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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...

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Autores principales: Drozdzik, Marek, Lapczuk-Romanska, Joanna, Wenzel, Christoph, Szelag-Pieniek, Sylwia, Post, Mariola, Skalski, Łukasz, Kurzawski, Mateusz, Oswald, Stefan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
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.
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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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