German Federal Institute for Risk Assessment, Max-Dohrn-Str. 8-10, 10589 Berlin, Germany.
Chair of Food Safety, Veterinary Faculty, Ludwig-Maximilians-Universität München, Schoenleutnerstr. 8, 85764 Oberschleissheim, Germany.
Int J Mol Sci. 2022 Aug 16;23(16):9214. doi: 10.3390/ijms23169214.
Phytochemicals like pyrrolizidine alkaloids (PAs) can affect the health of humans and animals. PAs can occur for example in tea, honey or herbs. Some PAs are known to be cytotoxic, genotoxic, and carcinogenic. Upon intake of high amounts, hepatotoxic and pneumotoxic effects were observed in humans. This study aims to elucidate different toxicokinetic parameters like the uptake of PAs and their metabolism with in vitro models. We examined the transport rates of differently structured PAs (monoester, open-chained diester, cyclic diester) over a model of the intestinal barrier. After passing the intestinal barrier, PAs reach the liver, where they are metabolized into partially instable electrophilic metabolites interacting with nucleophilic centers. We investigated this process by the usage of human liver, intestinal, and lung microsomal preparations for incubation with different PAs. These results are completed with the detection of apoptosis as indicator for bioactivation of the PAs. Our results show a structure-dependent passage of PAs over the intestinal barrier. PAs are structure-dependently metabolized by liver microsomes and, to a smaller extent, by lung microsomes. The detection of apoptosis of A549 cells treated with lasiocarpine and monocrotaline following bioactivation by human liver or lung microsomes underlines this result. Conclusively, our results help to shape the picture of PA toxicokinetics which could further improve the knowledge of molecular processes leading to observed effects of PAs in vivo.
植物化学物质，如吡咯里西啶生物碱 (PAs)，会影响人类和动物的健康。例如，PA 可以存在于茶、蜂蜜或草药中。一些 PA 已被证明具有细胞毒性、遗传毒性和致癌性。在摄入高剂量时，人类会观察到肝毒性和肺毒性作用。本研究旨在阐明不同的毒代动力学参数，如 PA 的摄取及其在体外模型中的代谢。我们检查了不同结构的 PA（单酯、开链二酯、环二酯）在肠屏障模型中的转运速率。穿过肠屏障后，PA 到达肝脏，在那里它们被代谢成部分不稳定的亲电代谢物，与亲核中心相互作用。我们通过使用人肝、肠和肺微粒体制剂孵育不同的 PA 来研究这个过程。这些结果与作为 PA 生物活化指示剂的细胞凋亡检测结果相结合。我们的结果表明 PA 穿过肠屏障的过程与结构有关。PA 被肝微粒体和较小程度的肺微粒体结构依赖性地代谢。用拉西奥卡品和单克来曲汀处理 A549 细胞，用人肝或肺微粒体进行生物活化后检测到细胞凋亡，这进一步证实了这一结果。总之，我们的结果有助于描绘 PA 毒代动力学的情况，这可以进一步提高对体内观察到的 PA 分子过程的认识。
