High resolution NMR spectroscopic studies on the metabolism and futile deacetylation of 4-hydroxyacetanilide (paracetamol) in the rat

Aw, Nicholls; Caddick, Stephen; Wilson, Ian D.; Rd, Farrant; Lindon, John C.; Nicholson, Jeremy K.

doi:10.1016/0006-2952(95)98513-9

Cited by 33 publications

(14 citation statements)

References 19 publications

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“…In explorations of the mechanism of acetaminophen renal toxicity, deacetylation of acetaminophen to p‐aminophenol was demonstrated in the mouse kidney 57 . Subsequently, acetaminophen has been shown to undergo deacetylation to p‐aminophenol followed by reacetylation back to acetaminophen, a “futile deacetylation” that confounds attempts to measure the extent of conversion of acetaminophen to p‐aminophenol unless appropriate steps are taken to account for the futile deacetylation pathway 58 . Thus it is of interest that acetaminophen is quite potent as an inhibitor of renal PGHS 59 .…”

Section: Mechanism Of Action Of Acetaminophenmentioning

confidence: 61%

“…57 Subsequently, acetaminophen has been shown to undergo deacetylation to p-aminophenol followed by reacetylation back to acetaminophen, a "futile deacetylation" that confounds attempts to measure the extent of conversion of acetaminophen to p-aminophenol unless appropriate steps are taken to account for the futile deacetylation pathway. 58 Thus it is of interest that acetaminophen is quite potent as an inhibitor of renal PGHS. 59 Furthermore, inhibition of acetaminophen deacetylation reduces the nephrotoxicity caused by acetaminophen but not that resulting from p-aminophenol, suggesting an important role of this metabolic pathway in nephrotoxicity.…”

Section: Possible Role For Metabolites Of Acetaminophenmentioning

confidence: 99%

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New insights into the mechanism of action of acetaminophen: Its clinical pharmacologic characteristics reflect its inhibition of the two prostaglandin H2 synthases

Aronoff

Oates

Boutaud

2006

Clinical Pharmacology & Therapeutics

187

135

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Section: Mechanism Of Action Of Acetaminophenmentioning

confidence: 61%

Section: Possible Role For Metabolites Of Acetaminophenmentioning

confidence: 99%

New insights into the mechanism of action of acetaminophen: Its clinical pharmacologic characteristics reflect its inhibition of the two prostaglandin H2 synthases

Aronoff

Oates

Boutaud

2006

Clinical Pharmacology & Therapeutics

187

135

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“…The best known of these is a product of further epoxidation, namely 7,8-dihydrodiol 9,10-epoxide (see next Figure), also a substrate of epoxide hydrolase to form a so-called tetrol [209]. Indeed, 5.153 also undergoes futile cycling by deacetylation to p-aminophenol (5.164), followed by NAT-catalyzed re-acetylation [239] (see also Part 3 [2] [4]), a reaction of low quantitative significance in humans. Dihydrodiols can be oxidized by dihydrodiol dehydrogenases (AKR1A1, 1C1 to 1C4; see Part 2 [1] [4]) to catechols, followed by autoxidation or peroxidase-catalyzed oxidation to orthoquinones [211 -213].…”

Section: Fig 548mentioning

confidence: 99%

ChemInform Abstract: The Biochemistry of Drug Metabolism — An Introduction. Part 5. Metabolism and Bioactivity

Testa

Kraemer

2009

ChemInform

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The Part 5 of our biochemical introduction to drug metabolism presents the pharmacological and toxicological consequences of drug and xenobiotic metabolism. As we have already shown [1 -5] and discuss here with specific focus, the consequences of the biotransformation of foreign compounds explain to a large extent the immense significance this discipline has acquired. When it comes to drug metabolism, its consequences are of utmost relevance in fields such as drug discovery and development, clinical pharmacology and toxicology, and therapeutics. The same relevance is now recognized to xenobiotic metabolism in, e.g., agrochemistry and food chemistry, industrial hygiene, workplace safety, and environmental welfare.Presenting the pharmacological and toxicological consequences of drug and xenobiotic metabolism can be achieved by focusing on rules and general principles, with a high risk of remaining abstract and failing to impress readers. Or it can be done with examples only, with the consequence that readers will remember fragmental data which may not help them to generalize and reason by analogy. The didactic approach followed here is simply the middle course, whereby we start with principles and illustrate them with examples, while, at other occasions, discussing illustrative cases from which principles are then derived.

