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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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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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. |
format | Online Article Text |
id | pubmed-10527876 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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