2. Academic Validation
  3. Zanthoxylum armatum DC fruit ethyl acetate extract site induced hepatotoxicity by activating endoplasmic reticulum stress and inhibiting autophagy in BRL-3A models

Zanthoxylum armatum DC fruit ethyl acetate extract site induced hepatotoxicity by activating endoplasmic reticulum stress and inhibiting autophagy in BRL-3A models

  • J Ethnopharmacol. 2023 Oct 5;319(Pt 2):117245. doi: 10.1016/j.jep.2023.117245.
Jian Zhang 1,  Jiafu Guo 1,  Nannan Yang 1,  Yan Huang 2,  Jiayu Wen 1,  Qiwen Xiang 1,  Qiuyan Liu 1,  Yan Chen 1,  Tingting Hu 3,  Chaolong Rao 4
Affiliations

Affiliations

  • 1 School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, China; R&D Center for Efficiency, Safety and Application in Chinese Materia Medica with Medical and Edible Values, School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, China.
  • 2 State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, China.
  • 3 School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, China; R&D Center for Efficiency, Safety and Application in Chinese Materia Medica with Medical and Edible Values, School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, China. Electronic address: [email protected].
  • 4 School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, China; State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, China; R&D Center for Efficiency, Safety and Application in Chinese Materia Medica with Medical and Edible Values, School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, China. Electronic address: [email protected].
PMID: 37802376 DOI: 10.1016/j.jep.2023.117245
Abstract

Ethnopharmacological relevance: Zanthoxylum armatum DC (Z. armatum) is renowned not only as a culinary spice but also as a staple in traditional ethnic medicine, predominantly in Southeast Asia and various other regions. Recent research has unveiled its multifaceted pharmacological properties, including anti-inflammatory, Antibacterial, and toothache relief effects. Nonetheless, some studies have reported the potential toxicity of Z. armatum, emphasizing the need to further explore its toxicity mechanisms for safer application.

Aim of the study: This study investigated the effect and mechanism of hepatotoxicity in BRL-3A cells induced by Z. armatum.

Materials and methods: The compounds of the ethyl acetate extract of Z. armatum (ZADC-EA) were identified by ultrahigh performance liquid chromatography coupled with quadrupole-orbitrap high resolution mass spectrometry (UPLC-Q-Orbitrap HRMS). The hepatotoxicity of the extract was evaluated by detecting cell viability, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and Lactate Dehydrogenase (LDH) activity, and Apoptosis. Endoplasmic reticulum stress, Autophagy, and Apoptosis were detected by Ad-mCherry-GFP-LC3B, flow cytometry, and Western blot to explore the mechanism of hepatotoxicity induced by ZADC-EA.

Results: UPLC-Q-Orbitrap HRMS analysis revealed the presence of compounds belonging to Flavonoids, Terpenoids, and Alkaloids. The IC50 value of ZADC-EA was 62.43 μg/mL, the cell viability of BRL-3A decreased in a time-dose dependent manner, and the levels of AST, ALT, and LDH were upregulated. In addition, ZADC-EA-induced increased expression of eIF2α-ATF4-CHOP pathway proteins, inhibited Autophagy, and promoted Apoptosis.

Conclusions: This study provides insights into the hepatotoxicity mechanisms of ZADC-EA on BRL-3A cells. It was found that ZADC-EA could induce endoplasmic reticulum stress and inhibit Autophagy, then intensify Apoptosis, and endoplasmic reticulum stress could exacerbate Autophagy inhibition.

Keywords

Apoptosis; Autophagy; Endoplasmic reticulum stress; Hepatotoxicity; Zanthoxylum armatum DC.

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