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The effect of brain serotonin deficit (TPH2-KO) on the expression and activity of liver cytochrome P450 enzymes in aging male Dark Agouti rats
BACKGROUND: Liver cytochrome P450 (CYP) greatly contributes to the metabolism of endogenous substances and drugs. Recent studies have demonstrated that CYP expression in the liver is controlled by the central nervous system via hormonal pathways. In particular, the expression of hepatic CYPs is nega...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer International Publishing
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10661807/ https://www.ncbi.nlm.nih.gov/pubmed/37848703 http://dx.doi.org/10.1007/s43440-023-00540-x |
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author | Haduch, Anna Bromek, Ewa Kuban, Wojciech Basińska-Ziobroń, Agnieszka Danek, Przemysław J. Alenina, Natalia Bader, Michael Daniel, Władysława A. |
author_facet | Haduch, Anna Bromek, Ewa Kuban, Wojciech Basińska-Ziobroń, Agnieszka Danek, Przemysław J. Alenina, Natalia Bader, Michael Daniel, Władysława A. |
author_sort | Haduch, Anna |
collection | PubMed |
description | BACKGROUND: Liver cytochrome P450 (CYP) greatly contributes to the metabolism of endogenous substances and drugs. Recent studies have demonstrated that CYP expression in the liver is controlled by the central nervous system via hormonal pathways. In particular, the expression of hepatic CYPs is negatively regulated by the brain serotoninergic system. The present study aimed to investigate changes in the function of the main liver drug-metabolizing CYP enzymes as a result of serotonin depletion in the brain of aging rats, caused by knockout of brain tryptophan hydroxylase gene (TPH2-KO). METHODS: The hepatic CYP mRNA (qRT-PCR), protein level (Western blotting) and activity (HPLC), and serum hormone levels (ELISA) were measured in Dark Agouti wild-type (WT) male rats (mature 3.5-month-old and senescent 21-month-old) and in TPH2-KO senescent animals. RESULTS: The expression/activity of the studied CYPs decreased with age in the liver of wild-type rats. The deprivation of serotonin in the brain of aging males decreased the mRNA level of most of the studied CYPs (CYP1A/2A/2B/3A), and lowered the protein level of CYP2C11 and CYP3A. In contrast, the activities of CYP2C11, CYP3A and CYP2C6 were increased. The expression of cytochrome b(5) decreased in aging rats, but increased in TPH2-deficient senescent animals. The serum concentration of growth hormone declined in the aged and further dropped down in TPH2-deficient senescent rats. CONCLUSIONS: Rat liver cytochrome P450 functions deteriorate with age, which may impair drug metabolism. The TPH2 knockout, which deprives brain serotonin, affects cytochrome P450 expression and activity differently in mature and senescent male rats. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s43440-023-00540-x. |
format | Online Article Text |
id | pubmed-10661807 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Springer International Publishing |
record_format | MEDLINE/PubMed |
spelling | pubmed-106618072023-10-17 The effect of brain serotonin deficit (TPH2-KO) on the expression and activity of liver cytochrome P450 enzymes in aging male Dark Agouti rats Haduch, Anna Bromek, Ewa Kuban, Wojciech Basińska-Ziobroń, Agnieszka Danek, Przemysław J. Alenina, Natalia Bader, Michael Daniel, Władysława A. Pharmacol Rep Article BACKGROUND: Liver cytochrome P450 (CYP) greatly contributes to the metabolism of endogenous substances and drugs. Recent studies have demonstrated that CYP expression in the liver is controlled by the central nervous system via hormonal pathways. In particular, the expression of hepatic CYPs is negatively regulated by the brain serotoninergic system. The present study aimed to investigate changes in the function of the main liver drug-metabolizing CYP enzymes as a result of serotonin depletion in the brain of aging rats, caused by knockout of brain tryptophan hydroxylase gene (TPH2-KO). METHODS: The hepatic CYP mRNA (qRT-PCR), protein level (Western blotting) and activity (HPLC), and serum hormone levels (ELISA) were measured in Dark Agouti wild-type (WT) male rats (mature 3.5-month-old and senescent 21-month-old) and in TPH2-KO senescent animals. RESULTS: The expression/activity of the studied CYPs decreased with age in the liver of wild-type rats. The deprivation of serotonin in the brain of aging males decreased the mRNA level of most of the studied CYPs (CYP1A/2A/2B/3A), and lowered the protein level of CYP2C11 and CYP3A. In contrast, the activities of CYP2C11, CYP3A and CYP2C6 were increased. The expression of cytochrome b(5) decreased in aging rats, but increased in TPH2-deficient senescent animals. The serum concentration of growth hormone declined in the aged and further dropped down in TPH2-deficient senescent rats. CONCLUSIONS: Rat liver cytochrome P450 functions deteriorate with age, which may impair drug metabolism. The TPH2 knockout, which deprives brain serotonin, affects cytochrome P450 expression and activity differently in mature and senescent male rats. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s43440-023-00540-x. Springer International Publishing 2023-10-17 2023 /pmc/articles/PMC10661807/ /pubmed/37848703 http://dx.doi.org/10.1007/s43440-023-00540-x Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This 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 | Article Haduch, Anna Bromek, Ewa Kuban, Wojciech Basińska-Ziobroń, Agnieszka Danek, Przemysław J. Alenina, Natalia Bader, Michael Daniel, Władysława A. The effect of brain serotonin deficit (TPH2-KO) on the expression and activity of liver cytochrome P450 enzymes in aging male Dark Agouti rats |
title | The effect of brain serotonin deficit (TPH2-KO) on the expression and activity of liver cytochrome P450 enzymes in aging male Dark Agouti rats |
title_full | The effect of brain serotonin deficit (TPH2-KO) on the expression and activity of liver cytochrome P450 enzymes in aging male Dark Agouti rats |
title_fullStr | The effect of brain serotonin deficit (TPH2-KO) on the expression and activity of liver cytochrome P450 enzymes in aging male Dark Agouti rats |
title_full_unstemmed | The effect of brain serotonin deficit (TPH2-KO) on the expression and activity of liver cytochrome P450 enzymes in aging male Dark Agouti rats |
title_short | The effect of brain serotonin deficit (TPH2-KO) on the expression and activity of liver cytochrome P450 enzymes in aging male Dark Agouti rats |
title_sort | effect of brain serotonin deficit (tph2-ko) on the expression and activity of liver cytochrome p450 enzymes in aging male dark agouti rats |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10661807/ https://www.ncbi.nlm.nih.gov/pubmed/37848703 http://dx.doi.org/10.1007/s43440-023-00540-x |
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