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Proteomic analysis of hepatic effects of phenobarbital in mice with humanized liver

Activation of the constitutive androstane receptor (CAR) may induce adaptive but also adverse effects in rodent liver, including the induction of drug-metabolizing enzymes, transient hepatocellular proliferation, and promotion of liver tumor growth. Human relevance of CAR-related adverse hepatic eff...

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Autores principales: Sprenger, Heike, Rasinger, Josef Daniel, Hammer, Helen, Naboulsi, Wael, Zabinsky, Elke, Planatscher, Hannes, Schwarz, Michael, Poetz, Oliver, Braeuning, Albert
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9352639/
https://www.ncbi.nlm.nih.gov/pubmed/35881160
http://dx.doi.org/10.1007/s00204-022-03338-7
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author Sprenger, Heike
Rasinger, Josef Daniel
Hammer, Helen
Naboulsi, Wael
Zabinsky, Elke
Planatscher, Hannes
Schwarz, Michael
Poetz, Oliver
Braeuning, Albert
author_facet Sprenger, Heike
Rasinger, Josef Daniel
Hammer, Helen
Naboulsi, Wael
Zabinsky, Elke
Planatscher, Hannes
Schwarz, Michael
Poetz, Oliver
Braeuning, Albert
author_sort Sprenger, Heike
collection PubMed
description Activation of the constitutive androstane receptor (CAR) may induce adaptive but also adverse effects in rodent liver, including the induction of drug-metabolizing enzymes, transient hepatocellular proliferation, and promotion of liver tumor growth. Human relevance of CAR-related adverse hepatic effects is controversially debated. Here, we used the chimeric FRG-KO mouse model with livers largely repopulated by human hepatocytes, in order to study human hepatocytes and their response to treatment with the model CAR activator phenobarbital (PB) in vivo. Mice received an intraperitoneal injection with 50 mg/kg body weight PB or saline, and were sacrificed after 72–144 h. Non-repopulated FRG-KO mice were used as additional control. Comprehensive proteomics datasets were generated by merging data obtained by targeted as well as non-targeted proteomics approaches. For the first time, a novel proteomics workflow was established to comparatively analyze the effects of PB on human and murine proteins within one sample. Analysis of merged proteome data sets and bioinformatics data mining revealed comparable responses in murine and human hepatocytes with respect to nuclear receptor activation and induction of xenobiotic metabolism. By contrast, activation of MYC, a key regulator of proliferation, was predicted only for mouse but not human hepatocytes. Analyses of 5-bromo-2′-deoxyuridine incorporation confirmed this finding. In summary, this study for the first time presents a comprehensive proteomic analysis of CAR-dependent effects in human and mouse hepatocytes from humanized FRG-KO mice. The data support the hypothesis that PB does induce adaptive metabolic responses, but not hepatocellular proliferation in human hepatocytes in vivo. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00204-022-03338-7.
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spelling pubmed-93526392022-08-06 Proteomic analysis of hepatic effects of phenobarbital in mice with humanized liver Sprenger, Heike Rasinger, Josef Daniel Hammer, Helen Naboulsi, Wael Zabinsky, Elke Planatscher, Hannes Schwarz, Michael Poetz, Oliver Braeuning, Albert Arch Toxicol Toxicogenomics and Omics Technologies Activation of the constitutive androstane receptor (CAR) may induce adaptive but also adverse effects in rodent liver, including the induction of drug-metabolizing enzymes, transient hepatocellular proliferation, and promotion of liver tumor growth. Human relevance of CAR-related adverse hepatic effects is controversially debated. Here, we used the chimeric FRG-KO mouse model with livers largely repopulated by human hepatocytes, in order to study human hepatocytes and their response to treatment with the model CAR activator phenobarbital (PB) in vivo. Mice received an intraperitoneal injection with 50 mg/kg body weight PB or saline, and were sacrificed after 72–144 h. Non-repopulated FRG-KO mice were used as additional control. Comprehensive proteomics datasets were generated by merging data obtained by targeted as well as non-targeted proteomics approaches. For the first time, a novel proteomics workflow was established to comparatively analyze the effects of PB on human and murine proteins within one sample. Analysis of merged proteome data sets and bioinformatics data mining revealed comparable responses in murine and human hepatocytes with respect to nuclear receptor activation and induction of xenobiotic metabolism. By contrast, activation of MYC, a key regulator of proliferation, was predicted only for mouse but not human hepatocytes. Analyses of 5-bromo-2′-deoxyuridine incorporation confirmed this finding. In summary, this study for the first time presents a comprehensive proteomic analysis of CAR-dependent effects in human and mouse hepatocytes from humanized FRG-KO mice. The data support the hypothesis that PB does induce adaptive metabolic responses, but not hepatocellular proliferation in human hepatocytes in vivo. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00204-022-03338-7. Springer Berlin Heidelberg 2022-07-26 2022 /pmc/articles/PMC9352639/ /pubmed/35881160 http://dx.doi.org/10.1007/s00204-022-03338-7 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Toxicogenomics and Omics Technologies
Sprenger, Heike
Rasinger, Josef Daniel
Hammer, Helen
Naboulsi, Wael
Zabinsky, Elke
Planatscher, Hannes
Schwarz, Michael
Poetz, Oliver
Braeuning, Albert
Proteomic analysis of hepatic effects of phenobarbital in mice with humanized liver
title Proteomic analysis of hepatic effects of phenobarbital in mice with humanized liver
title_full Proteomic analysis of hepatic effects of phenobarbital in mice with humanized liver
title_fullStr Proteomic analysis of hepatic effects of phenobarbital in mice with humanized liver
title_full_unstemmed Proteomic analysis of hepatic effects of phenobarbital in mice with humanized liver
title_short Proteomic analysis of hepatic effects of phenobarbital in mice with humanized liver
title_sort proteomic analysis of hepatic effects of phenobarbital in mice with humanized liver
topic Toxicogenomics and Omics Technologies
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9352639/
https://www.ncbi.nlm.nih.gov/pubmed/35881160
http://dx.doi.org/10.1007/s00204-022-03338-7
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