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High-resolution mass spectrometry identifies delayed biomarkers for improved precision in acetaminophen/paracetamol human biomonitoring

Gorrochategui, Eva ; Le Vee, Marc ; Selmi, Habiba ; Gérard, Anne ; Chaker, Jade ; Krais, Annette M. LU orcid ; Lindh, Christian LU orcid ; Fardel, Olivier ; Chevrier, Cécile and Le Cann, Pierre , et al. (2023) In Environment International 181.
Abstract

Paracetamol/acetaminophen (N-acetyl-p-aminophenol, APAP) is a top selling analgesic used in more than 600 prescription and non-prescription pharmaceuticals. To study efficiently some of the potential undesirable effects associated with increasing APAP consumption (e.g., developmental disorders, drug-induced liver injury), there is a need to improve current APAP biomonitoring methods that are limited by APAP short half-life. Here, we demonstrate using high-resolution mass spectrometry (HRMS) in several human studies that APAP thiomethyl metabolite conjugates (S-methyl-3-thioacetaminophen sulfate and S-methyl-3-thioacetaminophen sulphoxide sulfate) are stable biomarkers with delayed excretion rates compared to conventional APAP... (More)

Paracetamol/acetaminophen (N-acetyl-p-aminophenol, APAP) is a top selling analgesic used in more than 600 prescription and non-prescription pharmaceuticals. To study efficiently some of the potential undesirable effects associated with increasing APAP consumption (e.g., developmental disorders, drug-induced liver injury), there is a need to improve current APAP biomonitoring methods that are limited by APAP short half-life. Here, we demonstrate using high-resolution mass spectrometry (HRMS) in several human studies that APAP thiomethyl metabolite conjugates (S-methyl-3-thioacetaminophen sulfate and S-methyl-3-thioacetaminophen sulphoxide sulfate) are stable biomarkers with delayed excretion rates compared to conventional APAP metabolites, that could provide a more reliable history of APAP ingestion in epidemiological studies. We also show that these biomarkers could serve as relevant clinical markers to diagnose APAP acute intoxication in overdosed patients, when free APAP have nearly disappeared from blood. Using in vitro liver models (HepaRG cells and primary human hepatocytes), we then confirm that these thiomethyl metabolites are directly linked to the toxic N-acetyl-p-benzoquinone imine (NAPQI) elimination, and produced via an overlooked pathway called the thiomethyl shunt pathway. Further studies will be needed to determine whether the production of the reactive hepatotoxic NAPQI metabolites is currently underestimated in human. Nevertheless, these biomarkers could already serve to improve APAP human biomonitoring, and investigate, for instance, inter-individual variability in NAPQI production to study underlying causes involved in APAP-induced hepatotoxicity. Overall, our findings demonstrate the potential of exposomics-based HRMS approach to advance towards a better precision for human biomonitoring.

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type
Contribution to journal
publication status
published
subject
keywords
Acetaminophen/paracetamol, Chemical exposome, Exposomics, High-resolution mass spectrometry, Human biomonitoring, Thiomethyl metabolites
in
Environment International
volume
181
article number
108299
publisher
Elsevier
external identifiers
  • pmid:37951015
  • scopus:85176223140
ISSN
0160-4120
DOI
10.1016/j.envint.2023.108299
language
English
LU publication?
yes
additional info
Funding Information: We thanks Thibaut Léger and Christine Monfort for technical assistance. This study was supported by the MoU signed between Inserm and the Mailman School of Public Health of Columbia University on Nov. 12 2019. EG was funded by the Inserm and the Mailman School of Public Health of Columbia University collaboration project obtained under this MoU. A.D., J.C., and R.B acknowledge the research infrastructure France Exposome. The first observational study with PWs was partially funded by the French Agency for Environmental Health Safety (PNREST Anses, 2018/1/084). The PELAGIE cohort has been funded by Inserm, the French Ministries of Health (2003-2004), Labor (2002-2003), and Research (ATC 2003-2004) and the French National Institute for Public Health Surveillance (InVS, 2002-2006). Publisher Copyright: © 2023
id
e8ae13fb-57e9-4016-a25b-1dc62c5813d8
date added to LUP
2023-11-23 22:37:58
date last changed
2024-04-21 01:53:04
@article{e8ae13fb-57e9-4016-a25b-1dc62c5813d8,
  abstract     = {{<p>Paracetamol/acetaminophen (N-acetyl-p-aminophenol, APAP) is a top selling analgesic used in more than 600 prescription and non-prescription pharmaceuticals. To study efficiently some of the potential undesirable effects associated with increasing APAP consumption (e.g., developmental disorders, drug-induced liver injury), there is a need to improve current APAP biomonitoring methods that are limited by APAP short half-life. Here, we demonstrate using high-resolution mass spectrometry (HRMS) in several human studies that APAP thiomethyl metabolite conjugates (S-methyl-3-thioacetaminophen sulfate and S-methyl-3-thioacetaminophen sulphoxide sulfate) are stable biomarkers with delayed excretion rates compared to conventional APAP metabolites, that could provide a more reliable history of APAP ingestion in epidemiological studies. We also show that these biomarkers could serve as relevant clinical markers to diagnose APAP acute intoxication in overdosed patients, when free APAP have nearly disappeared from blood. Using in vitro liver models (HepaRG cells and primary human hepatocytes), we then confirm that these thiomethyl metabolites are directly linked to the toxic N-acetyl-p-benzoquinone imine (NAPQI) elimination, and produced via an overlooked pathway called the thiomethyl shunt pathway. Further studies will be needed to determine whether the production of the reactive hepatotoxic NAPQI metabolites is currently underestimated in human. Nevertheless, these biomarkers could already serve to improve APAP human biomonitoring, and investigate, for instance, inter-individual variability in NAPQI production to study underlying causes involved in APAP-induced hepatotoxicity. Overall, our findings demonstrate the potential of exposomics-based HRMS approach to advance towards a better precision for human biomonitoring.</p>}},
  author       = {{Gorrochategui, Eva and Le Vee, Marc and Selmi, Habiba and Gérard, Anne and Chaker, Jade and Krais, Annette M. and Lindh, Christian and Fardel, Olivier and Chevrier, Cécile and Le Cann, Pierre and Miller, Gary W. and Barouki, Robert and Jégou, Bernard and Gicquel, Thomas and Kristensen, David M. and David, Arthur}},
  issn         = {{0160-4120}},
  keywords     = {{Acetaminophen/paracetamol; Chemical exposome; Exposomics; High-resolution mass spectrometry; Human biomonitoring; Thiomethyl metabolites}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{Environment International}},
  title        = {{High-resolution mass spectrometry identifies delayed biomarkers for improved precision in acetaminophen/paracetamol human biomonitoring}},
  url          = {{http://dx.doi.org/10.1016/j.envint.2023.108299}},
  doi          = {{10.1016/j.envint.2023.108299}},
  volume       = {{181}},
  year         = {{2023}},
}