Glück Josephin, Henricsson Marcus, Braeuning Albert, Hessel-Pras Stefanie
Department of Food Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Straße 8-10, 10589 Berlin, Germany.
Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, 413 45 Gothenburg, Sweden.
Foods. 2021 May 18;10(5):1114. doi: 10.3390/foods10051114.
Pyrrolizidine alkaloids (PAs) are a group of secondary plant metabolites being contained in various plant species. The consumption of contaminated food can lead to acute intoxications in humans and exert severe hepatotoxicity. The development of jaundice and elevated bile acid concentrations in blood have been reported in acute human PA intoxication, indicating a connection between PA exposure and the induction of cholestasis. Additionally, it is considered that differences in toxicity of individual PAs is based on their individual chemical structures. Therefore, we aimed to elucidate the structure-dependent disturbance of bile acid homeostasis by PAs in the human hepatoma cell line HepaRG. A set of 14 different PAs, including representatives of all major structural characteristics, namely, the four different necine bases retronecine, heliotridine, otonecine and platynecine and different grades of esterification, was analyzed in regard to the expression of genes involved in bile acid synthesis, metabolism and transport. Additionally, intra- and extracellular bile acid levels were analyzed after PA treatment. In summary, our data show significant structure-dependent effects of PAs on bile acid homeostasis. Especially PAs of diester type caused the strongest dysregulation of expression of genes associated with cholestasis and led to a strong decrease of intra- and extracellular bile acid concentrations.
吡咯里西啶生物碱（PAs）是一类存在于多种植物物种中的次生植物代谢产物。食用受污染的食物会导致人类急性中毒，并产生严重的肝毒性。急性人类PA中毒已报告出现黄疸和血液中胆汁酸浓度升高，表明PA暴露与胆汁淤积的诱导之间存在联系。此外，人们认为单个PA的毒性差异基于其各自的化学结构。因此，我们旨在阐明PAs在人肝癌细胞系HepaRG中对胆汁酸稳态的结构依赖性干扰。分析了一组14种不同的PAs，包括所有主要结构特征的代表，即四种不同的 necine 碱（倒千里光碱、天芥菜碱、奥托千里光碱和平卧千里光碱）以及不同程度的酯化，以研究其对参与胆汁酸合成、代谢和转运的基因表达的影响。此外，在PA处理后分析了细胞内和细胞外胆汁酸水平。总之，我们的数据显示PAs对胆汁酸稳态具有显著的结构依赖性影响。尤其是二酯型PAs导致与胆汁淤积相关的基因表达失调最为严重，并导致细胞内和细胞外胆汁酸浓度大幅下降。
