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A Rapid Assessment Model for Liver Toxicity of Macrolides and an Integrative Evaluation for Azithromycin Impurities

Impurities in pharmaceuticals of potentially hazardous materials may cause drug safety problems. Macrolide antibiotic preparations include active pharmaceutical ingredients (APIs) and different types of impurities with similar structures, and the amount of these impurities is usually very low and di...

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Autores principales: Zhang, Miao-Qing, Zhang, Jing-Pu, Hu, Chang-Qin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9014295/
https://www.ncbi.nlm.nih.gov/pubmed/35444552
http://dx.doi.org/10.3389/fphar.2022.860702
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author Zhang, Miao-Qing
Zhang, Jing-Pu
Hu, Chang-Qin
author_facet Zhang, Miao-Qing
Zhang, Jing-Pu
Hu, Chang-Qin
author_sort Zhang, Miao-Qing
collection PubMed
description Impurities in pharmaceuticals of potentially hazardous materials may cause drug safety problems. Macrolide antibiotic preparations include active pharmaceutical ingredients (APIs) and different types of impurities with similar structures, and the amount of these impurities is usually very low and difficult to be separated for toxicity evaluation. Our previous study indicated that hepatotoxicity induced by macrolides was correlated with c-fos overexpression. Here, we report an assessment of macrolide-related liver toxicity by ADMET prediction, molecular docking, structure–toxicity relationship, and experimental verification via detection of the c-fos gene expression in liver cells. The results showed that a rapid assessment model for the prediction of hepatotoxicity of macrolide antibiotics could be established by calculation of the -CDOCKER interaction energy score with the FosB/JunD bZIP domain and then confirmed by the detection of the c-fos gene expression in L02 cells. Telithromycin, a positive compound of liver toxicity, was used to verify the correctness of the model through comparative analysis of liver toxicity in zebrafish and cytotoxicity in L02 cells exposed to telithromycin and azithromycin. The prediction interval (48.1∼53.1) for quantitative hepatotoxicity in the model was calculated from the docking scores of seven macrolide antibiotics commonly used in clinics. We performed the prediction interval to virtual screening of azithromycin impurities with high hepatotoxicity and then experimentally confirmed by liver toxicity in zebrafish and c-fos gene expression. Simultaneously, we found the hepatotoxicity of azithromycin impurities may be related to the charge of nitrogen (N) atoms on the side chain group at the C5 position via structure–toxicity relationship of azithromycin impurities with different structures. This study provides a theoretical basis for improvement of the quality of macrolide antibiotics.
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spelling pubmed-90142952022-04-19 A Rapid Assessment Model for Liver Toxicity of Macrolides and an Integrative Evaluation for Azithromycin Impurities Zhang, Miao-Qing Zhang, Jing-Pu Hu, Chang-Qin Front Pharmacol Pharmacology Impurities in pharmaceuticals of potentially hazardous materials may cause drug safety problems. Macrolide antibiotic preparations include active pharmaceutical ingredients (APIs) and different types of impurities with similar structures, and the amount of these impurities is usually very low and difficult to be separated for toxicity evaluation. Our previous study indicated that hepatotoxicity induced by macrolides was correlated with c-fos overexpression. Here, we report an assessment of macrolide-related liver toxicity by ADMET prediction, molecular docking, structure–toxicity relationship, and experimental verification via detection of the c-fos gene expression in liver cells. The results showed that a rapid assessment model for the prediction of hepatotoxicity of macrolide antibiotics could be established by calculation of the -CDOCKER interaction energy score with the FosB/JunD bZIP domain and then confirmed by the detection of the c-fos gene expression in L02 cells. Telithromycin, a positive compound of liver toxicity, was used to verify the correctness of the model through comparative analysis of liver toxicity in zebrafish and cytotoxicity in L02 cells exposed to telithromycin and azithromycin. The prediction interval (48.1∼53.1) for quantitative hepatotoxicity in the model was calculated from the docking scores of seven macrolide antibiotics commonly used in clinics. We performed the prediction interval to virtual screening of azithromycin impurities with high hepatotoxicity and then experimentally confirmed by liver toxicity in zebrafish and c-fos gene expression. Simultaneously, we found the hepatotoxicity of azithromycin impurities may be related to the charge of nitrogen (N) atoms on the side chain group at the C5 position via structure–toxicity relationship of azithromycin impurities with different structures. This study provides a theoretical basis for improvement of the quality of macrolide antibiotics. Frontiers Media S.A. 2022-04-04 /pmc/articles/PMC9014295/ /pubmed/35444552 http://dx.doi.org/10.3389/fphar.2022.860702 Text en Copyright © 2022 Zhang, Zhang and Hu. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Zhang, Miao-Qing
Zhang, Jing-Pu
Hu, Chang-Qin
A Rapid Assessment Model for Liver Toxicity of Macrolides and an Integrative Evaluation for Azithromycin Impurities
title A Rapid Assessment Model for Liver Toxicity of Macrolides and an Integrative Evaluation for Azithromycin Impurities
title_full A Rapid Assessment Model for Liver Toxicity of Macrolides and an Integrative Evaluation for Azithromycin Impurities
title_fullStr A Rapid Assessment Model for Liver Toxicity of Macrolides and an Integrative Evaluation for Azithromycin Impurities
title_full_unstemmed A Rapid Assessment Model for Liver Toxicity of Macrolides and an Integrative Evaluation for Azithromycin Impurities
title_short A Rapid Assessment Model for Liver Toxicity of Macrolides and an Integrative Evaluation for Azithromycin Impurities
title_sort rapid assessment model for liver toxicity of macrolides and an integrative evaluation for azithromycin impurities
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9014295/
https://www.ncbi.nlm.nih.gov/pubmed/35444552
http://dx.doi.org/10.3389/fphar.2022.860702
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