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Gene Expression and Protein Abundance of Hepatic Drug Metabolizing Enzymes in Liver Pathology
Hepatic drug metabolizing enzymes (DMEs) markedly affect drug pharmacokinetics. Because liver diseases may alter enzymatic function and in turn drug handling and clinical efficacy, we investigated DMEs expression in dependence on liver pathology and liver failure state. In 5 liver pathologies (hepat...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8471929/ https://www.ncbi.nlm.nih.gov/pubmed/34575411 http://dx.doi.org/10.3390/pharmaceutics13091334 |
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author | Drozdzik, Marek Lapczuk-Romanska, Joanna Wenzel, Christoph Szelag-Pieniek, Sylwia Post, Mariola Skalski, Łukasz Kurzawski, Mateusz Oswald, Stefan |
author_facet | Drozdzik, Marek Lapczuk-Romanska, Joanna Wenzel, Christoph Szelag-Pieniek, Sylwia Post, Mariola Skalski, Łukasz Kurzawski, Mateusz Oswald, Stefan |
author_sort | Drozdzik, Marek |
collection | PubMed |
description | Hepatic drug metabolizing enzymes (DMEs) markedly affect drug pharmacokinetics. Because liver diseases may alter enzymatic function and in turn drug handling and clinical efficacy, we investigated DMEs expression in dependence on liver pathology and liver failure state. In 5 liver pathologies (hepatitis C, alcoholic liver disease, autoimmune hepatitis, primary biliary cholangitis and primary sclerosing cholangitis) and for the first time stratified according to the Child–Pugh score, 10 CYPs (CYP1A1, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP3A5) and 4 UGTs (UGT1A1, UGT1A3, UGT2B7 and UGT2B) enzymes were quantified for protein abundance (LC-MS/MS) and gene expression (qRT-PCR). CYP2E1 was the most vulnerable enzyme, and its protein levels were significantly reduced just in Child–Pugh class A livers. The protein abundance of CYP1A1, CYP2B6, CYP2C19, CYP2D6 as well as UGT1A1, UGT1A3 and UGT2B15 was relatively stable in the course of progression of liver function deterioration. Alcoholic liver disease and primary biliary cholangitis were involved in the most prominent changes in the protein abundances, with downregulation of 6 (CYP1A2, CYP2C8, CYP2D6, CYP2E1, CYP3A4, UGT2B7) and 5 (CYP1A1, CYP2B6, CYP2C8, CYP2E1, CYP3A4) significantly downregulated enzymes, respectively. The results of the study demonstrate that DMEs protein abundance is affected both by the type of liver pathology as well as functional state of the organ. |
format | Online Article Text |
id | pubmed-8471929 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-84719292021-09-28 Gene Expression and Protein Abundance of Hepatic Drug Metabolizing Enzymes in Liver Pathology Drozdzik, Marek Lapczuk-Romanska, Joanna Wenzel, Christoph Szelag-Pieniek, Sylwia Post, Mariola Skalski, Łukasz Kurzawski, Mateusz Oswald, Stefan Pharmaceutics Article Hepatic drug metabolizing enzymes (DMEs) markedly affect drug pharmacokinetics. Because liver diseases may alter enzymatic function and in turn drug handling and clinical efficacy, we investigated DMEs expression in dependence on liver pathology and liver failure state. In 5 liver pathologies (hepatitis C, alcoholic liver disease, autoimmune hepatitis, primary biliary cholangitis and primary sclerosing cholangitis) and for the first time stratified according to the Child–Pugh score, 10 CYPs (CYP1A1, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP3A5) and 4 UGTs (UGT1A1, UGT1A3, UGT2B7 and UGT2B) enzymes were quantified for protein abundance (LC-MS/MS) and gene expression (qRT-PCR). CYP2E1 was the most vulnerable enzyme, and its protein levels were significantly reduced just in Child–Pugh class A livers. The protein abundance of CYP1A1, CYP2B6, CYP2C19, CYP2D6 as well as UGT1A1, UGT1A3 and UGT2B15 was relatively stable in the course of progression of liver function deterioration. Alcoholic liver disease and primary biliary cholangitis were involved in the most prominent changes in the protein abundances, with downregulation of 6 (CYP1A2, CYP2C8, CYP2D6, CYP2E1, CYP3A4, UGT2B7) and 5 (CYP1A1, CYP2B6, CYP2C8, CYP2E1, CYP3A4) significantly downregulated enzymes, respectively. The results of the study demonstrate that DMEs protein abundance is affected both by the type of liver pathology as well as functional state of the organ. MDPI 2021-08-25 /pmc/articles/PMC8471929/ /pubmed/34575411 http://dx.doi.org/10.3390/pharmaceutics13091334 Text en © 2021 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 Drozdzik, Marek Lapczuk-Romanska, Joanna Wenzel, Christoph Szelag-Pieniek, Sylwia Post, Mariola Skalski, Łukasz Kurzawski, Mateusz Oswald, Stefan Gene Expression and Protein Abundance of Hepatic Drug Metabolizing Enzymes in Liver Pathology |
title | Gene Expression and Protein Abundance of Hepatic Drug Metabolizing Enzymes in Liver Pathology |
title_full | Gene Expression and Protein Abundance of Hepatic Drug Metabolizing Enzymes in Liver Pathology |
title_fullStr | Gene Expression and Protein Abundance of Hepatic Drug Metabolizing Enzymes in Liver Pathology |
title_full_unstemmed | Gene Expression and Protein Abundance of Hepatic Drug Metabolizing Enzymes in Liver Pathology |
title_short | Gene Expression and Protein Abundance of Hepatic Drug Metabolizing Enzymes in Liver Pathology |
title_sort | gene expression and protein abundance of hepatic drug metabolizing enzymes in liver pathology |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8471929/ https://www.ncbi.nlm.nih.gov/pubmed/34575411 http://dx.doi.org/10.3390/pharmaceutics13091334 |
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