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Pyrrolizidine alkaloids disturb bile acid homeostasis in the human hepatoma cell line heparg

Affiliation
Department of Food Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Straße 8-10, Berlin, Germany
Waizenegger, Julia;
Affiliation
German Federal Institute for Risk Assessment (BfR), Department 5 Food Safety, Unit 51 Effect-based Analytics and Toxicogenomics, Germany
Glück, Josephin;
Affiliation
Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
Henricsson, Marcus;
Affiliation
German Federal Institute for Risk Assessment (BfR), Department 5 Food Safety, Unit 52 Food Toxicology, Germany
Luckert, Claudia;
Affiliation
German Federal Institute for Risk Assessment (BfR), Department 5 Food Safety, Unit 51 Effect-based Analytics and Toxicogenomics, Germany
Braeuning, Albert;
ORCID
0000-0002-6153-0035
Affiliation
German Federal Institute for Risk Assessment (BfR), Department 5 Food Safety, Unit 52 Food Toxicology, Germany
Hessel-Pras, Stefanie

1,2-unsaturated pyrrolizidine alkaloids (PAs) belong to a group of secondary plant metabo-lites. Exposure to PA-contaminated feed and food may cause severe hepatotoxicity. a pathway possibly involved in PA toxicity is the disturbance of bile acid homeostasis. Therefore, in this study, the influence of four structurally different PAs on bile acid homeostasis was investigated after single (24 h) and repeated (14 days) exposure using the human hepatoma cell line HepaRG. PAs induce a downregulation of gene expression of various hepatobiliary transporters, enzymes involved in bile acid synthesis, and conjugation, as well as several transcription regulators in HepaRG cells. This repression may lead to a progressive impairment of bile acid homeostasis, having the potential to accumulate toxic bile acids. However, a significant intracellular and extracellular decrease in bile acids was determined, pointing to an overall inhibition of bile acid synthesis and transport. In summary, our data clearly show that PAs structure-dependently impair bile acid homeostasis and secretion by inhibiting the expression of relevant genes involved in bile acid homeostasis. Furthermore, important biliary efflux mechanisms seem to be disturbed due to PA exposure. These mole-cular mechanisms may play an important role in the development of severe liver damage in PA-intoxicated humans.

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