Enge Anne-Margarethe, Kaltner Florian, Gottschalk Christoph, Kin Angelina, Kirstgen Michael, Geyer Joachim, These Anja, Hammer Helen, Pötz Oliver, Braeuning Albert, Hessel-Pras Stefanie
German Federal Institute for Risk Assessment, Max-Dohrn-Str. 8-10, 10589, Berlin, Germany.
Chair of Food Safety and Analytics, Ludwig Maximilian University of Munich, Schoenleutnerstr. 8, 85764, Oberschleissheim, Germany.
Mol Nutr Food Res. 2022 Jan;66(2):e2100800. doi: 10.1002/mnfr.202100800. Epub 2021 Dec 11.
1,2-unsaturated pyrrolizidine alkaloids (PAs) are secondary plant metabolites that are found in many plant species throughout the world. They are of concern for risk assessment as consumption of contaminated foodstuff can cause severe liver damage. Of late, transporter-mediated uptake and transport has advanced as a vital determinant of PA toxicity. In this study, the authors investigate a transporter-mediated uptake of PAs and its implications in PA toxicity.
We show that transporter expression levels are significantly affected by treatment with the PAs senecionine (Sc) and retrorsine (Re) in the human hepatoma cell line HepaRG. Furthermore, the specific contribution to PA uptake of the two transporters Na /taurocholate co-transporting polypeptide (SLC10A1) and organic cation transporter I (SLC22A1), both belonging to the heterogeneous solute carrier super family, is investigated by means of a siRNA-mediated knockdown approach. Knockdown of both uptake transporters result in reduced uptake of Re and Sc in a time-dependent manner and attenuated PA-mediated cytotoxic effects in HepaRG cells.
Our results confirm previous findings of active transport mechanisms of PAs into hepatocytes and highlight the importance of toxicokinetic studies for the risk assessment of PAs.
1,2 - 不饱和吡咯里西啶生物碱（PAs）是植物的次生代谢产物，在世界各地的许多植物物种中都有发现。由于食用受污染的食品会导致严重的肝脏损伤，因此它们是风险评估关注的对象。最近，转运蛋白介导的摄取和运输已成为PA毒性的一个重要决定因素。在本研究中，作者研究了转运蛋白介导的PAs摄取及其对PA毒性的影响。
我们发现，在人肝癌细胞系HepaRG中，用PAs千里光碱（Sc）和倒千里光碱（Re）处理会显著影响转运蛋白的表达水平。此外，通过siRNA介导的敲低方法，研究了两种均属于异质溶质载体超家族的转运蛋白——钠/牛磺胆酸盐共转运多肽（SLC10A1）和有机阳离子转运体I（SLC22A1）对PA摄取的具体贡献。两种摄取转运蛋白的敲低均导致Re和Sc的摄取以时间依赖性方式减少，并减弱了PA对HepaRG细胞的细胞毒性作用。
我们的结果证实了先前关于PAs进入肝细胞的主动转运机制的发现，并强调了毒代动力学研究对PAs风险评估的重要性。
