keywords

CYP3A4; Metabolism; Poisoning; Yunaconitine.

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