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Fasting-Induced Changes in Hepatic P450 Mediated Drug Metabolism Are Largely Independent of the Constitutive Androstane Receptor CAR

INTRODUCTION: Hepatic drug metabolism by cytochrome P450 enzymes is altered by the nutritional status of patients. The expression of P450 enzymes is partly regulated by the constitutive androstane receptor (CAR). Fasting regulates the expression of both P450 enzymes and CAR and affects hepatic drug...

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Autores principales: de Vries, E. M., Lammers, L. A., Achterbergh, R., Klümpen, H-J, Mathot, R. A. A., Boelen, A., Romijn, J. A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4951123/
https://www.ncbi.nlm.nih.gov/pubmed/27434302
http://dx.doi.org/10.1371/journal.pone.0159552
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author de Vries, E. M.
Lammers, L. A.
Achterbergh, R.
Klümpen, H-J
Mathot, R. A. A.
Boelen, A.
Romijn, J. A.
author_facet de Vries, E. M.
Lammers, L. A.
Achterbergh, R.
Klümpen, H-J
Mathot, R. A. A.
Boelen, A.
Romijn, J. A.
author_sort de Vries, E. M.
collection PubMed
description INTRODUCTION: Hepatic drug metabolism by cytochrome P450 enzymes is altered by the nutritional status of patients. The expression of P450 enzymes is partly regulated by the constitutive androstane receptor (CAR). Fasting regulates the expression of both P450 enzymes and CAR and affects hepatic drug clearance. We hypothesized that the fasting-induced alterations in P450 mediated drug clearance are mediated by CAR. METHODS: To investigate this we used a drug cocktail validated in humans consisting of five widely prescribed drugs as probes for specific P450 enzymes: caffeine (CYP1A2), metoprolol (CYP2D6), omeprazole (CYP2C19), midazolam (CYP3A4) and s-warfarin (CYP2C9). This cocktail was administered to wild type (WT, C57Bl/6) mice or mice deficient for CAR (CAR(-/-)) that were either fed ad libitum or fasted for 24 hours. Blood was sampled at predefined intervals and drug concentrations were measured as well as hepatic mRNA expression of homologous/orthologous P450 enzymes (Cyp1a2, Cyp2d22, Cyp3a11, Cyp2c37, Cyp2c38 and Cyp2c65). RESULTS: Fasting decreased Cyp1a2 and Cyp2d22 expression and increased Cyp3a11 and Cyp2c38 expression in both WT and CAR(-/-) mice. The decrease in Cyp1a2 was diminished in CAR(-/-) in comparison with WT mice. Basal Cyp2c37 expression was lower in CAR(-/-) compared to WT mice. Fasting decreased the clearance of all drugs tested in both WT and CAR(-/-) mice. The absence of CAR was associated with an decrease in the clearance of omeprazole, metoprolol and midazolam in fed mice. The fasting-induced reduction in clearance of s-warfarin was greater in WT than in CAR(-/-). The changes in drug clearance correlated with the expression pattern of the specific P450 enzymes in case of Cyp1a2-caffeine and Cyp2c37-omeprazole. CONCLUSION: We conclude that CAR is important for hepatic clearance of several widely prescribed drugs metabolized by P450 enzymes. However the fasting-induced alterations in P450 mediated drug clearance are largely independent of CAR.
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spelling pubmed-49511232016-08-08 Fasting-Induced Changes in Hepatic P450 Mediated Drug Metabolism Are Largely Independent of the Constitutive Androstane Receptor CAR de Vries, E. M. Lammers, L. A. Achterbergh, R. Klümpen, H-J Mathot, R. A. A. Boelen, A. Romijn, J. A. PLoS One Research Article INTRODUCTION: Hepatic drug metabolism by cytochrome P450 enzymes is altered by the nutritional status of patients. The expression of P450 enzymes is partly regulated by the constitutive androstane receptor (CAR). Fasting regulates the expression of both P450 enzymes and CAR and affects hepatic drug clearance. We hypothesized that the fasting-induced alterations in P450 mediated drug clearance are mediated by CAR. METHODS: To investigate this we used a drug cocktail validated in humans consisting of five widely prescribed drugs as probes for specific P450 enzymes: caffeine (CYP1A2), metoprolol (CYP2D6), omeprazole (CYP2C19), midazolam (CYP3A4) and s-warfarin (CYP2C9). This cocktail was administered to wild type (WT, C57Bl/6) mice or mice deficient for CAR (CAR(-/-)) that were either fed ad libitum or fasted for 24 hours. Blood was sampled at predefined intervals and drug concentrations were measured as well as hepatic mRNA expression of homologous/orthologous P450 enzymes (Cyp1a2, Cyp2d22, Cyp3a11, Cyp2c37, Cyp2c38 and Cyp2c65). RESULTS: Fasting decreased Cyp1a2 and Cyp2d22 expression and increased Cyp3a11 and Cyp2c38 expression in both WT and CAR(-/-) mice. The decrease in Cyp1a2 was diminished in CAR(-/-) in comparison with WT mice. Basal Cyp2c37 expression was lower in CAR(-/-) compared to WT mice. Fasting decreased the clearance of all drugs tested in both WT and CAR(-/-) mice. The absence of CAR was associated with an decrease in the clearance of omeprazole, metoprolol and midazolam in fed mice. The fasting-induced reduction in clearance of s-warfarin was greater in WT than in CAR(-/-). The changes in drug clearance correlated with the expression pattern of the specific P450 enzymes in case of Cyp1a2-caffeine and Cyp2c37-omeprazole. CONCLUSION: We conclude that CAR is important for hepatic clearance of several widely prescribed drugs metabolized by P450 enzymes. However the fasting-induced alterations in P450 mediated drug clearance are largely independent of CAR. Public Library of Science 2016-07-19 /pmc/articles/PMC4951123/ /pubmed/27434302 http://dx.doi.org/10.1371/journal.pone.0159552 Text en © 2016 de Vries 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, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
de Vries, E. M.
Lammers, L. A.
Achterbergh, R.
Klümpen, H-J
Mathot, R. A. A.
Boelen, A.
Romijn, J. A.
Fasting-Induced Changes in Hepatic P450 Mediated Drug Metabolism Are Largely Independent of the Constitutive Androstane Receptor CAR
title Fasting-Induced Changes in Hepatic P450 Mediated Drug Metabolism Are Largely Independent of the Constitutive Androstane Receptor CAR
title_full Fasting-Induced Changes in Hepatic P450 Mediated Drug Metabolism Are Largely Independent of the Constitutive Androstane Receptor CAR
title_fullStr Fasting-Induced Changes in Hepatic P450 Mediated Drug Metabolism Are Largely Independent of the Constitutive Androstane Receptor CAR
title_full_unstemmed Fasting-Induced Changes in Hepatic P450 Mediated Drug Metabolism Are Largely Independent of the Constitutive Androstane Receptor CAR
title_short Fasting-Induced Changes in Hepatic P450 Mediated Drug Metabolism Are Largely Independent of the Constitutive Androstane Receptor CAR
title_sort fasting-induced changes in hepatic p450 mediated drug metabolism are largely independent of the constitutive androstane receptor car
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4951123/
https://www.ncbi.nlm.nih.gov/pubmed/27434302
http://dx.doi.org/10.1371/journal.pone.0159552
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