NAPQI imine

NAP Neutrophil-activating peptide NAPQI N-acetyl-p-benzoquinone imine... 

Figure 7.19 Proposed metabolic activation of paracetamol to a toxic, reactive intermediate /V-acetyl-p-benzoquinone imine (NAPQI). This can react with glutathione (GSH) to form a conjugate or with tissue proteins. Alternatively, NAPQI can be reduced back to paracetamol by glutathione, forming oxidized glutathione (GSSG).

Figure 18.8. Structures of acetaminophen and N-accty l-/ -bcnzoquinone imine (NAPQI) metabolites and GSH defense.

AAPCC-TESS American Association of Poison Control Centers-Toxic Exposure Surveillance System ALT Alanine aminotransferase ARDS Adult respiratory distress syndrome AST Aspartate aminotransferase BUN Blood urea nitrogen ECG Electrocardiogram INR International normalization ratio NAPQI A-acetyl-/>-benzoquinone-imine PPPA Poison Prevention Packaging Act (of 1970)... 

ALT alanine aminotransferase AST aspartate aminotransferase CYP cytochrome P450 liver enzyme system NAPQI V-acetyl-p-benzoquinone imine NAT2 N-acetyltransferase 2 genotype... 

NAPQI A-acetyl -/7-benzoq ui n on e imine. nephron functional unit of the kidney. 

SCHEME 11.9 Bioactivation of acetaminophen to form a reactive A-acetyl-p-benzoquinone imine (NAPQI) and trapping of the electrophilic intermediate by GSH. 

Acetaminophen (APAP, N-acetyl-p-aminophenol, paracetamol) is a widely used over-the-counter analgesic. At erapeutic doses it is a safe drug. However, at high doses it may produce severe hepatic necrosis and has also been reported in some individuals to be nephrotoxic (1-3). Available evidence indicates that acetaminophen hepatotoxicity is not a result of the parent compound but is mediated by a reactive metabolite N-acetyl-g-benzoquinone imine (NAPQI). This metabolite is the two-electron oxidation product of acetaminophen and is formed by the microsomal cytochrome P-450 mixed function oxidase system (4-8). Following a therapeutic dose of acetaminophen the reactive metabolite is detoxified Current address National Institutes of Health, Bethesda, MD 20892 Current address Rohm and Haas Company, Spring House, PA 19477... 

Immunologic techniques were used to study acetaminophen toxicity in mice to elucidate mechanisms of liver toxicity. The hepatotoxicity of acetaminophen is mediated by a reactive metabolite, N-acetyl-p-ben-zoquinone imine (NAPQI). The metabolite binds to protein as 3-(cystein-S-yl)acetaminophen (3-Cys-A) and the amount of binding correlates with toxicity. This covalent binding, and in particular the 3-Cys-A adduct, is the most reliable biomarker of acetaminophen toxicity (9-12). 

However, in a pharmacokinetic study in 10 healthy subjects of both slow and fast acetylator status, isoniazid 300 mg daily for 7 days modestly decreased the total clearance of a single 500-mg dose of paracetamol by 15%. Moreover, the clearance of paracetamol to oxidative metabolites was decreased Similarly, in a further study in 10 healthy slow acetylators of isoniazid, the formation of paracetamol thioether metabolites and oxidative metabolites was reduced by 63% and 49%, respectively, by isoniazid 300 mg daily. However, one day after stopping isoniazid, the formation of thioether metabolites was increased by 56%, and this returned to pretreatment values 3 days after the discontinuation of isoniazid. In yet another study in 10 healthy subjects taking isoniazid prophylaxis, the formation clearance of paracetamol to A -acetyl-p-benzo-quinone imine (NAPQI) was inhibited by 56% when the paracetamol was given simultaneously with the daily isoniazid dose, but when the paracetamol was taken 12 hours after the isoniazid, there was no difference in NAPQI formation clearance, compared with the control phase (1 to 2 weeks after isoniazid had been discontinued). However, when the results were analysed by acetylator status, it appeared that the NAPQI formation clearance was increased in fast acetylators taking paracetamol 12 hours after the isoniazid dose. ... 

The metabolite to paracetamol ratio for glucuronides was twice as high in 10 patients treated with rifampicin 600 mg daily than in 14 healthy control subjects. In contrast the ratio for sulfates did not differ between the two groups. In a crossover study in healthy subjects, rifampicin 600 mg daily for 1 week, given before paracetamol 500 mg, had no effect on the formation of V-acetyl-p-benzoquinone imine (NAPQI) or the recovery of thiol... 

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