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Paracetamol metabolism, hepatotoxicity, biomarkers and therapeutic interventions: a perspective.

ABSTRACT: 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.

SUBMITTER: Athersuch TJ

PROVIDER: S-EPMC6062253 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Paracetamol metabolism, hepatotoxicity, biomarkers and therapeutic interventions: a perspective.

Athersuch Toby J TJ Antoine Daniel J DJ Boobis Alan R AR Coen Muireann M Daly Ann K AK Possamai Lucia L Nicholson Jeremy K JK Wilson Ian D ID

Toxicology research 20180306 3

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- ...[more]

PMID: 30090586

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Project description:Background and purposeParacetamol, a major cause of acute liver failure (ALF) represents a significant clinical problem. Adrenoceptor stimulation or antagonism can modulate chemical-induced hepatotoxicity. We investigated the role of endogenous catecholamines and alpha(1)-adrenoceptors in the development of paracetamol- induced hepatotoxicity.Experimental approachParacetamol (3.5 mmol kg(-1)) was administered to male CD-1 mice, with and without alpha(1)-adrenoceptor antagonists (prazosin, doxazosin, terazosin and tamsulosin; 35.7 micromol kg(-1)). Serum transaminases and hepatic glutathione (GSH) levels were assessed as markers of hepatic damage. Paracetamol bioactivation was assessed by covalent binding, hepatic and urinary conjugate formation and uridine glucuronosyltransferase activity. Plasma catecholamines levels and hepatic congestion were also analysed.Key resultsPlasma catecholamine levels were significantly elevated 5 h post paracetamol administration. Prazosin prevented hepatotoxicity when administered 1 h before a toxic paracetamol insult and importantly, when administered up to 1 h post paracetamol injection. Prazosin had no effect on paracetamol-induced depletion of hepatic GSH, paracetamol bioactivation or paracetamol-induced transcription of defence genes. Paracetamol toxicity is associated with marked accumulation of erythrocytes within hepatic sinusoids and prazosin completely prevented this accumulation.Conclusion and implicationsParacetamol-induced hepatocellular damage is associated with increased circulating catecholamines. alpha(1)-Adrenoceptor antagonists conferred complete protection from paracetamol -induced hepatotoxicity. Protection was associated with absence of hepatic erythrocyte accumulation. Increased catecholamine levels may contribute to the pathophysiology of paracetamol-induced hepatotoxicity by compromising hepatic perfusion. Protection against paracetamol toxicity by alpha(1) antagonists in mice has implications for therapeutic management of patients presenting with paracetamol overdose and ALF.

Dataset Information

Paracetamol metabolism, hepatotoxicity, biomarkers and therapeutic interventions: a perspective.

Publications

Paracetamol metabolism, hepatotoxicity, biomarkers and therapeutic interventions: a perspective.

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