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Article

Active Transport of Hepatotoxic Pyrrolizidine Alkaloids in HepaRG Cells

1
Department of Food Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Str. 8–10, 10589 Berlin, Germany
2
Chair of Food Safety and Analytics, Veterinary Faculty, Ludwig Maximilian University of Munich, Schoenleutnerstr. 8, 85764 Oberschleissheim, Germany
*
Author to whom correspondence should be addressed.
Academic Editor: Makoto Kimura
Int. J. Mol. Sci. 2021, 22(8), 3821; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22083821
Received: 29 January 2021 / Revised: 24 March 2021 / Accepted: 31 March 2021 / Published: 7 April 2021
(This article belongs to the Special Issue Molecular Biology and Chemistry of Mycotoxins and Phytotoxins)
1,2-unsaturated pyrrolizidine alkaloids (PAs) are secondary plant metabolites occurring as food contaminants that can cause severe liver damage upon metabolic activation in hepatocytes. However, it is yet unknown how these contaminants enter the cells. The role of hepatic transporters is only at the beginning of being recognized as a key determinant of PA toxicity. Therefore, this study concentrated on assessing the general mode of action of PA transport in the human hepatoma cell line HepaRG using seven structurally different PAs. Furthermore, several hepatic uptake and efflux transporters were targeted with pharmacological inhibitors to identify their role in the uptake of the PAs retrorsine and senecionine and in the disposition of their N-oxides (PANO). For this purpose, PA and PANO content was measured in the supernatant using LC-MS/MS. Also, PA-mediated cytotoxicity was analyzed after transport inhibition. It was found that PAs are taken up into HepaRG cells in a predominantly active and structure-dependent manner. This pattern correlates with other experimental endpoints such as cytotoxicity. Pharmacological inhibition of the influx transporters Na+/taurocholate co-transporting polypeptide (SLC10A1) and organic cation transporter 1 (SLC22A1) led to a reduced uptake of retrorsine and senecionine into HepaRG cells, emphasizing the relevance of these transporters for PA toxicokinetics. View Full-Text
Keywords: pyrrolizidine alkaloids; structure-dependency; uptake; hepatic transporter pyrrolizidine alkaloids; structure-dependency; uptake; hepatic transporter
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MDPI and ACS Style

Enge, A.-M.; Kaltner, F.; Gottschalk, C.; Braeuning, A.; Hessel-Pras, S. Active Transport of Hepatotoxic Pyrrolizidine Alkaloids in HepaRG Cells. Int. J. Mol. Sci. 2021, 22, 3821. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22083821

AMA Style

Enge A-M, Kaltner F, Gottschalk C, Braeuning A, Hessel-Pras S. Active Transport of Hepatotoxic Pyrrolizidine Alkaloids in HepaRG Cells. International Journal of Molecular Sciences. 2021; 22(8):3821. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22083821

Chicago/Turabian Style

Enge, Anne-Margarethe, Florian Kaltner, Christoph Gottschalk, Albert Braeuning, and Stefanie Hessel-Pras. 2021. "Active Transport of Hepatotoxic Pyrrolizidine Alkaloids in HepaRG Cells" International Journal of Molecular Sciences 22, no. 8: 3821. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22083821

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