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.
KeywordsCovalent Binding Hepatic Necrosis Disulfide Bond Formation Bovine Serum Albumin Molecule Quinone Imine
Unable to display preview. Download preview PDF.
- Eyer, P., Lierheimer, E., and Strosar, M., 1983, Site and mechanism of covalent binding of 4-dimethylaminophenol to human hemoglobin, and its implications to the functional properties, Mol.Pharmacol., 23: 282.Google Scholar
- Fernando, C. R., Calder, I. C., and Ham, K. N., 1980, Studies on the mechanism of toxicity of acetaminophen: synthesis and reactions of N-acetyl-2,6-dimethyl-and N-acetyl-3,5-dimethyl-p-benzoquinone imines, J. Med. Chem., 23: 1153.Google Scholar
- Mitchell, J. R., Potter, W. Z., Hinson, J. A., Snodgrass, W. R., Timbrell, J. A., and Gillette, J. R., 1975, Toxic drug reactions, in: Concepts in Biochemical Pharmacology, Vol. XXVIII/3, J. R. Gillette and J. R. Mitchell, eds., Springer, New York, p. 383.Google Scholar
- Nelson, E. B., 1980, The Pharmacology and toxicology of meta-substituted acetanilide. I. Acute toxicity of 3-hydroxyacetanilide in mice, Res. Commun. Chem.Path. Pharmacol., 28: 447.Google Scholar
- Pedersen, K. O., 1962, Exclusion chromatography, Arch.Biochem. Biophys.,suppl. 1: 157.Google Scholar
- Potter, W. Z., Thorgeirsson, S. S., Jollow, D. J., and Mitchell, J. R., 1974, Acetaminophen-induced hepatic necrosis. V. Correlation of hepatic necrosis, covalent binding and glutathione depletion in hamsters, Pharmawîugy, 12: 123.Google Scholar
- Roberts, S. A., and Jollow, D. J., 1978, Acetaminophen structure-toxicity relationships: why is 3-hydroxyacetanilide not hepatotoxic?, Pharmacologist, 20: 259.Google Scholar
- Roberts, S. A., and Jollow, D. J., 1979, Acetaminophen structure-toxicity studies: In vivo covalent binding of a non-hepatotoxic analog, 3-hydroxyacetanilide, Fed. Proc., 38: 426.Google Scholar
- Rosen, G. M., Rauckman, E. J., Ellington, S. P., Dahlin, D. C., Christie, J. L., and Nelson, S. D., 1984, Reduction and glutathione conjugation reactions of N-acetyl-benzoquinone imine and two dimethylated analogues, Mol. Pharmacol., 25: 151.Google Scholar
- Rotman, A., Daly, J. W., and Creveling, C. R., 1976, Oxygen-dependent reaction of 6-hydroxydopamine, 5,6-dihydroxytryptamine, and related compounds with proteins in vitro: A model for cytotoxicity, Mol. Pharmacol., 12: 887.Google Scholar
- Streeter, A. J., and Baillie, T. A., 1985, 2-Acetamido-k-benzoquinone: a reactive arylating metabolite of 3’-hydroxyacetanilide, Biochem. Pharmacol., in press.Google Scholar