The key role of gut-liver axis in pyrrolizidine alkaloid-induced hepatotoxicity and enterotoxicity

作     者：Yisheng He Jiang Ma Xiaoyu Fan Liang Ding Xinxin Ding Qing-Yu Zhang Ge Lin Yisheng He;Jiang Ma;Xiaoyu Fan;Liang Ding;Xinxin Ding;Qing-Yu Zhang;Ge Lin

作者机构：School of Biomedical SciencesFaculty of Medicinethe Chinese University of Hong KongHong Kong SAR 999077China Department of Pharmacology&ToxicologyCollege of PharmacyUniversity of ArizonaTucsonAZ 85721USA 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2021年第11卷第12期

页      面：3820-3835页

核心收录：

学科分类：100405[医学-卫生毒理学] 1004[医学-公共卫生与预防医学(可授医学、理学学位)] 10[医学] 

基　　金：supported by Research Grants Council of Hong Kong Special Administrative Region (GRF Project Nos. 14160817 and 14106318 to Ge Lin, China) a grant from the National Institutes of Health (No. R01 GM082978 to Qing-Yu Zhang, USA) 

主　　题：Pyrrolizidine alkaloid Cytochrome P450 Inflammatory bowel disease Intestinal injury Liver injury Gut-liver axis 

摘      要：Pyrrolizidine alkaloids(PAs) are the most common phytotoxins with documented human *** require metabolic activation by cytochromes P450 to generate toxic intermediates which bind to proteins and form protein adducts,thereby causing *** study investigated the role of the gut-liver axis in PA intoxication and the underlying *** exposed mice to retrorsine(RTS),a representative PA,and for the first time found RTS-induced intestinal epithelium damage and disruption to intestinal barrier *** mice with tissue-selective ablation of P450 activity,we found that hepatic P450 s,but not intestinal P450 s,were essential for PA ***,in RTS-exposed,bile duct-cannulated rats,we found the liver-derived reactive PA metabolites were transported by bile into the intestine to exert *** impact of gut-derived pathogenic factors in RTS-induced hepatotoxicity was further studied in mice with dextran sulfate sodium(DSS)-induced chronic *** treatment increased the hepatic endotoxin level and depleted hepatic reduced glutathione,thereby suppressing the PA detoxification *** to RTS-exposed normal mice,the colitic mice displayed more severe RTS-induced hepatic vasculature damage,fibrosis,and ***,our findings provide the first mode-of-action evidence of PA-induced enterotoxicity and highlight the importance of gut barrier function in PA-induced liver injury.