Simultaneously discovering the fate and biochemical effects of pharmaceuticals through untargeted metabolomics

Tara J. Bowen; Andrew D. Southam; Andrew R. Hall; Ralf J. M. Weber; Gavin R. Lloyd; Ruth Macdonald; Amanda Wilson; Amy Pointon; Mark R. Viant

doi:10.1038/s41467-023-40333-7

Simultaneously discovering the fate and biochemical effects of pharmaceuticals through untargeted metabolomics

Tara J. Bowen, Andrew D. Southam, Andrew R. Hall, Ralf J. M. Weber, Gavin R. Lloyd, Ruth Macdonald, Amanda Wilson, Amy Pointon, Mark R. Viant^*

^*Corresponding author for this work

Biosciences

Research output: Contribution to journal › Article › peer-review

42 Downloads (Pure)

Abstract

Untargeted metabolomics is an established approach in toxicology for characterising endogenous metabolic responses to xenobiotic exposure. Detecting the xenobiotic and its biotransformation products as part of the metabolomics analysis provides an opportunity to simultaneously gain deep insights into its fate and metabolism, and to associate the internal relative dose directly with endogenous metabolic responses. This integration of untargeted exposure and response measurements into a single assay has yet to be fully demonstrated. Here we assemble a workflow to discover and analyse pharmaceutical-related measurements from routine untargeted UHPLC-MS metabolomics datasets, derived from in vivo (rat plasma and cardiac tissue, and human plasma) and in vitro (human cardiomyocytes) studies that were principally designed to investigate endogenous metabolic responses to drug exposure. Our findings clearly demonstrate how untargeted metabolomics can discover extensive biotransformation maps, temporally-changing relative systemic exposure, and direct associations of endogenous biochemical responses to the internal dose.

Original language	English
Article number	4653
Number of pages	18
Journal	Nature Communications
Volume	14
Issue number	1
Early online date	3 Aug 2023
DOIs	https://doi.org/10.1038/s41467-023-40333-7
Publication status	Published - Dec 2023

Bibliographical note

Funding Information:
We gratefully acknowledge the contribution to this publication made by the University of Birmingham’s Human Biomaterials Resource Centre which has been supported through Birmingham Science City—Experimental Medicine Network of Excellence project. The authors thank Thermo Fisher Scientific for their support of this project via the University of Birmingham—Thermo Fisher Scientific Technology Alliance Partnership. We also thank Dr. Lukáš Najedkr and Dr. Andris Jankevics (Phenome Centre Birmingham, UK) for their scientific advice. We thank the BBSRC (BB/S507064/1) and AstraZeneca for funding this project via a PhD studentship awarded to T.J.B.

Publisher Copyright:
© 2023, The Author(s).

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

Access to Document

10.1038/s41467-023-40333-7Licence: Creative Commons: Attribution (CC BY)

BowenT2023SimultaneouslyFinal published version, 3.11 MBLicence: Creative Commons: Attribution (CC BY)

Cite this

@article{4e09b034751e4b9da867a4cf20c77fc9,

title = "Simultaneously discovering the fate and biochemical effects of pharmaceuticals through untargeted metabolomics",

abstract = "Untargeted metabolomics is an established approach in toxicology for characterising endogenous metabolic responses to xenobiotic exposure. Detecting the xenobiotic and its biotransformation products as part of the metabolomics analysis provides an opportunity to simultaneously gain deep insights into its fate and metabolism, and to associate the internal relative dose directly with endogenous metabolic responses. This integration of untargeted exposure and response measurements into a single assay has yet to be fully demonstrated. Here we assemble a workflow to discover and analyse pharmaceutical-related measurements from routine untargeted UHPLC-MS metabolomics datasets, derived from in vivo (rat plasma and cardiac tissue, and human plasma) and in vitro (human cardiomyocytes) studies that were principally designed to investigate endogenous metabolic responses to drug exposure. Our findings clearly demonstrate how untargeted metabolomics can discover extensive biotransformation maps, temporally-changing relative systemic exposure, and direct associations of endogenous biochemical responses to the internal dose.",

author = "Bowen, {Tara J.} and Southam, {Andrew D.} and Hall, {Andrew R.} and Weber, {Ralf J. M.} and Lloyd, {Gavin R.} and Ruth Macdonald and Amanda Wilson and Amy Pointon and Viant, {Mark R.}",

