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Photomutagenicity of chlorpromazine and its N-demethylated metabolites assessed by NGS
The human genome is constantly attacked by endogenous and exogenous agents (ultraviolet light, xenobiotics, reactive oxygen species), which can induce chemical transformations leading to DNA lesions. To combat DNA damage, cells have developed several repair mechanisms; however, if the repair is defe...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181754/ https://www.ncbi.nlm.nih.gov/pubmed/32327675 http://dx.doi.org/10.1038/s41598-020-63651-y |
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author | Agúndez, José A. G. García-Martín, Elena García-Lainez, Guillermo Miranda, Miguel A. Andreu, Inmaculada |
author_facet | Agúndez, José A. G. García-Martín, Elena García-Lainez, Guillermo Miranda, Miguel A. Andreu, Inmaculada |
author_sort | Agúndez, José A. G. |
collection | PubMed |
description | The human genome is constantly attacked by endogenous and exogenous agents (ultraviolet light, xenobiotics, reactive oxygen species), which can induce chemical transformations leading to DNA lesions. To combat DNA damage, cells have developed several repair mechanisms; however, if the repair is defective, DNA lesions lead to permanent mutations. Single-cell gel electrophoresis (COMET assay) is a sensitive and well-established technique for quantifying DNA damage in individual cells. Nevertheless, this tool lacks relationship with mutagenesis. Therefore, to identify errors that give rise to mutations it would be convenient to test an alternative known procedure, such as next generation sequencing (NGS). Thus, the present work aims to evaluate the photomutagenicity of neuroleptic drug chlorpromazine (CPZ), and its N-demethylated metabolites using COMET assay and to test NGS as an alternative method to assess photomutagenesis. In this context, upon exposure to UVA radiation, COMET assay reveals CPZ-photosensitized DNA damage partially repaired by cells. Conversely with this result, metabolites demethylchlorpromazine (DMCPZ) and didemethylchlorpromazine (DDMCPZ) promote extensive DNA-photodamage, hardly repaired under the same conditions. Parallel assessment of mutagenesis by NGS is consistent with these results with minor discrepancies for DDMCPZ. To our knowledge, this is the first example demonstrating the utility of NGS for evaluating drug-induced photomutagenicity. |
format | Online Article Text |
id | pubmed-7181754 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-71817542020-04-29 Photomutagenicity of chlorpromazine and its N-demethylated metabolites assessed by NGS Agúndez, José A. G. García-Martín, Elena García-Lainez, Guillermo Miranda, Miguel A. Andreu, Inmaculada Sci Rep Article The human genome is constantly attacked by endogenous and exogenous agents (ultraviolet light, xenobiotics, reactive oxygen species), which can induce chemical transformations leading to DNA lesions. To combat DNA damage, cells have developed several repair mechanisms; however, if the repair is defective, DNA lesions lead to permanent mutations. Single-cell gel electrophoresis (COMET assay) is a sensitive and well-established technique for quantifying DNA damage in individual cells. Nevertheless, this tool lacks relationship with mutagenesis. Therefore, to identify errors that give rise to mutations it would be convenient to test an alternative known procedure, such as next generation sequencing (NGS). Thus, the present work aims to evaluate the photomutagenicity of neuroleptic drug chlorpromazine (CPZ), and its N-demethylated metabolites using COMET assay and to test NGS as an alternative method to assess photomutagenesis. In this context, upon exposure to UVA radiation, COMET assay reveals CPZ-photosensitized DNA damage partially repaired by cells. Conversely with this result, metabolites demethylchlorpromazine (DMCPZ) and didemethylchlorpromazine (DDMCPZ) promote extensive DNA-photodamage, hardly repaired under the same conditions. Parallel assessment of mutagenesis by NGS is consistent with these results with minor discrepancies for DDMCPZ. To our knowledge, this is the first example demonstrating the utility of NGS for evaluating drug-induced photomutagenicity. Nature Publishing Group UK 2020-04-23 /pmc/articles/PMC7181754/ /pubmed/32327675 http://dx.doi.org/10.1038/s41598-020-63651-y Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Agúndez, José A. G. García-Martín, Elena García-Lainez, Guillermo Miranda, Miguel A. Andreu, Inmaculada Photomutagenicity of chlorpromazine and its N-demethylated metabolites assessed by NGS |
title | Photomutagenicity of chlorpromazine and its N-demethylated metabolites assessed by NGS |
title_full | Photomutagenicity of chlorpromazine and its N-demethylated metabolites assessed by NGS |
title_fullStr | Photomutagenicity of chlorpromazine and its N-demethylated metabolites assessed by NGS |
title_full_unstemmed | Photomutagenicity of chlorpromazine and its N-demethylated metabolites assessed by NGS |
title_short | Photomutagenicity of chlorpromazine and its N-demethylated metabolites assessed by NGS |
title_sort | photomutagenicity of chlorpromazine and its n-demethylated metabolites assessed by ngs |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181754/ https://www.ncbi.nlm.nih.gov/pubmed/32327675 http://dx.doi.org/10.1038/s41598-020-63651-y |
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