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Toxic Prediction of Pyrrolizidine Alkaloids and Structure-Dependent Induction of Apoptosis in HepaRG Cells

Pyrrolizidine alkaloids (PAs) are common phytotoxins and could cause liver genotoxicity/carcinogenicity following metabolic activation. However, the toxicity of different structures remains unclear due to the wide variety of PAs. In this study, the absorption, distribution, metabolism, excretion, an...

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Autores principales: Zheng, Pimiao, Xu, Yuliang, Ren, Zhenhui, Wang, Zile, Wang, Sihan, Xiong, Jincheng, Zhang, Huixia, Jiang, Haiyang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801077/
https://www.ncbi.nlm.nih.gov/pubmed/33488944
http://dx.doi.org/10.1155/2021/8822304
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author Zheng, Pimiao
Xu, Yuliang
Ren, Zhenhui
Wang, Zile
Wang, Sihan
Xiong, Jincheng
Zhang, Huixia
Jiang, Haiyang
author_facet Zheng, Pimiao
Xu, Yuliang
Ren, Zhenhui
Wang, Zile
Wang, Sihan
Xiong, Jincheng
Zhang, Huixia
Jiang, Haiyang
author_sort Zheng, Pimiao
collection PubMed
description Pyrrolizidine alkaloids (PAs) are common phytotoxins and could cause liver genotoxicity/carcinogenicity following metabolic activation. However, the toxicity of different structures remains unclear due to the wide variety of PAs. In this study, the absorption, distribution, metabolism, excretion, and toxicity (ADMET) of 40 PAs were analyzed, and their toxicity was predicted by Komputer Assisted Technology (TOPKAT) using Discovery Studio software. The in silico results showed that all PAs except retronecine had good intestinal absorption, and all PAs were predicted to have different toxicity ranges. To verify the predictive results, 4 PAs were selected to investigate cell injury and possible mechanisms of the differentiation in HepaRG cells, including retronecine type of twelve-membered cyclic diester (retrorsine), eleven-membered cyclic diester (monocrotaline), noncyclic diester (retronecine), and platynecine type (platyphylline). After 24 h exposure, retronecine-type PAs exhibited concentration-dependent cytotoxicity. The high-content screening assay showed that cell oxidative stress, mitochondrial damage, endoplasmic reticulum stress, and the concentration of calcium ions increased, and neutral lipid metabolism was changed notably in HepaRG cells. Induced apoptosis by PAs was indicated by cell cycle arrest in the G2/M phase, disrupting the mitochondrial membrane potential. Overall, our study revealed structure-dependent cytotoxicity and apoptosis after PA exposure, suggesting that the prediction results of in silico have certain reference values for compound toxicity. A 1,2-membered cyclic diester seems to be a more potent apoptosis inducer than other PAs.
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spelling pubmed-78010772021-01-22 Toxic Prediction of Pyrrolizidine Alkaloids and Structure-Dependent Induction of Apoptosis in HepaRG Cells Zheng, Pimiao Xu, Yuliang Ren, Zhenhui Wang, Zile Wang, Sihan Xiong, Jincheng Zhang, Huixia Jiang, Haiyang Oxid Med Cell Longev Research Article Pyrrolizidine alkaloids (PAs) are common phytotoxins and could cause liver genotoxicity/carcinogenicity following metabolic activation. However, the toxicity of different structures remains unclear due to the wide variety of PAs. In this study, the absorption, distribution, metabolism, excretion, and toxicity (ADMET) of 40 PAs were analyzed, and their toxicity was predicted by Komputer Assisted Technology (TOPKAT) using Discovery Studio software. The in silico results showed that all PAs except retronecine had good intestinal absorption, and all PAs were predicted to have different toxicity ranges. To verify the predictive results, 4 PAs were selected to investigate cell injury and possible mechanisms of the differentiation in HepaRG cells, including retronecine type of twelve-membered cyclic diester (retrorsine), eleven-membered cyclic diester (monocrotaline), noncyclic diester (retronecine), and platynecine type (platyphylline). After 24 h exposure, retronecine-type PAs exhibited concentration-dependent cytotoxicity. The high-content screening assay showed that cell oxidative stress, mitochondrial damage, endoplasmic reticulum stress, and the concentration of calcium ions increased, and neutral lipid metabolism was changed notably in HepaRG cells. Induced apoptosis by PAs was indicated by cell cycle arrest in the G2/M phase, disrupting the mitochondrial membrane potential. Overall, our study revealed structure-dependent cytotoxicity and apoptosis after PA exposure, suggesting that the prediction results of in silico have certain reference values for compound toxicity. A 1,2-membered cyclic diester seems to be a more potent apoptosis inducer than other PAs. Hindawi 2021-01-02 /pmc/articles/PMC7801077/ /pubmed/33488944 http://dx.doi.org/10.1155/2021/8822304 Text en Copyright © 2021 Pimiao Zheng et al. https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Zheng, Pimiao
Xu, Yuliang
Ren, Zhenhui
Wang, Zile
Wang, Sihan
Xiong, Jincheng
Zhang, Huixia
Jiang, Haiyang
Toxic Prediction of Pyrrolizidine Alkaloids and Structure-Dependent Induction of Apoptosis in HepaRG Cells
title Toxic Prediction of Pyrrolizidine Alkaloids and Structure-Dependent Induction of Apoptosis in HepaRG Cells
title_full Toxic Prediction of Pyrrolizidine Alkaloids and Structure-Dependent Induction of Apoptosis in HepaRG Cells
title_fullStr Toxic Prediction of Pyrrolizidine Alkaloids and Structure-Dependent Induction of Apoptosis in HepaRG Cells
title_full_unstemmed Toxic Prediction of Pyrrolizidine Alkaloids and Structure-Dependent Induction of Apoptosis in HepaRG Cells
title_short Toxic Prediction of Pyrrolizidine Alkaloids and Structure-Dependent Induction of Apoptosis in HepaRG Cells
title_sort toxic prediction of pyrrolizidine alkaloids and structure-dependent induction of apoptosis in heparg cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801077/
https://www.ncbi.nlm.nih.gov/pubmed/33488944
http://dx.doi.org/10.1155/2021/8822304
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