Division of Toxicology, Wageningen University, PO Box 8000, 6700 EA Wageningen, The Netherlands.
Division of Toxicology, Wageningen University, PO Box 8000, 6700 EA Wageningen, The Netherlands.
Food Chem Toxicol. 2018 Jun;116(Pt B):216-226. doi: 10.1016/j.fct.2018.04.012. Epub 2018 Apr 7.
Lasiocarpine and riddelliine are pyrrolizidine alkaloids (PAs) present in food and able to cause liver toxicity. The aim of this study was to investigate whether physiologically based kinetic (PBK) modelling-facilitated reverse dosimetry can adequately translate in vitro concentration-response curves for toxicity of lasiocarpine and riddelliine to in vivo liver toxicity data for the rat. To this purpose, PBK models were developed for lasiocarpine and riddelliine, and predicted blood concentrations were compared to available literature data to evaluate the models. Concentration-response curves obtained from in vitro cytotoxicity assays in primary rat hepatocytes were converted to in vivo dose-response curves from which points of departure (PODs) were derived and that were compared to available literature data on in vivo liver toxicity. The results showed that the predicted PODs fall well within the range of PODs derived from available in vivo toxicity data. To conclude, this study shows the proof-of-principle for a method to predict in vivo liver toxicity for PAs by an alternative testing strategy integrating in vitro cytotoxicity assays with in silico PBK modelling-facilitated reverse dosimetry. The approach may facilitate prediction of acute liver toxicity for the large number of PAs for which in vivo toxicity data are lacking.
蝙蝠葛堿和千里光裂环烯醚萜碱是存在于食物中的吡咯里西啶生物碱（PAs），能够引起肝毒性。本研究旨在探讨基于生理的药代动力学（PBK）建模辅助反向剂量测定是否能够充分将蝙蝠葛堿和千里光裂环烯醚萜碱的体外浓度-反应曲线转化为大鼠体内肝毒性数据。为此，为蝙蝠葛堿和千里光裂环烯醚萜碱开发了 PBK 模型，并将预测的血液浓度与可用的文献数据进行比较，以评估模型。从原代大鼠肝细胞的体外细胞毒性测定中获得的浓度-反应曲线被转化为体内剂量-反应曲线，从中得出了起始剂量（POD），并与体内肝毒性的可用文献数据进行了比较。结果表明，预测的 POD 很好地落在了可用的体内毒性数据中 POD 的范围内。总之，本研究通过将体外细胞毒性测定与基于计算的 PBK 建模辅助反向剂量测定相结合的替代测试策略，展示了预测 PAs 体内肝毒性的原理验证。该方法可以预测大量缺乏体内毒性数据的 PAs 的急性肝毒性。
