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Identification of the major covalent adduct formed in vitro and in vivo between acetaminophen and mouse liver proteins

KJ Hoffmann, AJ Streeter, DB Axworthy and TA Baillie

Improved analytical methodology has been developed for the structural characterization of covalently bound drug-protein adducts and has been applied to an investigation of the conjugates formed in vivo and in vitro between [14C]acetaminophen and mouse liver proteins. The major adduct released by acid hydrolysis of hepatic protein samples, which accounted for approximately 70% of the bound radioactivity in vivo and in vitro, was identified as 3-cystein-S-yl-4-hydroxyaniline, a derivative whose structure reflects the predominance of acetaminophen thioether adducts in drug-modified proteins. It is concluded that the reactive, electrophilic metabolite of acetaminophen, which most likely is N-acetyl-p-benzoquinoneimine, binds with a high degree of selectivity to cysteinyl thiol groups on protein, formally in a Michael- type addition reaction. Cysteine residues thus represent primary target sites for arylation by the reactive metabolite of acetaminophen, and proteins rich in free thiols may be especially vulnerable to damage by this toxic intermediate.

Volume 27, Issue 5, pp. 566-573, 05/01/1985
Copyright © 1985 by American Society for Pharmacology and Experimental Therapeutics




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Copyright © 1985 by the American Society for Pharmacology and Experimental Therapeutics