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Mutual Modulation of the Activities of Human CYP2D6 and Four UGTs during the Metabolism of Propranolol

Cytochromes P450 (CYP) and UDP-glucuronosyltransferases (UGT) are two enzyme families that play an important role in drug metabolism, catalyzing either the functionalization or glucuronidation of xenobiotics. However, their mutual interactions are poorly understood. In this study, the functional int...

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Autores principales: Yang, Fan, Sharma, Sangeeta Shrestha, Bureik, Matthias, Parr, Maria Kristina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10527876/
https://www.ncbi.nlm.nih.gov/pubmed/37754235
http://dx.doi.org/10.3390/cimb45090451
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author Yang, Fan
Sharma, Sangeeta Shrestha
Bureik, Matthias
Parr, Maria Kristina
author_facet Yang, Fan
Sharma, Sangeeta Shrestha
Bureik, Matthias
Parr, Maria Kristina
author_sort Yang, Fan
collection PubMed
description Cytochromes P450 (CYP) and UDP-glucuronosyltransferases (UGT) are two enzyme families that play an important role in drug metabolism, catalyzing either the functionalization or glucuronidation of xenobiotics. However, their mutual interactions are poorly understood. In this study, the functional interactions of human CYP2D6 with four human UGTs (UGT1A7, UGT1A8, UGT1A9, and UGT2A1) were investigated using our previously established co-expression model system in the fission yeast Schizosaccharomyces pombe. The substrate employed was propranolol because it is well metabolized by CYP2D6. Moreover, the CYP2D6 metabolite 4-hydroxypropranolol is a known substrate for the four UGTs included in this study. Co-expression of either UGT1A7, UGT1A8, or UGT1A9 was found to increase the activity of CYP2D6 by a factor of 3.3, 2.1 or 2.8, respectively, for the conversion of propranolol to 4-hydroxypropranolol. In contrast, UGT2A1 co-expression did not change CYP2D6 activity. On the other hand, the activities of all four UGTs were completely suppressed by co-expression of CYP2D6. This data corroborates our previous report that CYP2D6 is involved in functional CYP-UGT interactions and suggest that such interactions can contribute to both adverse drug reactions and changes in drug efficacy.
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spelling pubmed-105278762023-09-28 Mutual Modulation of the Activities of Human CYP2D6 and Four UGTs during the Metabolism of Propranolol Yang, Fan Sharma, Sangeeta Shrestha Bureik, Matthias Parr, Maria Kristina Curr Issues Mol Biol Article Cytochromes P450 (CYP) and UDP-glucuronosyltransferases (UGT) are two enzyme families that play an important role in drug metabolism, catalyzing either the functionalization or glucuronidation of xenobiotics. However, their mutual interactions are poorly understood. In this study, the functional interactions of human CYP2D6 with four human UGTs (UGT1A7, UGT1A8, UGT1A9, and UGT2A1) were investigated using our previously established co-expression model system in the fission yeast Schizosaccharomyces pombe. The substrate employed was propranolol because it is well metabolized by CYP2D6. Moreover, the CYP2D6 metabolite 4-hydroxypropranolol is a known substrate for the four UGTs included in this study. Co-expression of either UGT1A7, UGT1A8, or UGT1A9 was found to increase the activity of CYP2D6 by a factor of 3.3, 2.1 or 2.8, respectively, for the conversion of propranolol to 4-hydroxypropranolol. In contrast, UGT2A1 co-expression did not change CYP2D6 activity. On the other hand, the activities of all four UGTs were completely suppressed by co-expression of CYP2D6. This data corroborates our previous report that CYP2D6 is involved in functional CYP-UGT interactions and suggest that such interactions can contribute to both adverse drug reactions and changes in drug efficacy. MDPI 2023-08-26 /pmc/articles/PMC10527876/ /pubmed/37754235 http://dx.doi.org/10.3390/cimb45090451 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Yang, Fan
Sharma, Sangeeta Shrestha
Bureik, Matthias
Parr, Maria Kristina
Mutual Modulation of the Activities of Human CYP2D6 and Four UGTs during the Metabolism of Propranolol
title Mutual Modulation of the Activities of Human CYP2D6 and Four UGTs during the Metabolism of Propranolol
title_full Mutual Modulation of the Activities of Human CYP2D6 and Four UGTs during the Metabolism of Propranolol
title_fullStr Mutual Modulation of the Activities of Human CYP2D6 and Four UGTs during the Metabolism of Propranolol
title_full_unstemmed Mutual Modulation of the Activities of Human CYP2D6 and Four UGTs during the Metabolism of Propranolol
title_short Mutual Modulation of the Activities of Human CYP2D6 and Four UGTs during the Metabolism of Propranolol
title_sort mutual modulation of the activities of human cyp2d6 and four ugts during the metabolism of propranolol
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10527876/
https://www.ncbi.nlm.nih.gov/pubmed/37754235
http://dx.doi.org/10.3390/cimb45090451
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