Cross-linking of protein molecules by the reactive metabolite of acetaminophen, N-acetyl-p-benzoquinone imine, and related quinoid compounds.

Acetaminophen (4’-hydroxyacetanilide; 4HAA; Fig. 1) is a widely used analgesic and antipyretic agent which, while considered to be safe at therapeutic dose levels, has been found to cause acute hepatic centrilobular necrosis in both humans and experimental animals when consumed in large doses (Prescott et al., 1971; Boyd and Bereczky, 1966). Evidence from a variety of animal studies (Mitchell et al., 1975; Dahlin et al., 1984) has indicated that cytochrome P-450 plays an important role in the oxidation of acetaminophen to a chemically-reactive and potentially toxic electrophilic metabolite, N-acetyl-p-benzoquinone imine (NAPQI; Fig. 1), which binds covalently to hepatic protein. Recently, we have shown that the major covalent adduct formed between 4HAA and proteins is a 3’-cystein-S-yl conjugate of the drug (Streeter et al., 1984b; Hoffmann et al., 1985a,b). This finding supports the contention that 4HAA is first metabolized to NAPQI, which then arylates proteins by selective reaction with cysteinyl thiol residues.