note = "Funding Information: We gratefully acknowledge the contribution to this publication made by the University of Birmingham{\textquoteright}s Human Biomaterials Resource Centre which has been supported through Birmingham Science City—Experimental Medicine Network of Excellence project. The authors thank Thermo Fisher Scientific for their support of this project via the University of Birmingham—Thermo Fisher Scientific Technology Alliance Partnership. We also thank Dr. Luk{\'a}{\v s} Najedkr and Dr. Andris Jankevics (Phenome Centre Birmingham, UK) for their scientific advice. We thank the BBSRC (BB/S507064/1) and AstraZeneca for funding this project via a PhD studentship awarded to T.J.B. Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = dec,

doi = "10.1038/s41467-023-40333-7",

language = "English",

volume = "14",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Springer",

number = "1",

}

TY - JOUR

T1 - Simultaneously discovering the fate and biochemical effects of pharmaceuticals through untargeted metabolomics

AU - Bowen, Tara J.

AU - Southam, Andrew D.

AU - Hall, Andrew R.

AU - Weber, Ralf J. M.

AU - Lloyd, Gavin R.

AU - Macdonald, Ruth

AU - Wilson, Amanda

AU - Pointon, Amy

AU - Viant, Mark R.

N1 - Funding Information: We gratefully acknowledge the contribution to this publication made by the University of Birmingham’s Human Biomaterials Resource Centre which has been supported through Birmingham Science City—Experimental Medicine Network of Excellence project. The authors thank Thermo Fisher Scientific for their support of this project via the University of Birmingham—Thermo Fisher Scientific Technology Alliance Partnership. We also thank Dr. Lukáš Najedkr and Dr. Andris Jankevics (Phenome Centre Birmingham, UK) for their scientific advice. We thank the BBSRC (BB/S507064/1) and AstraZeneca for funding this project via a PhD studentship awarded to T.J.B. Publisher Copyright: © 2023, The Author(s).

PY - 2023/12

Y1 - 2023/12

N2 - Untargeted metabolomics is an established approach in toxicology for characterising endogenous metabolic responses to xenobiotic exposure. Detecting the xenobiotic and its biotransformation products as part of the metabolomics analysis provides an opportunity to simultaneously gain deep insights into its fate and metabolism, and to associate the internal relative dose directly with endogenous metabolic responses. This integration of untargeted exposure and response measurements into a single assay has yet to be fully demonstrated. Here we assemble a workflow to discover and analyse pharmaceutical-related measurements from routine untargeted UHPLC-MS metabolomics datasets, derived from in vivo (rat plasma and cardiac tissue, and human plasma) and in vitro (human cardiomyocytes) studies that were principally designed to investigate endogenous metabolic responses to drug exposure. Our findings clearly demonstrate how untargeted metabolomics can discover extensive biotransformation maps, temporally-changing relative systemic exposure, and direct associations of endogenous biochemical responses to the internal dose.

AB - Untargeted metabolomics is an established approach in toxicology for characterising endogenous metabolic responses to xenobiotic exposure. Detecting the xenobiotic and its biotransformation products as part of the metabolomics analysis provides an opportunity to simultaneously gain deep insights into its fate and metabolism, and to associate the internal relative dose directly with endogenous metabolic responses. This integration of untargeted exposure and response measurements into a single assay has yet to be fully demonstrated. Here we assemble a workflow to discover and analyse pharmaceutical-related measurements from routine untargeted UHPLC-MS metabolomics datasets, derived from in vivo (rat plasma and cardiac tissue, and human plasma) and in vitro (human cardiomyocytes) studies that were principally designed to investigate endogenous metabolic responses to drug exposure. Our findings clearly demonstrate how untargeted metabolomics can discover extensive biotransformation maps, temporally-changing relative systemic exposure, and direct associations of endogenous biochemical responses to the internal dose.

UR - http://www.scopus.com/inward/record.url?scp=85166532935&partnerID=8YFLogxK

U2 - 10.1038/s41467-023-40333-7

DO - 10.1038/s41467-023-40333-7

M3 - Article

C2 - 37537184

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4653

ER -

Simultaneously discovering the fate and biochemical effects of pharmaceuticals through untargeted metabolomics

Abstract

Bibliographical note

ASJC Scopus subject areas

Access to Document

Fingerprint

Cite this