{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:18:30Z","timestamp":1792790310175,"version":"4.5.0"},"reference-count":65,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,11,28]],"date-time":"2021-11-28T00:00:00Z","timestamp":1638057600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Pyrrolizidine alkaloids (PAs) are common secondary plant compounds with hepatotoxicity. The consumption of herbal medicines and herbal teas containing PAs is one of the main causes of hepatic sinusoidal obstruction syndrome (HSOS), a potentially life-threatening condition. The present study aimed to reveal the mechanism underlying the cytotoxicity of intermedine (Im), the main PA in Comfrey. We evaluated the toxicity of the retronecine-type PAs with different structures to cell lines derived from mammalian tissues, including primary mouse hepatocytes, human hepatocytes (HepD), mouse hepatoma-22 (H22) and human hepatocellular carcinoma (HepG2) cells. The cytotoxicity of Im to hepatocyte was evaluated by using cell counting kit-8 assay, colony formation experiment, wound healing assay and dead\/live fluorescence imaging. In vitro characterization showed that these PAs were cytotoxic and induced cell apoptosis in a dose-dependent manner. We also demonstrated that Im induced cell apoptosis by generating excessive reactive oxygen species (ROS), changing the mitochondrial membrane potential and releasing cytochrome c (Cyt c) before activating the caspase-3 pathway. Importantly, we directly observed the destruction of the cell mitochondrial structure after Im treatment through transmission electron microscopy (TEM). This study provided the first direct evidence of Im inducing hepatotoxicity through mitochondria-mediated apoptosis. These results supplemented the basic toxicity data of PAs and facilitated the comprehensive and systematic evaluation of the toxicity caused by PA compounds.<\/jats:p>","DOI":"10.3390\/toxins13120849","type":"journal-article","created":{"date-parts":[[2021,12,1]],"date-time":"2021-12-01T03:12:56Z","timestamp":1638328376000},"page":"849","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Hepatotoxicity of Pyrrolizidine Alkaloid Compound Intermedine: Comparison with Other Pyrrolizidine Alkaloids and Its Toxicological Mechanism"],"prefix":"10.3390","volume":"13","author":[{"given":"Ziqi","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Tea Plant Biology and Utilization, School of Tea and Food Science & Technology, Anhui Agricultural University, Hefei 230036, China"},{"name":"Tea Research Institute, Chinese Academy of Agricultural Sciences, Hangzhou 310008, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haolei","family":"Han","sequence":"additional","affiliation":[{"name":"Tea Research Institute, Chinese Academy of Agricultural Sciences, Hangzhou 310008, China"},{"name":"Graduate School, Chinese Academy of Agricultural Sciences, Beijing 100081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Wang","sequence":"additional","affiliation":[{"name":"Tea Research Institute, Chinese Academy of Agricultural Sciences, Hangzhou 310008, China"},{"name":"Key Laboratory of Tea Quality and Safety & Risk Assessment, Ministry of Agriculture, Hangzhou 310008, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinqin","family":"Zheng","sequence":"additional","affiliation":[{"name":"Tea Research Institute, Chinese Academy of Agricultural Sciences, Hangzhou 310008, China"},{"name":"Graduate School, Chinese Academy of Agricultural Sciences, Beijing 100081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongping","family":"Chen","sequence":"additional","affiliation":[{"name":"Tea Research Institute, Chinese Academy of Agricultural Sciences, Hangzhou 310008, China"},{"name":"Key Laboratory of Tea Quality and Safety & Risk Assessment, Ministry of Agriculture, Hangzhou 310008, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9292-3563","authenticated-orcid":false,"given":"Xiangchun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Tea Research Institute, Chinese Academy of Agricultural Sciences, Hangzhou 310008, China"},{"name":"Key Laboratory of Tea Quality and Safety & Risk Assessment, Ministry of Agriculture, Hangzhou 310008, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4423-694X","authenticated-orcid":false,"given":"Ruyan","family":"Hou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Tea Plant Biology and Utilization, School of Tea and Food Science & Technology, Anhui Agricultural University, Hefei 230036, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.livres.2019.11.004","article-title":"Pyrrolizidine alkaloids: An update on their metabolism and hepatotoxicity mechanism","volume":"3","author":"Xu","year":"2019","journal-title":"Liver Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3753","DOI":"10.3748\/wjg.v25.i28.3753","article-title":"Pyrrolizidine alkaloids-induced hepatic sinusoidal obstruction syndrome: Pathogenesis, clinical manifestations, diagnosis, treatment, and outcomes","volume":"25","author":"Yang","year":"2019","journal-title":"World J. 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