The Role of Kinetics as Key Determinant in Toxicity of Pyrrolizidine Alkaloids and Their N-Oxides

Abstract

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 in vivo 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.

Toxins in Botanical Drugs and Plant-derived Food and Feed – from Science to Regulation: A Workshop Review

“…Thus, the toxicity and, thereby, also the REP PANO to PA value of PANOs depend on the rate and extent of PANO reduction to the parent PA and other kinetic factors such as absorption that would influence what the liver is exposed to. Although the PANO reduction in the liver may be included in the in vitro cell model used, these models generally do not consider the PANO reduction by the intestinal microbiota, nor do they accommodate gastrointestinal uptake 34 , 35 . Another factor that may influence the REP PANO to PA values is that the in vivo studies from which these REP PANO to PA values can be derived are generally performed at relatively high equimolar doses of the PANO and PA in order to enable detection of selected biomarkers, while estimated daily dietary intake for the human population occurs at dose levels that may be orders of magnitude lower 1 .…”

Exploring tea and herbal infusions consumption patterns and behaviours: The case of Portuguese consumers

“…There is a rising concern for food safety issues related to the consumption of THIs, which may pose challenges to public health due to toxic secondary metabolites (e.g. phytates and pyrrolizidine alkaloids) [ [36] , [37] , [38] , [39] , [40] ], contaminants [ [41] , [42] , [43] , [44] ] or contamination with other plant species. For instance, a recent quality assessment of marketed herbal infusion showed that chamomile crude flowers were most likely to be adulterated by other plant materials compared to chamomile bags [ 45 ].…”

Physiologically‐Based Kinetic Modeling Predicts Similar In Vivo Relative Potency of Senecionine N‐Oxide for Rat and Human at Realistic Low Exposure Levels

“…[ 4 ] Another reason for the selection was that for SENO kinetic data from an in vivo rat study [ 11 ] are available for PBK model evaluation. Given that different PAs show different kinetic profiles, [ 33 ] different PA‐N‐oxides might also demonstrate different kinetic profiles due to potential structure‐dependent differences in reduction of the N‐oxides to the parent PAs [ 20 ] and in metabolic clearance of the formed parent PAs. [ 34 ] Besides structure‐dependent differences, there might also be species‐dependent differences in the kinetics of PAs and their N‐oxides potentially resulting in different REP values in rat and human.…”