The key role of gut–liver axis in pyrrolizidine alkaloid-induced hepatotoxicity and enterotoxicity
Pyrrolizidine alkaloids (PAs) are the most common phytotoxins with documented human hepatotoxicity. PAs require metabolic activation by cytochromes P450 to generate toxic intermediates which bind to proteins and form protein adducts, thereby causing cytotoxicity. This study investigated the role of...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2021-12-01
|
| Series: | Acta Pharmaceutica Sinica B |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383521002628 |
| _version_ | 1819229522819547136 |
|---|---|
| author | Yisheng He Jiang Ma Xiaoyu Fan Liang Ding Xinxin Ding Qing-Yu Zhang Ge Lin |
| author_facet | Yisheng He Jiang Ma Xiaoyu Fan Liang Ding Xinxin Ding Qing-Yu Zhang Ge Lin |
| author_sort | Yisheng He |
| collection | DOAJ |
| description | Pyrrolizidine alkaloids (PAs) are the most common phytotoxins with documented human hepatotoxicity. PAs require metabolic activation by cytochromes P450 to generate toxic intermediates which bind to proteins and form protein adducts, thereby causing cytotoxicity. This study investigated the role of the gut–liver axis in PA intoxication and the underlying mechanisms. We exposed mice to retrorsine (RTS), a representative PA, and for the first time found RTS-induced intestinal epithelium damage and disruption to intestinal barrier function. Using mice with tissue-selective ablation of P450 activity, we found that hepatic P450s, but not intestinal P450s, were essential for PA bioactivation. Besides, in RTS-exposed, bile duct-cannulated rats, we found the liver-derived reactive PA metabolites were transported by bile into the intestine to exert enterotoxicity. The impact of gut-derived pathogenic factors in RTS-induced hepatotoxicity was further studied in mice with dextran sulfate sodium (DSS)-induced chronic colitis. DSS treatment increased the hepatic endotoxin level and depleted hepatic reduced glutathione, thereby suppressing the PA detoxification pathway. Compared to RTS-exposed normal mice, the colitic mice displayed more severe RTS-induced hepatic vasculature damage, fibrosis, and steatosis. Overall, 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. |
| first_indexed | 2024-12-23T11:14:31Z |
| format | Article |
| id | doaj.art-8ec1c36ad15b4605abe5aba153fe290d |
| institution | Directory Open Access Journal |
| issn | 2211-3835 |
| language | English |
| last_indexed | 2024-12-23T11:14:31Z |
| publishDate | 2021-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj.art-8ec1c36ad15b4605abe5aba153fe290d2022-12-21T17:49:15ZengElsevierActa Pharmaceutica Sinica B2211-38352021-12-01111238203835The key role of gut–liver axis in pyrrolizidine alkaloid-induced hepatotoxicity and enterotoxicityYisheng He0Jiang Ma1Xiaoyu Fan2Liang Ding3Xinxin Ding4Qing-Yu Zhang5Ge Lin6School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR 999077, ChinaSchool of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR 999077, ChinaDepartment of Pharmacology & Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USADepartment of Pharmacology & Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USADepartment of Pharmacology & Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USADepartment of Pharmacology & Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA; Corresponding authors. Tel.: +852 39436824, fax: +852 26035123 (Ge Lin); Tel.: +1 520 6213667; fax: +1 520 6262466 (Qing-Yu Zhang).School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR 999077, China; Corresponding authors. Tel.: +852 39436824, fax: +852 26035123 (Ge Lin); Tel.: +1 520 6213667; fax: +1 520 6262466 (Qing-Yu Zhang).Pyrrolizidine alkaloids (PAs) are the most common phytotoxins with documented human hepatotoxicity. PAs require metabolic activation by cytochromes P450 to generate toxic intermediates which bind to proteins and form protein adducts, thereby