Acetaminophen and Protein Thiol Modification

  • Sidney D. Nelson
  • Mark A. Tirmenstein
  • Mohamed S. Rashed
  • Timothy G. Myers
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 283)


Acetaminophen (4′-hydroxyacetanilide, APAP) is a widely-used analgesic and antipyretic drug which, while considered to be safe at therapeutic doses, can cause acute hepatic centrilobular necrosis in both humans and experimental animals when consumed in large doses (Boyd and Bereczky, 1966; Prescott et al., 1971; for a review see Hinson, 1980). In a series of classic studies (Mitchell et al., 1973a,b; Jollow et al., 1973, 1974; Potter et al., 1973, 1974), protein thiol group arylation by a reactive quinone imine metabolite of APAP was implicated in the pathogenesis of hepatotoxicity. Indirect evidence to support the hypothesis that cysteinyl thiol groups were arylated was provided by mass spectral characterization of thioether metabolites of acetaminophen (Jollow et al., 1974; Knox and Jurand, 1977; Nelson et al., 1981), and the 3-position of the aromatic ring was determined by 1H and 13C-NMR to be the site of conjugation with glutathione (Hinson et al., 1982). A few years later (Streeter et al., 1984; Hoffman et al., 1985), cysteinyl thioether conjugates at the same position of the aromatic ring were characterized as the major protein bound residues of acetaminophen.


Glutathione Cysteine Adduct Disulfide Thiol 


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Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Sidney D. Nelson
    • 1
  • Mark A. Tirmenstein
    • 1
  • Mohamed S. Rashed
    • 1
  • Timothy G. Myers
    • 1
  1. 1.Department of Medicinal Chemistry, BG-20University of WashingtonSeattleUSA

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