High-resolution mass spectrometry identifies delayed biomarkers for improved precision in acetaminophen/paracetamol human biomonitoring
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...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-11-01
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| Series: | Environment International |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S016041202300572X |
| _version_ | 1797616015433007104 |
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| author | Eva Gorrochategui Marc Le Vee Habiba Selmi Anne Gérard Jade Chaker Annette M. Krais Christian Lindh Olivier Fardel Cécile Chevrier Pierre Le Cann Gary W. Miller Robert Barouki Bernard Jégou Thomas Gicquel David M. Kristensen Arthur David |
| author_facet | Eva Gorrochategui Marc Le Vee Habiba Selmi Anne Gérard Jade Chaker Annette M. Krais Christian Lindh Olivier Fardel Cécile Chevrier Pierre Le Cann Gary W. Miller Robert Barouki Bernard Jégou Thomas Gicquel David M. Kristensen Arthur David |
| author_sort | Eva Gorrochategui |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T07:35:10Z |
| format | Article |
| id | doaj.art-b0e163d6b97d4499a77e2ca8b8f6626a |
| institution | Directory Open Access Journal |
| issn | 0160-4120 |
| language | English |
| last_indexed | 2024-03-11T07:35:10Z |
| publishDate | 2023-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Environment International |
| spelling | doaj.art-b0e163d6b97d4499a77e2ca8b8f6626a2023-11-17T05:24:54ZengElsevierEnvironment International0160-41202023-11-01181108299High-resolution mass spectrometry identifies delayed biomarkers for improved precision in acetaminophen/paracetamol human biomonitoringEva Gorrochategui0Marc Le Vee1Habiba Selmi2Anne Gérard3Jade Chaker4Annette M. Krais5Christian Lindh6Olivier Fardel7Cécile Chevrier8Pierre Le Cann9Gary W. Miller10Robert Barouki11Bernard Jégou12Thomas Gicquel13David M. Kristensen14Arthur David15Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) – UMR_S 1085, Rennes, FranceUniv Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) – UMR_S 1085, Rennes, FranceUniv Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) – UMR_S 1085, Rennes, FranceUniv Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) – UMR_S 1085, Rennes, FranceUniv Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) – UMR_S 1085, Rennes, FranceDivision of Occupational and Environmental Medicine, Lund University, Lund, SwedenDivision of Occupational and Environmental Medicine, Lund University, Lund, SwedenUniv Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) – UMR_S 1085, Rennes, FranceUniv Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) – UMR_S 1085, Rennes, FranceUniv Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) – UMR_S 1085, Rennes, FranceDepartment of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USAUnité UMR-S 1124 Inserm-Université Paris Descartes “Toxicologie Pharmacologie et Signalisation Cellulaire”, Paris, FranceUniv Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) – UMR_S 1085, Rennes, FranceNuMeCan Institute (Nutrition, Metabolisms and Cancer), CHU Rennes, Univ Rennes, INSERM, INRAE, UMR_A 1341, UMR_S 1317, 35000 Rennes, FranceUniv Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) – UMR_S 1085, Rennes, France; Department of Science and Environment, Roskilde University, Roskilde, Denmark; Department of Growth and Reproduction, Copenhagen University Hospital – Rigshospitalet, University of Copenhagen, DenmarkUniv Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) – UMR_S 1085, Rennes, France; Corresponding author.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.http://www.sciencedirect.com/science/article/pii/S016041202300572XHuman biomonitoringHigh-resolution mass spectrometryAcetaminophen/paracetamolExposomicsThiomethyl metabolitesChemical exposome |
| spellingShingle | Eva Gorrochategui Marc Le Vee Habiba Selmi Anne Gérard Jade Chaker Annette M. Krais Christian Lindh Olivier Fardel Cécile Chevrier Pierre Le Cann Gary W. Miller Robert Barouki Bernard Jégou Thomas Gicquel David M. Kristensen Arthur David High-resolution mass spectrometry identifies delayed biomarkers for improved precision in acetaminophen/paracetamol human biomonitoring Environment International Human biomonitoring High-resolution mass spectrometry Acetaminophen/paracetamol Exposomics Thiomethyl metabolites Chemical exposome |
| title | High-resolution mass spectrometry identifies delayed biomarkers for improved precision in acetaminophen/paracetamol human biomonitoring |
| title_full | High-resolution mass spectrometry identifies delayed biomarkers for improved precision in acetaminophen/paracetamol human biomonitoring |
| title_fullStr | High-resolution mass spectrometry identifies delayed biomarkers for improved precision in acetaminophen/paracetamol human biomonitoring |
| title_full_unstemmed | High-resolution mass spectrometry identifies delayed biomarkers for improved precision in acetaminophen/paracetamol human biomonitoring |
| title_short | High-resolution mass spectrometry identifies delayed biomarkers for improved precision in acetaminophen/paracetamol human biomonitoring |
| title_sort | high resolution mass spectrometry identifies delayed biomarkers for improved precision in acetaminophen paracetamol human biomonitoring |
| topic | Human biomonitoring High-resolution mass spectrometry Acetaminophen/paracetamol Exposomics Thiomethyl metabolites Chemical exposome |
| url | http://www.sciencedirect.com/science/article/pii/S016041202300572X |
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