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“…Metabonomics (and the related field of metabolomics) has found widespread application in the investigation of molecular toxicology, where the site- and mechanism-specific effects of a toxin or therapeutic intervention can be investigated (Coen 2014; Coen et al 2008; Lindon et al 2005). Earlier metabonomic studies have been applied to investigate the metabolism of APAP in both in vivo models and humans (Bales et al 1984; Nicholls et al 1995; Spurway et al 1990). More recently, studies of APAP in mice reported a significant perturbation of metabolites involved in the biosynthesis of glutathione; opthalmate, 5-oxoproline and taurine (Soga et al 2006; Ghauri et al 1993), as well as numerous system-level metabolic changes that together suggested a disturbance of energy metabolism, more specifically of increased rates of glycolysis and impaired β-oxidation (Coen et al 2003, 2004).…”

Section: Introductionmentioning

confidence: 99%

Comparative metabonomic analysis of hepatotoxicity induced by acetaminophen and its less toxic meta-isomer

et al. 2016

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The leading cause of drug-induced liver injury in the developed world is overdose with N-acetyl-p-aminophenol (APAP). A comparative metabonomic approach was applied to the study of both xenobiotic and endogenous metabolic profiles reflective of in vivo exposure to APAP (300 mg/kg) and its structural isomer N-acetyl-m-aminophenol (AMAP; 300 mg/kg) in C57BL/6J mice, which was anchored with histopathology. Liver and urine samples were collected at 1 h, 3 h and 6 h post-treatment and analyzed by 1H nuclear magnetic resonance (NMR) spectroscopy and gas chromatography–mass spectrometry (liver only). Histopathology revealed the presence of centrilobular necrosis from 3 h post-APAP treatment, while an AMAP-mediated necrotic endpoint was not observed within the timescale of this study, yet two of five treated mice showed minimal centrilobular eosinophilia. The 1H-NMR xenobiotic metabolic profile of APAP-treated animals comprised of mercapturate (urine and liver) and glutathionyl (liver) conjugates detected at 1 h post-treatment. This finding corroborated the hepatic endogenous metabolic profile which showed depletion of glutathione from 1 h onwards. In contrast, AMAP glutathionyl conjugates were not detected, nor was AMAP-induced depletion of hepatic glutathione observed. APAP administration induced significant endogenous hepatic metabolic perturbations, primarily linked to oxidative and energetic stress, and perturbation of amino acid metabolism. Early depletion of glutathione was followed by depletion of additional sulfur-containing metabolites, while altered levels of mitochondrial and glycolytic metabolites indicated a disruption of energy homeostasis. In contrast, AMAP administration caused minimal, transient, distinct metabolic perturbations and by 6 h the metabolic profiles of AMAP-treated mice were indistinguishable from those of controls.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-015-1655-x) contains supplementary material, which is available to authorized users.

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High resolution NMR spectroscopic studies on the metabolism and futile deacetylation of 4-hydroxyacetanilide (paracetamol) in the rat

Cited by 33 publications

References 19 publications

New insights into the mechanism of action of acetaminophen: Its clinical pharmacologic characteristics reflect its inhibition of the two prostaglandin H2 synthases

New insights into the mechanism of action of acetaminophen: Its clinical pharmacologic characteristics reflect its inhibition of the two prostaglandin H2 synthases

ChemInform Abstract: The Biochemistry of Drug Metabolism — An Introduction. Part 5. Metabolism and Bioactivity

Comparative metabonomic analysis of hepatotoxicity induced by acetaminophen and its less toxic meta-isomer

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