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Selective Binding of Acetaminophen (APAP) to Liver Proteins in Mice and Men

  • Raymond B. Birge
  • John B. Bartolone
  • Charles A. Tyson
  • Susan G. Emeigh Hart
  • Steven D. Cohen
  • Edward A. Khairallah
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 283)

Abstract

Acetaminophen (N-acetyl-p-aminophenol, APAP) toxicity is dependent upon APAP activation by cytochrome P450 to a metabolite which binds covalently to macromolecules as cellular glutathione becomes depleted (Potter, et al., 1973; Mitchell, et al., 1973; Jollow, et al., 1973; Dahlin, et al., 1984). Studies with an affinity purified anti-APAP antibody have demonstrated that, in mice, the covalent binding is not random, but is highly selective, and that binding to cytosolic protein(s) of approximately 58kD was most closely associated with APAP toxicity (Bartolone, et al., 1987; 1988; 1989a; Birge, et al., 1988; 1989; Beierschmitt, et al., 1989). While human liver has been demonstrated to activate APAP in vitro (Dybing, 1977), covalent binding has not been demonstrated during human APAP poisoning. The present study demonstrates for the first time that a similar, selective arylation of proteins also occurs in humans during APAP hepatotoxicity.

Keywords

Human Liver Covalent Binding Liver Protein Benzoquinone Imine APAP Hepatotoxicity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Raymond B. Birge
    • 1
    • 2
  • John B. Bartolone
    • 2
  • Charles A. Tyson
    • 3
    • 4
  • Susan G. Emeigh Hart
    • 1
    • 3
    • 4
  • Steven D. Cohen
    • 1
  • Edward A. Khairallah
    • 2
  1. 1.Toxicology Program; Departments of Pharmacology and ToxicologyUniversity of ConnecticutStorrsUSA
  2. 2.Toxicology Program; Departments of Molecular and Cell BiologyUniversity of ConnecticutStorrsUSA
  3. 3.Toxicology Program; Departments of PathobiologyUniversity of ConnecticutStorrsUSA
  4. 4.SRI InternationalMenlo ParkUSA

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