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A modeling approach to evaluate the balance between bioactivation and detoxification of MeIQx in human hepatocytes
BACKGROUND: Heterocyclic aromatic amines (HAA) are environmental and food contaminants that are potentially carcinogenic for humans. 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) is one of the most abundant HAA formed in cooked meat. MeIQx is metabolized by cytochrome P450 1A2 in the human l...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
PeerJ Inc.
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5582613/ https://www.ncbi.nlm.nih.gov/pubmed/28879062 http://dx.doi.org/10.7717/peerj.3703 |
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author | Delannée, Victorien Langouët, Sophie Théret, Nathalie Siegel, Anne |
author_facet | Delannée, Victorien Langouët, Sophie Théret, Nathalie Siegel, Anne |
author_sort | Delannée, Victorien |
collection | PubMed |
description | BACKGROUND: Heterocyclic aromatic amines (HAA) are environmental and food contaminants that are potentially carcinogenic for humans. 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) is one of the most abundant HAA formed in cooked meat. MeIQx is metabolized by cytochrome P450 1A2 in the human liver into detoxificated and bioactivated products. Once bioactivated, MeIQx metabolites can lead to DNA adduct formation responsible for further genome instability. METHODS: Using a computational approach, we developed a numerical model for MeIQx metabolism in the liver that predicts the MeIQx biotransformation into detoxification or bioactivation pathways according to the concentration of MeIQx. RESULTS: Our results demonstrate that (1) the detoxification pathway predominates, (2) the ratio between detoxification and bioactivation pathways is not linear and shows a maximum at 10 µM of MeIQx in hepatocyte cell models, and (3) CYP1A2 is a key enzyme in the system that regulates the balance between bioactivation and detoxification. Our analysis suggests that such a ratio could be considered as an indicator of MeIQx genotoxicity at a low concentration of MeIQx. CONCLUSIONS: Our model permits the investigation of the balance between bioactivation (i.e., DNA adduct formation pathway through the prediction of potential genotoxic compounds) and detoxification of MeIQx in order to predict the behaviour of this environmental contaminant in the human liver. It highlights the importance of complex regulations of enzyme competitions that should be taken into account in any further multi-organ models. |
format | Online Article Text |
id | pubmed-5582613 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | PeerJ Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-55826132017-09-06 A modeling approach to evaluate the balance between bioactivation and detoxification of MeIQx in human hepatocytes Delannée, Victorien Langouët, Sophie Théret, Nathalie Siegel, Anne PeerJ Computational Biology BACKGROUND: Heterocyclic aromatic amines (HAA) are environmental and food contaminants that are potentially carcinogenic for humans. 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) is one of the most abundant HAA formed in cooked meat. MeIQx is metabolized by cytochrome P450 1A2 in the human liver into detoxificated and bioactivated products. Once bioactivated, MeIQx metabolites can lead to DNA adduct formation responsible for further genome instability. METHODS: Using a computational approach, we developed a numerical model for MeIQx metabolism in the liver that predicts the MeIQx biotransformation into detoxification or bioactivation pathways according to the concentration of MeIQx. RESULTS: Our results demonstrate that (1) the detoxification pathway predominates, (2) the ratio between detoxification and bioactivation pathways is not linear and shows a maximum at 10 µM of MeIQx in hepatocyte cell models, and (3) CYP1A2 is a key enzyme in the system that regulates the balance between bioactivation and detoxification. Our analysis suggests that such a ratio could be considered as an indicator of MeIQx genotoxicity at a low concentration of MeIQx. CONCLUSIONS: Our model permits the investigation of the balance between bioactivation (i.e., DNA adduct formation pathway through the prediction of potential genotoxic compounds) and detoxification of MeIQx in order to predict the behaviour of this environmental contaminant in the human liver. It highlights the importance of complex regulations of enzyme competitions that should be taken into account in any further multi-organ models. PeerJ Inc. 2017-09-01 /pmc/articles/PMC5582613/ /pubmed/28879062 http://dx.doi.org/10.7717/peerj.3703 Text en ©2017 Delannée et al. http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited. |
spellingShingle | Computational Biology Delannée, Victorien Langouët, Sophie Théret, Nathalie Siegel, Anne A modeling approach to evaluate the balance between bioactivation and detoxification of MeIQx in human hepatocytes |
title | A modeling approach to evaluate the balance between bioactivation and detoxification of MeIQx in human hepatocytes |
title_full | A modeling approach to evaluate the balance between bioactivation and detoxification of MeIQx in human hepatocytes |
title_fullStr | A modeling approach to evaluate the balance between bioactivation and detoxification of MeIQx in human hepatocytes |
title_full_unstemmed | A modeling approach to evaluate the balance between bioactivation and detoxification of MeIQx in human hepatocytes |
title_short | A modeling approach to evaluate the balance between bioactivation and detoxification of MeIQx in human hepatocytes |
title_sort | modeling approach to evaluate the balance between bioactivation and detoxification of meiqx in human hepatocytes |
topic | Computational Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5582613/ https://www.ncbi.nlm.nih.gov/pubmed/28879062 http://dx.doi.org/10.7717/peerj.3703 |
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