| Title: | Pyrrolizidine Alkaloids Induce Cell Death in Human HepaRG Cells in a Structure-Dependent Manner |
| Author(s): | Gluck J; Waizenegger J; Braeuning A; Hessel-Pras S; |
| Address: | "Department of Food Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Str. 8-10, 10589 Berlin, Germany. German Nutrition Society, Godesberger Allee 18, 53175 Bonn, Germany" |
| ISSN/ISBN: | 1422-0067 (Electronic) 1422-0067 (Linking) |
| Abstract: | "Pyrrolizidine alkaloids (PAs) are a group of secondary metabolites produced in various plant species as a defense mechanism against herbivores. PAs consist of a necine base, which is esterified with one or two necine acids. Humans are exposed to PAs by consumption of contaminated food. PA intoxication in humans causes acute and chronic hepatotoxicity. It is considered that enzymatic PA toxification in hepatocytes is structure-dependent. In this study, we aimed to elucidate the induction of PA-induced cell death associated with apoptosis activation. Therefore, 22 structurally different PAs were analyzed concerning the disturbance of cell viability in the metabolically competent human hepatoma cell line HepaRG. The chosen PAs represent the main necine base structures and the different esterification types. Open-chained and cyclic heliotridine- and retronecine-type diesters induced strong cytotoxic effects, while treatment of HepaRG with monoesters did not affect cell viability. For more detailed investigation of apoptosis induction, comprising caspase activation and gene expression analysis, 14 PA representatives were selected. The proapoptotic effects were in line with the potency observed in cell viability studies. In vitro data point towards a strong structure-activity relationship whose effectiveness needs to be investigated in vivo and can then be the basis for a structure-associated risk assessment" |
| Keywords: | "Caspases/metabolism Cell Death Cell Line, Tumor Humans Molecular Structure Pyrrolizidine Alkaloids/chemistry/*toxicity apoptosis hepatotoxicity pyrrolizidine alkaloids structure dependency;" |
| Notes: | "MedlineGluck, Josephin Waizenegger, Julia Braeuning, Albert Hessel-Pras, Stefanie eng LA1177/12-1/Deutsche Forschungsgemeinschaft/ 1322-624/Gereman Federal Institute for Risk Assessment/ Comparative Study Switzerland 2021/01/01 Int J Mol Sci. 2020 Dec 28; 22(1):202. doi: 10.3390/ijms22010202" |
