Selective Binding of Acetaminophen (APAP) to Liver Proteins in Mice and Men
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.
KeywordsHuman Liver Covalent Binding Liver Protein Benzoquinone Imine APAP Hepatotoxicity
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