causing cytotoxicity. This study investigated the role of the gut–liver axis in PA intoxication and the underlying mechanisms. We exposed mice to retrorsine (RTS), a representative PA, and for the first time found RTS-induced intestinal epithelium damage and disruption to intestinal barrier function. Using mice with tissue-selective ablation of P450 activity, we found that hepatic P450s, but not intestinal P450s, were essential for PA bioactivation. Besides, in RTS-exposed, bile duct-cannulated rats, we found the liver-derived reactive PA metabolites were transported by bile into the intestine to exert enterotoxicity. The impact of gut-derived pathogenic factors in RTS-induced hepatotoxicity was further studied in mice with dextran sulfate sodium (DSS)-induced chronic colitis. DSS treatment increased the hepatic endotoxin level and depleted hepatic reduced glutathione, thereby suppressing the PA detoxification pathway. Compared to RTS-exposed normal mice, the colitic mice displayed more severe RTS-induced hepatic vasculature damage, fibrosis, and steatosis. Overall, 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.http://www.sciencedirect.com/science/article/pii/S2211383521002628Pyrrolizidine alkaloidCytochrome P450Inflammatory bowel diseaseIntestinal injuryLiver injuryGut–liver axis |
| spellingShingle | Yisheng He Jiang Ma Xiaoyu Fan Liang Ding Xinxin Ding Qing-Yu Zhang Ge Lin The key role of gut–liver axis in pyrrolizidine alkaloid-induced hepatotoxicity and enterotoxicity Acta Pharmaceutica Sinica B Pyrrolizidine alkaloid Cytochrome P450 Inflammatory bowel disease Intestinal injury Liver injury Gut–liver axis |
| title | The key role of gut–liver axis in pyrrolizidine alkaloid-induced hepatotoxicity and enterotoxicity |
| title_full | The key role of gut–liver axis in pyrrolizidine alkaloid-induced hepatotoxicity and enterotoxicity |
| title_fullStr | The key role of gut–liver axis in pyrrolizidine alkaloid-induced hepatotoxicity and enterotoxicity |
| title_full_unstemmed | The key role of gut–liver axis in pyrrolizidine alkaloid-induced hepatotoxicity and enterotoxicity |
| title_short | The key role of gut–liver axis in pyrrolizidine alkaloid-induced hepatotoxicity and enterotoxicity |
| title_sort | key role of gut liver axis in pyrrolizidine alkaloid induced hepatotoxicity and enterotoxicity |
| topic | Pyrrolizidine alkaloid Cytochrome P450 Inflammatory bowel disease Intestinal injury Liver injury Gut–liver axis |
| url | http://www.sciencedirect.com/science/article/pii/S2211383521002628 |
| work_keys_str_mv | AT yishenghe thekeyroleofgutliveraxisinpyrrolizidinealkaloidinducedhepatotoxicityandenterotoxicity AT jiangma thekeyroleofgutliveraxisinpyrrolizidinealkaloidinducedhepatotoxicityandenterotoxicity AT xiaoyufan thekeyroleofgutliveraxisinpyrrolizidinealkaloidinducedhepatotoxicityandenterotoxicity AT liangding thekeyroleofgutliveraxisinpyrrolizidinealkaloidinducedhepatotoxicityandenterotoxicity AT xinxinding thekeyroleofgutliveraxisinpyrrolizidinealkaloidinducedhepatotoxicityandenterotoxicity AT qingyuzhang thekeyroleofgutliveraxisinpyrrolizidinealkaloidinducedhepatotoxicityandenterotoxicity AT gelin thekeyroleofgutliveraxisinpyrrolizidinealkaloidinducedhepatotoxicityandenterotoxicity AT yishenghe keyroleofgutliveraxisinpyrrolizidinealkaloidinducedhepatotoxicityandenterotoxicity AT jiangma keyroleofgutliveraxisinpyrrolizidinealkaloidinducedhepatotoxicityandenterotoxicity AT xiaoyufan keyroleofgutliveraxisinpyrrolizidinealkaloidinducedhepatotoxicityandenterotoxicity AT liangding keyroleofgutliveraxisinpyrrolizidinealkaloidinducedhepatotoxicityandenterotoxicity AT xinxinding keyroleofgutliveraxisinpyrrolizidinealkaloidinducedhepatotoxicityandenterotoxicity AT qingyuzhang keyroleofgutliveraxisinpyrrolizidinealkaloidinducedhepatotoxicityandenterotoxicity AT gelin keyroleofgutliveraxisinpyrrolizidinealkaloidinducedhepatotoxicityandenterotoxicity |