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

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, metabol...

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Autores principales: Widjaja, Frances, Alhejji, Yasser, Rietjens, Ivonne M. C. M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Georg Thieme Verlag KG 2021
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8807025/
https://www.ncbi.nlm.nih.gov/pubmed/34741297
http://dx.doi.org/10.1055/a-1582-9794
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author Widjaja, Frances
Alhejji, Yasser
Rietjens, Ivonne M. C. M.
author_facet Widjaja, Frances
Alhejji, Yasser
Rietjens, Ivonne M. C. M.
author_sort Widjaja, Frances
collection PubMed
description 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.
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spelling pubmed-88070252022-02-02 The Role of Kinetics as Key Determinant in Toxicity of Pyrrolizidine Alkaloids and Their N-Oxides Widjaja, Frances Alhejji, Yasser Rietjens, Ivonne M. C. M. Planta Med 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. Georg Thieme Verlag KG 2021-11-05 /pmc/articles/PMC8807025/ /pubmed/34741297 http://dx.doi.org/10.1055/a-1582-9794 Text en The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License, which permits unrestricted reproduction and distribution, for non-commercial purposes only; and use and reproduction, but not distribution, of adapted material for non-commercial purposes only, provided the original work is properly cited.
spellingShingle Widjaja, Frances
Alhejji, Yasser
Rietjens, Ivonne M. C. M.
The Role of Kinetics as Key Determinant in Toxicity of Pyrrolizidine Alkaloids and Their N-Oxides
title The Role of Kinetics as Key Determinant in Toxicity of Pyrrolizidine Alkaloids and Their N-Oxides
title_full The Role of Kinetics as Key Determinant in Toxicity of Pyrrolizidine Alkaloids and Their N-Oxides
title_fullStr The Role of Kinetics as Key Determinant in Toxicity of Pyrrolizidine Alkaloids and Their N-Oxides
title_full_unstemmed The Role of Kinetics as Key Determinant in Toxicity of Pyrrolizidine Alkaloids and Their N-Oxides
title_short The Role of Kinetics as Key Determinant in Toxicity of Pyrrolizidine Alkaloids and Their N-Oxides
title_sort role of kinetics as key determinant in toxicity of pyrrolizidine alkaloids and their n-oxides
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8807025/
https://www.ncbi.nlm.nih.gov/pubmed/34741297
http://dx.doi.org/10.1055/a-1582-9794
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