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Sex-dependent dynamics of metabolism in primary mouse hepatocytes

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Název: Sex-dependent dynamics of metabolism in primary mouse hepatocytes
Autoři: Luise Hochmuth, Christiane Körner, Fritzi Ott, Daniela Volke, Kaja Blagotinšek Cokan, Peter Juvan, Mario Brosch, Ute Hofmann, Ralf Hoffmann, Damjana Rozman, Thomas Berg, Madlen Matz-Soja
Zdroj: Arch Toxicol
Informace o vydavateli: Springer Science and Business Media LLC, 2021.
Rok vydání: 2021
Témata: Male, 0301 basic medicine, Serotonin, Sex Characteristics, 0303 health sciences, Proteome, Transcriptome/physiology [MeSH], Drug metabolism, Mice, Inbred C57BL [MeSH], Melatonin/metabolism [MeSH], Liver, Male [MeSH], Signal Transduction/physiology [MeSH], Toxicokinetics and Metabolism, Aryl Hydrocarbon Hydroxylases/genetics [MeSH], Sex Characteristics [MeSH], Sex Factors [MeSH], Female [MeSH], Serotonin/metabolism [MeSH], Sexual dimorphism, Animals [MeSH], Hepatocytes/metabolism [MeSH], Hepatocytes, Cytochrome P-450 Enzyme System/genetics [MeSH], Cytochrome P450 Family 2/genetics [MeSH], Steroid Hydroxylases/genetics [MeSH], Lipid metabolism, Mice [MeSH], Proteome/physiology [MeSH], Cytochrome P450, Metabolome/physiology [MeSH], Gene Expression Regulation/physiology [MeSH], Mice, Inbred C57BL, Mice, 03 medical and health sciences, Sex Factors, Cytochrome P-450 Enzyme System, Gene Expression Regulation, 13. Climate action, Steroid Hydroxylases, Metabolome, Animals, Female, Aryl Hydrocarbon Hydroxylases, Cytochrome P450 Family 2, Transcriptome, Melatonin, Signal Transduction
Popis: The liver is one of the most sexually dimorphic organs. The hepatic metabolic pathways that are subject to sexual dimorphism include xenobiotic, amino acid and lipid metabolism. Non-alcoholic fatty liver disease and hepatocellular carcinoma are among diseases with sex-dependent prevalence, progression and outcome. Although male and female livers differ in their abilities to metabolize foreign compounds, including drugs, sex-dependent treatment and pharmacological dynamics are rarely applied in all relevant cases. Therefore, it is important to consider hepatic sexual dimorphism when developing new treatment strategies and to understand the underlying mechanisms in model systems. We isolated primary hepatocytes from male and female C57BL6/N mice and examined the sex-dependent transcriptome, proteome and extracellular metabolome parameters in the course of culturing them for 96 h. The sex-specific gene expression of the general xenobiotic pathway altered and the female-specific expression of Cyp2b13 and Cyp2b9 was significantly reduced during culture. Sex-dependent differences of several signaling pathways increased, including genes related to serotonin and melatonin degradation. Furthermore, the ratios of male and female gene expression were inversed for other pathways, such as amino acid degradation, beta-oxidation, androgen signaling and hepatic steatosis. Because the primary hepatocytes were cultivated without the influence of known regulators of sexual dimorphism, these results suggest currently unknown modulatory mechanisms of sexual dimorphism in vitro. The large sex-dependent differences in the regulation and dynamics of drug metabolism observed during cultivation can have an immense influence on the evaluation of pharmacodynamic processes when conducting initial preclinical trials to investigate potential new drugs.
Druh dokumentu: Article
Other literature type
Jazyk: English
ISSN: 1432-0738
0340-5761
DOI: 10.1007/s00204-021-03118-9
Přístupová URL adresa: https://link.springer.com/content/pdf/10.1007/s00204-021-03118-9.pdf
https://pubmed.ncbi.nlm.nih.gov/34241659
https://www.ncbi.nlm.nih.gov/pubmed/34241659
https://link.springer.com/content/pdf/10.1007/s00204-021-03118-9.pdf
https://pubmed.ncbi.nlm.nih.gov/34241659/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380230
https://link.springer.com/article/10.1007/s00204-021-03118-9
https://repository.publisso.de/resource/frl:6451653
Rights: CC BY
URL: http://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/ (http://creativecommons.org/licenses/by/4.0/) .
Přístupové číslo: edsair.doi.dedup.....b40f970b0160ad1c0058cbe96d937f46
Databáze: OpenAIRE
Popis
Abstrakt:The liver is one of the most sexually dimorphic organs. The hepatic metabolic pathways that are subject to sexual dimorphism include xenobiotic, amino acid and lipid metabolism. Non-alcoholic fatty liver disease and hepatocellular carcinoma are among diseases with sex-dependent prevalence, progression and outcome. Although male and female livers differ in their abilities to metabolize foreign compounds, including drugs, sex-dependent treatment and pharmacological dynamics are rarely applied in all relevant cases. Therefore, it is important to consider hepatic sexual dimorphism when developing new treatment strategies and to understand the underlying mechanisms in model systems. We isolated primary hepatocytes from male and female C57BL6/N mice and examined the sex-dependent transcriptome, proteome and extracellular metabolome parameters in the course of culturing them for 96 h. The sex-specific gene expression of the general xenobiotic pathway altered and the female-specific expression of Cyp2b13 and Cyp2b9 was significantly reduced during culture. Sex-dependent differences of several signaling pathways increased, including genes related to serotonin and melatonin degradation. Furthermore, the ratios of male and female gene expression were inversed for other pathways, such as amino acid degradation, beta-oxidation, androgen signaling and hepatic steatosis. Because the primary hepatocytes were cultivated without the influence of known regulators of sexual dimorphism, these results suggest currently unknown modulatory mechanisms of sexual dimorphism in vitro. The large sex-dependent differences in the regulation and dynamics of drug metabolism observed during cultivation can have an immense influence on the evaluation of pharmacodynamic processes when conducting initial preclinical trials to investigate potential new drugs.
ISSN:14320738
03405761
DOI:10.1007/s00204-021-03118-9