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2018-06-15Metadata
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Mathematical Models in the Description of Pregnane X Receptor (PXR)-Regulated Cytochrome P450 Enzyme Induction
Abstract
The pregnane X receptor (PXR) is a drug/xenobiotic-activated transcription factor of crucial importance for major cytochrome P450 xenobiotic-metabolizing enzymes (CYP) expression and regulation in the liver and the intestine. One of the major target genes regulated by PXR is the cytochrome P450 enzyme (CYP3A4), which is the most important human drug-metabolizing enzyme. In addition, PXR is supposed to be involved both in basal and/or inducible expression of many other CYPs, such as CYP2B6, CYP2C8, 2C9 and 2C19, CYP3A5, CYP3A7, and CYP2A6. Interestingly, the dynamics of PXR-mediated target genes regulation has not been systematically studied and we have only a few mechanistic mathematical and biologically based models describing gene expression dynamics after PXR activation in cellular models. Furthermore, few indirect mathematical PKPD models for prediction of CYP3A metabolic activity in vivo have been built based on compartmental models with respect to drug–drug interactions or hormonal crosstalk. Importantly, several negative feedback loops have been described in PXR regulation. Although current mathematical models propose these adaptive mechanisms, a comprehensive mathematical model based on sufficient experimental data is still missing. In the current review, we summarize and compare these models and address some issues that should be considered for the improvement of PXR-mediated gene regulation modelling as well as for our better understanding of the quantitative and spatial dynamics of CYPs expression.
Sponsorship
This work was supported by SVV 260 414, GAUK 110/50/75006, Czech Scientific agency (GACR 17-06841S), and EFSA-CDN (No. CZ.02.1.01/0.0/0.0/16_019/0000841) co-funded by ERDF and project No. 00.265.2015 of the Klaus Tschira Stiftung GmbH.Citation
@article{doi:10.17170/kobra-2024082310711,
author={Tebbens, Erik Jurjen Duintjer and Azar, Malek and Friedmann, Elfriede and Lanzendörfer, Martin and Pávek, Petr},
title={Mathematical Models in the Description of Pregnane X Receptor (PXR)-Regulated Cytochrome P450 Enzyme Induction},
journal={International Journal of Molecular Sciences},
year={2018}
}
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<resource xsi:schemaLocation="http://datacite.org/schema/kernel-2.2 http://schema.datacite.org/meta/kernel-2.2/metadata.xsd"> 2024-08-26T16:15:39Z 2024-08-26T16:15:39Z 2018-06-15 doi:10.17170/kobra-2024082310711 http://hdl.handle.net/123456789/15987 This work was supported by SVV 260 414, GAUK 110/50/75006, Czech Scientific agency (GACR 17-06841S), and EFSA-CDN (No. CZ.02.1.01/0.0/0.0/16_019/0000841) co-funded by ERDF and project No. 00.265.2015 of the Klaus Tschira Stiftung GmbH. eng Namensnennung 4.0 International http://creativecommons.org/licenses/by/4.0/ pregnane X receptor gene regulation mathematical models simulation 510 600 Mathematical Models in the Description of Pregnane X Receptor (PXR)-Regulated Cytochrome P450 Enzyme Induction Aufsatz The pregnane X receptor (PXR) is a drug/xenobiotic-activated transcription factor of crucial importance for major cytochrome P450 xenobiotic-metabolizing enzymes (CYP) expression and regulation in the liver and the intestine. One of the major target genes regulated by PXR is the cytochrome P450 enzyme (CYP3A4), which is the most important human drug-metabolizing enzyme. In addition, PXR is supposed to be involved both in basal and/or inducible expression of many other CYPs, such as CYP2B6, CYP2C8, 2C9 and 2C19, CYP3A5, CYP3A7, and CYP2A6. Interestingly, the dynamics of PXR-mediated target genes regulation has not been systematically studied and we have only a few mechanistic mathematical and biologically based models describing gene expression dynamics after PXR activation in cellular models. Furthermore, few indirect mathematical PKPD models for prediction of CYP3A metabolic activity in vivo have been built based on compartmental models with respect to drug–drug interactions or hormonal crosstalk. Importantly, several negative feedback loops have been described in PXR regulation. Although current mathematical models propose these adaptive mechanisms, a comprehensive mathematical model based on sufficient experimental data is still missing. In the current review, we summarize and compare these models and address some issues that should be considered for the improvement of PXR-mediated gene regulation modelling as well as for our better understanding of the quantitative and spatial dynamics of CYPs expression. open access Tebbens, Erik Jurjen Duintjer Azar, Malek Friedmann, Elfriede Lanzendörfer, Martin Pávek, Petr doi:10.3390/ijms19061785 project No. 00.265.2015 Genregulation Mathematisches Modell Simulation publishedVersion eissn:1422-0067 Issue 6 International Journal of Molecular Sciences Volume 19 false 1785 </resource>
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