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Autoren: Abdelfatah, Sara
Naß, Janine
Knorz, Caroline
Klauck, Sabine M.
Küpper, Jan-Heiner
Efferth, Thomas
Titel: Pyrrolizidine alkaloids cause cell cycle and DNA damage repair defects as analyzed by transcriptomics in cytochrome P450 3A4-overexpressing HepG2 clone 9 cells
Online-Publikationsdatum: 4-Jul-2022
Erscheinungsdatum: 2022
Sprache des Dokuments: Englisch
Zusammenfassung/Abstract: Pyrrolizidine alkaloids (PAs) are a large group of highly toxic chemical compounds, which are found as cross-contaminants in numerous food products (e.g., honey), dietary supplements, herbal teas, and pharmaceutical herbal medicines. PA contaminations are responsible for serious hepatotoxicity and hepatocarcinogenesis. Health authorities have to set legal limit values to guarantee the safe consumption of plant-based nutritional and medical products without harmful health. Toxicological and chemical analytical methods are conventionally applied to determine legally permitted limit values for PAs. In the present investigation, we applied a highly sensitive transcriptomic approach to investigate the effect of low concentrations of five PAs (lasiocarpine, riddelliine, lycopsamine, echimidine, and monocrotaline) on human cytochrome P450 3A4-overexpressing HepG2 clone 9 hepatocytes. The transcriptomic profiling of deregulated gene expression indicated that the PAs disrupted important signaling pathways related to cell cycle regulation and DNA damage repair in the transfected hepatocytes, which may explain the carcinogenic PA effects. As PAs affected the expression of genes that involved in cell cycle regulation, we applied flow cytometric cell cycle analyses to verify the transcriptomic data. Interestingly, PA treatment led to an arrest in the S phase of the cell cycle, and this effect was more pronounced with more toxic PAs (i.e., lasiocarpine and riddelliine) than with the less toxic monocrotaline. Using immunofluorescence, high fractions of cells were detected with chromosome congression defects upon PA treatment, indicating mitotic failure. In conclusion, the tested PAs revealed threshold concentrations, above which crucial signaling pathways were deregulated resulting in cell damage and carcinogenesis. Cell cycle arrest and DNA damage repair point to the mutagenicity of PAs. The disturbance of chromosome congression is a novel mechanism of Pas, which may also contribute to PA-mediated carcinogenesis. Transcriptomic, cell cycle, and immunofluorescence analyses should supplement the standard techniques in toxicology to unravel the biological effects of PA exposure in liver cells as the primary target during metabolization of PAs.
DDC-Sachgruppe: 570 Biowissenschaften
570 Life sciences
610 Medizin
610 Medical sciences
Veröffentlichende Institution: Johannes Gutenberg-Universität Mainz
Organisationseinheit: FB 09 Chemie, Pharmazie u. Geowissensch.
Veröffentlichungsort: Mainz
ROR: https://ror.org/023b0x485
DOI: http://doi.org/10.25358/openscience-7284
Version: Published version
Publikationstyp: Zeitschriftenaufsatz
Nutzungsrechte: CC BY
Informationen zu den Nutzungsrechten: https://creativecommons.org/licenses/by/4.0/
Zeitschrift: Cell biology and toxicology
38
Seitenzahl oder Artikelnummer: 325
345
Verlag: Springer Science + Business Media B.V.
Verlagsort: Dordrecht
Erscheinungsdatum: 2022
ISSN: 1573-6822
DOI der Originalveröffentlichung: 10.1007/s10565-021-09599-9
Enthalten in den Sammlungen:JGU-Publikationen

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