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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Predictive Toxicology
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1378758
This article is part of the Research Topic Methods in Predictive Toxicology 2023 View all 3 articles

Potential Mechanisms Underlying Podophyllotoxin-induced Cardiotoxicity in Male Rats: Toxicological Evidence Chain (TEC) Concept

Provisionally accepted
Kaiyue Ma Kaiyue Ma 1*Lu Sun Lu Sun 2*Chunxue Jia Chunxue Jia 1*Hongqian Kui Hongqian Kui 1Jiaqi Xie Jiaqi Xie 1*Shidan Zang Shidan Zang 1*Shixin Huang Shixin Huang 3Jinfeng Que Jinfeng Que 1*Chuanxin Liu Chuanxin Liu 4*Jianmei Huang Jianmei Huang 1*
  • 1 School of Chinese Materia Medica, Beijing University of Chinese Medicines, Beijing, Beijing Municipality, China
  • 2 College of Chinese Materia Medica and Food Engineering, Shanxi University of Chinese Medicine, Yuci, China
  • 3 Eye hospital China Academy of Chinese Medical Sciences, Beijing, China
  • 4 Luoyang Key Laboratory of Clinical Multiomics and Translational Medicine, Henan Key Laboratory of Rare Diseases, Endocrine and Metabolic Disease Center, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, China

The final, formatted version of the article will be published soon.

    Podophyllotoxin (PPT) is a high-content and activity compound extracted from the traditional Chinese medicine Dysosma Versipellis (DV), exhibiting various biological activities. However, its severe toxicity limits its use. In clinical settings, patients with DV poisoning often experience adverse reactions when taking large doses in a short period, and the heart is an important toxic target organ. Therefore, it is necessary to conduct 24-hour acute cardiac toxicity studies on PPT to understand the underlying toxicity mechanism. Methods: Based on the concept of toxicological evidence chain (TEC), we utilized targeted metabolomics and transcriptomics analyses to reveal the mechanism of acute cardiotoxicity of PPT. Results: Injury Phenotype Evidence (IPE) showed significant epistaxis, hypokinesia, and hunched posture in PPT group rats within 24 h after exposure to 120 mg/kg PPT. Adverse Outcomes Evidence (AOE) indicated that PPT induced cardiac injury in rats within 24 h by increasing serum myocardial enzyme levels, increasing the concentration of cardiac injury biomarkers, and altering cardiac cell morphology, indicating some cardiac toxicity. Conclusion: A comprehensive analysis of the transcriptome and metabolome revealed the mechanism of PPT-2 induced acute cardiotoxicity, which involved oxidative stress, apoptosis, inflammatory response, and disorder in energy metabolism.

    Keywords: toxicological evidence chain (TEC)1, podophyllotoxin2, cardiotoxicity3, Transcriptomics4, arachidonic acid metabolism5

    Received: 30 Jan 2024; Accepted: 31 Jul 2024.

    Copyright: © 2024 Ma, Sun, Jia, Kui, Xie, Zang, Huang, Que, Liu and Huang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Kaiyue Ma, School of Chinese Materia Medica, Beijing University of Chinese Medicines, Beijing, 10248, Beijing Municipality, China
    Lu Sun, College of Chinese Materia Medica and Food Engineering, Shanxi University of Chinese Medicine, Yuci, China
    Chunxue Jia, School of Chinese Materia Medica, Beijing University of Chinese Medicines, Beijing, 10248, Beijing Municipality, China
    Jiaqi Xie, School of Chinese Materia Medica, Beijing University of Chinese Medicines, Beijing, 10248, Beijing Municipality, China
    Shidan Zang, School of Chinese Materia Medica, Beijing University of Chinese Medicines, Beijing, 10248, Beijing Municipality, China
    Jinfeng Que, School of Chinese Materia Medica, Beijing University of Chinese Medicines, Beijing, 10248, Beijing Municipality, China
    Chuanxin Liu, Luoyang Key Laboratory of Clinical Multiomics and Translational Medicine, Henan Key Laboratory of Rare Diseases, Endocrine and Metabolic Disease Center, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, China
    Jianmei Huang, School of Chinese Materia Medica, Beijing University of Chinese Medicines, Beijing, 10248, Beijing Municipality, China

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