Paracetamol metabolism, hepatotoxicity, biomarkers and therapeutic interventions: a perspective
Autor: | Ian D. Wilson, Jeremy K. Nicholson, Muireann Coen, Daniel J. Antoine, Alan R. Boobis, Ann K. Daly, Lucia A. Possamai, Toby J. Athersuch |
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Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
SPECIES-DIFFERENCES NAPQI Health Toxicology and Mutagenesis Metabolite Toxicology Bioinformatics 03 medical and health sciences chemistry.chemical_compound INDUCED HEPATIC-NECROSIS ACETAMINOPHEN HEPATOTOXICITY GLUTATHIONE DEPLETION COVALENT BINDING medicine FAILURE Mode of action ISOLATED HEPATOCYTES Science & Technology INDUCED LIVER-INJURY business.industry digestive oral and skin physiology Glutathione Acetaminophen MICE 030104 developmental biology chemistry DRUG-METABOLISM Toxicity AM404 business Life Sciences & Biomedicine Drug metabolism medicine.drug |
Zdroj: | Toxicology Research. 7:347-357 |
ISSN: | 2045-4538 |
DOI: | 10.1039/c7tx00340d |
Popis: | After over 60 years of therapeutic use in the UK, paracetamol (acetaminophen, N-acetyl-p-aminophenol, APAP) remains the subject of considerable research into both its mode of action and toxicity. The pharmacological properties of APAP are the focus of some activity, with the role of the metabolite N-arachidonoylaminophenol (AM404) still a topic of debate. However, that the hepatotoxicity of APAP results from the production of the reactive metabolite N-acetyl-p-benzoquinoneimine (NAPQI/NABQI) that can deplete glutathione, react with cellular macromolecules, and initiate cell death, is now beyond dispute. The disruption of cellular pathways that results from the production of NAPQI provides a source of potential biomarkers of the severity of the damage. Research in this area has provided new diagnostic markers such as the microRNA miR-122 as well as mechanistic biomarkers associated with apoptosis, mitochondrial dysfunction, inflammation and tissue regeneration. Additionally, biomarkers of, and systems biology models for, glutathione depletion have been developed. Furthermore, there have been significant advances in determining the role of both the innate immune system and genetic factors that might predispose individuals to APAP-mediated toxicity. This perspective highlights some of the progress in current APAP-related research. |
Databáze: | OpenAIRE |
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