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Untargeted Metabolomic Analysis Combined With Multivariate Statistics Reveal Distinct Metabolic Changes in GPR40 Agonist-Treated Animals Related to Bile Acid Metabolism
Metabolomics has been increasingly applied to biomarker discovery, as untargeted metabolic profiling represents a powerful exploratory tool for identifying causal links between biomarkers and disease phenotypes. In the present work, we used untargeted metabolomics to investigate plasma specimens of...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843463/ https://www.ncbi.nlm.nih.gov/pubmed/33521051 http://dx.doi.org/10.3389/fmolb.2020.598369 |
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author | Doerfler, Hannes Botesteanu, Dana-Adriana Blech, Stefan Laux, Ralf |
author_facet | Doerfler, Hannes Botesteanu, Dana-Adriana Blech, Stefan Laux, Ralf |
author_sort | Doerfler, Hannes |
collection | PubMed |
description | Metabolomics has been increasingly applied to biomarker discovery, as untargeted metabolic profiling represents a powerful exploratory tool for identifying causal links between biomarkers and disease phenotypes. In the present work, we used untargeted metabolomics to investigate plasma specimens of rats, dogs, and mice treated with small-molecule drugs designed for improved glycemic control of type 2 diabetes mellitus patients via activation of GPR40. The in vivo pharmacology of GPR40 is not yet fully understood. Compounds targeting this receptor have been found to induce drug-induced liver injury (DILI). Metabolomic analysis facilitating an integrated UPLC-TWIMS-HRMS platform was used to detect metabolic differences between treated and non-treated animals within two 4-week toxicity studies in rat and dog, and one 2-week toxicity study in mouse. Multivariate statistics of untargeted metabolomics data subsequently revealed the presence of several significantly upregulated endogenous compounds in the treated animals whose plasma level is known to be affected during DILI. A specific bile acid metabolite useful as endogenous probe for drug–drug interaction studies was identified (chenodeoxycholic acid-24 glucuronide), as well as a metabolic precursor indicative of acidic bile acid biosynthesis (7α-hydroxy-3-oxo-4-cholestenoic acid). These results correlate with typical liver toxicity parameters on the individual level. |
format | Online Article Text |
id | pubmed-7843463 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-78434632021-01-30 Untargeted Metabolomic Analysis Combined With Multivariate Statistics Reveal Distinct Metabolic Changes in GPR40 Agonist-Treated Animals Related to Bile Acid Metabolism Doerfler, Hannes Botesteanu, Dana-Adriana Blech, Stefan Laux, Ralf Front Mol Biosci Molecular Biosciences Metabolomics has been increasingly applied to biomarker discovery, as untargeted metabolic profiling represents a powerful exploratory tool for identifying causal links between biomarkers and disease phenotypes. In the present work, we used untargeted metabolomics to investigate plasma specimens of rats, dogs, and mice treated with small-molecule drugs designed for improved glycemic control of type 2 diabetes mellitus patients via activation of GPR40. The in vivo pharmacology of GPR40 is not yet fully understood. Compounds targeting this receptor have been found to induce drug-induced liver injury (DILI). Metabolomic analysis facilitating an integrated UPLC-TWIMS-HRMS platform was used to detect metabolic differences between treated and non-treated animals within two 4-week toxicity studies in rat and dog, and one 2-week toxicity study in mouse. Multivariate statistics of untargeted metabolomics data subsequently revealed the presence of several significantly upregulated endogenous compounds in the treated animals whose plasma level is known to be affected during DILI. A specific bile acid metabolite useful as endogenous probe for drug–drug interaction studies was identified (chenodeoxycholic acid-24 glucuronide), as well as a metabolic precursor indicative of acidic bile acid biosynthesis (7α-hydroxy-3-oxo-4-cholestenoic acid). These results correlate with typical liver toxicity parameters on the individual level. Frontiers Media S.A. 2021-01-15 /pmc/articles/PMC7843463/ /pubmed/33521051 http://dx.doi.org/10.3389/fmolb.2020.598369 Text en Copyright © 2021 Doerfler, Botesteanu, Blech and Laux. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Molecular Biosciences Doerfler, Hannes Botesteanu, Dana-Adriana Blech, Stefan Laux, Ralf Untargeted Metabolomic Analysis Combined With Multivariate Statistics Reveal Distinct Metabolic Changes in GPR40 Agonist-Treated Animals Related to Bile Acid Metabolism |
title | Untargeted Metabolomic Analysis Combined With Multivariate Statistics Reveal Distinct Metabolic Changes in GPR40 Agonist-Treated Animals Related to Bile Acid Metabolism |
title_full | Untargeted Metabolomic Analysis Combined With Multivariate Statistics Reveal Distinct Metabolic Changes in GPR40 Agonist-Treated Animals Related to Bile Acid Metabolism |
title_fullStr | Untargeted Metabolomic Analysis Combined With Multivariate Statistics Reveal Distinct Metabolic Changes in GPR40 Agonist-Treated Animals Related to Bile Acid Metabolism |
title_full_unstemmed | Untargeted Metabolomic Analysis Combined With Multivariate Statistics Reveal Distinct Metabolic Changes in GPR40 Agonist-Treated Animals Related to Bile Acid Metabolism |
title_short | Untargeted Metabolomic Analysis Combined With Multivariate Statistics Reveal Distinct Metabolic Changes in GPR40 Agonist-Treated Animals Related to Bile Acid Metabolism |
title_sort | untargeted metabolomic analysis combined with multivariate statistics reveal distinct metabolic changes in gpr40 agonist-treated animals related to bile acid metabolism |
topic | Molecular Biosciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843463/ https://www.ncbi.nlm.nih.gov/pubmed/33521051 http://dx.doi.org/10.3389/fmolb.2020.598369 |
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