{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T21:12:12Z","timestamp":1791666732127,"version":"4.3.4"},"reference-count":46,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,10,13]],"date-time":"2021-10-13T00:00:00Z","timestamp":1634083200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The Chinese University of Hong Kong","award":["4054503"],"award-info":[{"award-number":["4054503"]}]},{"name":"Research Grant Council of Hong Kong","award":["14111816"],"award-info":[{"award-number":["14111816"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Pyrrolizidine alkaloids (PAs) with 1,2-unsaturated necine base are hepatotoxic phytotoxins. Acute PA intoxication is initiated by the formation of adducts between PA-derived reactive pyrrolic metabolites with cellular proteins. The present study aimed to investigate the correlation between the formation of hepatic pyrrole\u2013protein adducts and occurrence of PA-induced liver injury (PA-ILI), and to further explore the use of such adducts for rapidly screening the hepatotoxic potency of natural products which contain PAs. Aqueous extracts of Crotalaria sessiliflora (containing one PA: monocrotaline) and Gynura japonica (containing two PAs: senecionine and seneciphylline) were orally administered to rats at different doses for 24 h to investigate PA-ILI. Serum alanine aminotransferase (ALT) activity, hepatic glutathione (GSH) level, and liver histological changes of the treated rats were evaluated to assess the severity of PA-ILI. The levels of pyrrole\u2013protein adducts formed in the rats\u2019 livers were determined by a well-established spectrophotometric method. The biological and histological results showed a dose-dependent hepatotoxicity with significantly different toxic severity among groups of rats treated with herbal extracts containing different PAs. Both serum ALT activity and the amount of hepatic pyrrole\u2013protein adducts increased in a dose-dependent manner. Moreover, the elevation of ALT activity correlated well with the formation of hepatic pyrrole\u2013protein adducts, regardless of the structures of different PAs. The findings revealed that the formation of hepatic pyrrole\u2013protein adducts\u2014which directly correlated with the elevation of serum ALT activity\u2014was a common insult leading to PA-ILI, suggesting a potential for using pyrrole\u2013protein adducts to screen hepatotoxicity and rank PA-containing natural products, which generally contain multiple PAs with different structures.<\/jats:p>","DOI":"10.3390\/toxins13100723","type":"journal-article","created":{"date-parts":[[2021,10,13]],"date-time":"2021-10-13T21:48:39Z","timestamp":1634161719000},"page":"723","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Pyrrolizidine Alkaloid-Induced Hepatotoxicity Associated with the Formation of Reactive Metabolite-Derived Pyrrole\u2013Protein Adducts"],"prefix":"10.3390","volume":"13","author":[{"given":"Jiang","family":"Ma","sequence":"first","affiliation":[{"name":"School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong 4054577, China"},{"name":"School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mi","family":"Li","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong 4054577, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Li","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong 4054577, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7114-1463","authenticated-orcid":false,"given":"Wood Yee","family":"Chan","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong 4054577, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4586-2603","authenticated-orcid":false,"given":"Ge","family":"Lin","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong 4054577, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"111107","DOI":"10.1016\/j.fct.2019.111107","article-title":"Pyrrolizidine alkaloids in food and phytomedicine: Occurrence, exposure, toxicity, mechanisms, and risk assessment\u2014A review","volume":"136","author":"Schrenk","year":"2020","journal-title":"Food Chem. 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