2. Academic Validation
  3. CYP3A4 and MRP2 are predominant metabolic regulators attribute to the toxicity/efficacy of aconitine derived from Fuzi

CYP3A4 and MRP2 are predominant metabolic regulators attribute to the toxicity/efficacy of aconitine derived from Fuzi

  • J Ethnopharmacol. 2025 Feb 13:343:119463. doi: 10.1016/j.jep.2025.119463.
Jingjing Yao 1,  Yajuan Guo 2,  Ting Wan 2,  Shaofang Yu 2,  Qinghong Shen 2,  Min Huang 2,  Yu Li 2,  Fuping Xu 3,  Huiyan Zeng 3,  Zhongqiu Liu 2,  Linlin Lu 4
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, State Key Laboratory of Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China; Chinese Medicine Guangdong Laboratory (Hengqin Laboratory), Hengqin, Guangdong, 519000, China; Institute of Taihang Materia Medica, Experimental Management Center, Shanxi University of Chinese Medicine, Jinzhong, 030619, China.
  • 2 Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, State Key Laboratory of Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China; Chinese Medicine Guangdong Laboratory (Hengqin Laboratory), Hengqin, Guangdong, 519000, China.
  • 3 Guandong Provincial Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China.
  • 4 Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, State Key Laboratory of Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China; Chinese Medicine Guangdong Laboratory (Hengqin Laboratory), Hengqin, Guangdong, 519000, China. Electronic address: lllu@gzucm.edu.cn.
PMID: 39954827 DOI: 10.1016/j.jep.2025.119463
Abstract

Ethnopharmacological relevance: Aconitum carmichaelii Debx. exhibits overwhelming efficacy against heart failure, inflammation and pain, but its clinical application is limited by concomitant cardiotoxicity and neurotoxicity. Aconitine (AC), the most abundant bioactive alkaloid, has narrow therapeutic window, with well-defined toxic and therapeutic thresholds. However, the overlapping molecular targets mediating dual toxicity and efficacy of AC remain poorly characterized.

Aims of the study: This study aimed to evaluate dual pharmacological and toxicological roles of AC through integrative pharmacology and transgenic mouse models.

Materials and methods: The overlapping targets of AC-related toxicity/efficacy were identified based on integrative pharmacology. By generating Cyp3a-/- transgenic mice expressing human CYP3A4 (hCYP3A4), Ugt1, P-gp, Mrp2, BCRP, and Nrf2 knockout mice, the effects of AC on toxicity, pain, inflammation, and heart failure were assessed.

Results: We identified 143 overlapping targets predominantly enriched in metabolic pathways. Symptom-based toxicity scores were strikingly elevated in AC-exposed hCYP3A4, Mrp2-/-, P-gp-/-, BCRP-/-, and Nrf2-/- mice compared to WT mice. Additionally, AC prolonged the latency of response by approximately 18s, 15s, 14s, and 5s, respectively, in hCYP3A4, Mrp2-/-, P-gp-/-, and Nrf2-/- mice by hot plate assay. Interestingly, both toxicity score and analgesic latency initially increased and subsequently decreased, peaking at 60 min. AC obviously decreased the acetic acid-induced writhing and permeability by 45.7% and 22.2% in hCYP3A4 mice, whereas these changes were amplified in Mrp2-/- mice compared to WT mice. Furthermore, AC attenuated DOX induced heart failure in hCYP3A4 mice, with an effective rate of 20.9%, with Septin4 implicated in AC-related metabolism.

Conclusions: Metabolic targets may elucidate the mechanistic overlap between the toxicity and efficacy of AC. Notably, hCYP3A4 exhibited heightened toxicity, alongside enhanced analgesic, anti-inflammatory, and cardioprotective effects. Our findings position metabolic pathways as critical nodes for AC-related dual effect, and establish Septin4 as a candidate mediator of its metabolic regulation.

Keywords

Aconitine; Analgesic; Anti-inflammatory; Heart failure; Toxicity.

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