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<title lang=en>A modeling approach to evaluate the balance between bioactivation and detoxification of MeIQx in human hepatocytes</title>
<creator>Delannée, Victorien</creator>
<creator>Langouët, Sophie</creator>
<creator>Théret, Nathalie</creator>
<creator>Siegel, Anne</creator>
<contributor>Institut de recherche, santé, environnement et travail [Rennes] (Irset) ; Université d'Angers (UA) - Université des Antilles et de la Guyane (UAG) - Université de Rennes 1 (UR1) - École des Hautes Études en Santé Publique [EHESP] (EHESP) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )</contributor>
<contributor>Dynamics, Logics and Inference for biological Systems and Sequences (Dyliss) ; Inria Rennes – Bretagne Atlantique ; Institut National de Recherche en Informatique et en Automatique (Inria) - Institut National de Recherche en Informatique et en Automatique (Inria) - GESTION DES DONNÉES ET DE LA CONNAISSANCE (IRISA_D7) ; Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA) ; Université de Rennes 1 (UR1) - Institut National des Sciences Appliquées - Rennes (INSA Rennes) - Université de Bretagne Sud (UBS) - École normale supérieure - Rennes (ENS Rennes) - Institut National de Recherche en Informatique et en Automatique (Inria) - CentraleSupélec - Centre National de la Recherche Scientifique (CNRS) - IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique) - Université de Rennes 1 (UR1) - Institut National des Sciences Appliquées - Rennes (INSA Rennes) - Université de Bretagne Sud (UBS) - École normale supérieure - Rennes (ENS Rennes) - Institut National de Recherche en Informatique et en Automatique (Inria) - CentraleSupélec - Centre National de la Recherche Scientifique (CNRS) - IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique) - Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA) ; Université de Rennes 1 (UR1) - Institut National des Sciences Appliquées - Rennes (INSA Rennes) - Université de Bretagne Sud (UBS) - École normale supérieure - Rennes (ENS Rennes) - Institut National de Recherche en Informatique et en Automatique (Inria) - CentraleSupélec - Centre National de la Recherche Scientifique (CNRS) - IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique) - Université de Rennes 1 (UR1) - Institut National des Sciences Appliquées - Rennes (INSA Rennes) - Université de Bretagne Sud (UBS) - École normale supérieure - Rennes (ENS Rennes) - CentraleSupélec - Centre National de la Recherche Scientifique (CNRS) - IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique)</contributor>
<description>International audience</description>
<source>ISSN: 2167-8359</source>
<source>PeerJ</source>
<publisher>PeerJ</publisher>
<identifier>hal-01575579</identifier>
<identifier>https://hal.inria.fr/hal-01575579</identifier>
<source>https://hal.inria.fr/hal-01575579</source>
<source>PeerJ, PeerJ, 2017, 5, pp.e3703. 〈10.7717/peerj.3703〉</source>
<identifier>PUBMED : 28879062</identifier>
<relation>info:eu-repo/semantics/altIdentifier/pmid/28879062</relation>
<identifier>DOI : 10.7717/peerj.3703</identifier>
<relation>info:eu-repo/semantics/altIdentifier/doi/10.7717/peerj.3703</relation>
<language>en</language>
<subject>[SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM]</subject>
<type>info:eu-repo/semantics/article</type>
<type>Journal articles</type>
<description lang=en>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 10µM of MeIQx in hepatocyte cell models, 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.</description>
<date>2017</date>
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