RT Journal Article
SR Electronic
T1 Identification of the major covalent adduct formed in vitro and in vivo between acetaminophen and mouse liver proteins.
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 566
OP 573
VO 27
IS 5
A1 K J Hoffmann
A1 A J Streeter
A1 D B Axworthy
A1 T A Baillie
YR 1985
UL http://molpharm.aspetjournals.org/content/27/5/566.abstract
AB 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.