Division of Toxicology, Wageningen University and Research, The Netherlands.
Department of Food Science and Human Nutrition, College of Agriculture and Veterinary Medicine, Qassim University, Buraydah, Saudi Arabia.
Planta Med. 2022 Feb;88(2):130-143. doi: 10.1055/a-1582-9794. Epub 2021 Nov 5.
Pyrrolizidine alkaloids (PAs) are a large group of plant constituents of which especially the 1,2- unsaturated PAs raise a concern because of their liver toxicity and potential genotoxic carcinogenicity. This toxicity of PAs depends on their kinetics. Differences in absorption, distribution, metabolism, and excretion (ADME) characteristics of PAs may substantially alter the relative toxicity of PAs. As a result, kinetics will also affect relative potency (REP) values. The present review summarizes the current state-of-the art on PA kinetics and resulting consequences for toxicity and illustrates how physiologically-based kinetic (PBK) modelling can be applied to take kinetics into account when defining the relative differences in toxicity between PAs in the situation. We conclude that toxicokinetics play an important role in the overall toxicity of pyrrolizidine alkaloids. and that kinetics should therefore be considered when defining REP values for combined risk assessment. New approach methodologies (NAMs) can be of use to quantify these kinetic differences between PAs and their N-oxides, thus contributing to the 3Rs (Replacement, Reduction and Refinement) in animal studies.
吡咯里西啶生物碱（PAs）是一大类植物成分，其中特别是 1,2-不饱和 PAs 因其肝毒性和潜在的遗传毒性致癌性而引起关注。这些 PAs 的毒性取决于它们的动力学。PAs 的吸收、分布、代谢和排泄（ADME）特征的差异可能会极大地改变 PAs 的相对毒性。因此，动力学也会影响相对效力（REP）值。本综述总结了 PA 动力学的最新进展及其对毒性的影响，并说明了如何在定义 PA 毒性的相对差异时，应用基于生理学的动力学（PBK）模型来考虑动力学因素。我们的结论是，毒代动力学在吡咯里西啶生物碱的整体毒性中起着重要作用，因此在定义联合风险评估的 REP 值时应考虑动力学因素。新方法方法（NAMs）可用于量化 PA 及其 N-氧化物之间的这些动力学差异，从而有助于动物研究中的 3R（替代、减少和优化）。
