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Metabolomics and Network Analyses Reveal Phenylalanine and Tyrosine as Signatures of Anthracycline-Induced Hepatotoxicity

The chemotherapy drug doxorubicin (DOX) is an anthracycline with over 30% incidence of liver injury in breast cancer patients, yet the mechanism of its hepatotoxicity remains unclear. To identify potential biomarkers for anthracycline-induced hepatotoxicity (AIH), we generated clinically-relevant mo...

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Autores principales: Liu, Peipei, Wu, Jing, Yu, Xinyue, Guo, Linling, Zhao, Ling, Ban, Tao, Huang, Yin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10302024/
https://www.ncbi.nlm.nih.gov/pubmed/37375744
http://dx.doi.org/10.3390/ph16060797
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author Liu, Peipei
Wu, Jing
Yu, Xinyue
Guo, Linling
Zhao, Ling
Ban, Tao
Huang, Yin
author_facet Liu, Peipei
Wu, Jing
Yu, Xinyue
Guo, Linling
Zhao, Ling
Ban, Tao
Huang, Yin
author_sort Liu, Peipei
collection PubMed
description The chemotherapy drug doxorubicin (DOX) is an anthracycline with over 30% incidence of liver injury in breast cancer patients, yet the mechanism of its hepatotoxicity remains unclear. To identify potential biomarkers for anthracycline-induced hepatotoxicity (AIH), we generated clinically-relevant mouse and rat models administered low-dose, long-term DOX. These models exhibited significant liver damage but no decline in cardiac function. Through untargeted metabolic profiling of the liver, we identified 27 differential metabolites in a mouse model and 28 in a rat model. We then constructed a metabolite-metabolite network for each animal model and computationally identified several potential metabolic markers, with particular emphasis on aromatic amino acids, including phenylalanine, tyrosine, and tryptophan. We further performed targeted metabolomics analysis on DOX-treated 4T1 breast cancer mice for external validation. We found significant (p < 0.001) reductions in hepatic levels of phenylalanine and tyrosine (but not tryptophan) following DOX treatment, which were strongly correlated with serum aminotransferases (ALT and AST) levels. In summary, the results of our study present compelling evidence supporting the use of phenylalanine and tyrosine as metabolic signatures of AIH.
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spelling pubmed-103020242023-06-29 Metabolomics and Network Analyses Reveal Phenylalanine and Tyrosine as Signatures of Anthracycline-Induced Hepatotoxicity Liu, Peipei Wu, Jing Yu, Xinyue Guo, Linling Zhao, Ling Ban, Tao Huang, Yin Pharmaceuticals (Basel) Article The chemotherapy drug doxorubicin (DOX) is an anthracycline with over 30% incidence of liver injury in breast cancer patients, yet the mechanism of its hepatotoxicity remains unclear. To identify potential biomarkers for anthracycline-induced hepatotoxicity (AIH), we generated clinically-relevant mouse and rat models administered low-dose, long-term DOX. These models exhibited significant liver damage but no decline in cardiac function. Through untargeted metabolic profiling of the liver, we identified 27 differential metabolites in a mouse model and 28 in a rat model. We then constructed a metabolite-metabolite network for each animal model and computationally identified several potential metabolic markers, with particular emphasis on aromatic amino acids, including phenylalanine, tyrosine, and tryptophan. We further performed targeted metabolomics analysis on DOX-treated 4T1 breast cancer mice for external validation. We found significant (p < 0.001) reductions in hepatic levels of phenylalanine and tyrosine (but not tryptophan) following DOX treatment, which were strongly correlated with serum aminotransferases (ALT and AST) levels. In summary, the results of our study present compelling evidence supporting the use of phenylalanine and tyrosine as metabolic signatures of AIH. MDPI 2023-05-26 /pmc/articles/PMC10302024/ /pubmed/37375744 http://dx.doi.org/10.3390/ph16060797 Text en © 2023 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
Liu, Peipei
Wu, Jing
Yu, Xinyue
Guo, Linling
Zhao, Ling
Ban, Tao
Huang, Yin
Metabolomics and Network Analyses Reveal Phenylalanine and Tyrosine as Signatures of Anthracycline-Induced Hepatotoxicity
title Metabolomics and Network Analyses Reveal Phenylalanine and Tyrosine as Signatures of Anthracycline-Induced Hepatotoxicity
title_full Metabolomics and Network Analyses Reveal Phenylalanine and Tyrosine as Signatures of Anthracycline-Induced Hepatotoxicity
title_fullStr Metabolomics and Network Analyses Reveal Phenylalanine and Tyrosine as Signatures of Anthracycline-Induced Hepatotoxicity
title_full_unstemmed Metabolomics and Network Analyses Reveal Phenylalanine and Tyrosine as Signatures of Anthracycline-Induced Hepatotoxicity
title_short Metabolomics and Network Analyses Reveal Phenylalanine and Tyrosine as Signatures of Anthracycline-Induced Hepatotoxicity
title_sort metabolomics and network analyses reveal phenylalanine and tyrosine as signatures of anthracycline-induced hepatotoxicity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10302024/
https://www.ncbi.nlm.nih.gov/pubmed/37375744
http://dx.doi.org/10.3390/ph16060797
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