Advertisement

Cross-Linking of Protein Molecules by the Reactive Metabolite of Acetaminophen, N-Acetyl-p-Benzoquinone Imine, and Related Quinoid Compounds

  • Anthony J. Streeter
  • Peter J. Harvison
  • Sidney D. Nelson
  • Thomas A. Baillie
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 197)

Abstract

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.

Keywords

Covalent Binding Hepatic Necrosis Disulfide Bond Formation Bovine Serum Albumin Molecule Quinone Imine 
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.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Andersson, L.-O., 1966, The heterogeneity of bovine serum albumin, Biochim. Biophys. Acta, 117: 115.PubMedCrossRefGoogle Scholar
  2. Boyd, E. M., and Bereczky, G. M., 1966, Liver necrosis from paracetamol, Br. J. Pharmacol. Chemother., 26: 606.PubMedGoogle Scholar
  3. Brown, J. R., 1976, Structural origins of mammalian albumin, Fed. Proc., 35: 2141.PubMedGoogle Scholar
  4. Dahlin, D. C., Miwa, G. T., Lu, A. Y. H., and Nelson, S. D., 1984, N-Acetyl-j-benzoquinone imine: a cytochrome P-450 mediated oxida-tion product of acetaminophen, Proc. Natl. Acad. Sci.U.S.A., 81: 1327.PubMedCrossRefGoogle Scholar
  5. Dahlin, D. C., and Nelson, S. D., 1982, Synthesis, decomposition kinetics, and preliminary toxicological studies of pure N-acetyl-p-benzoquinone imine, a proposed toxic metabolite of acetaminophen, J. Med.Chem., 25: 885.PubMedCrossRefGoogle Scholar
  6. Devalia, J. L., Ogilvie, R. C., and McLean, A. E. M., 1982, Dissociation of cell death from covalent binding of paracetamol by flavones in a hepatocyte system, Biochem. Pharmacol., 31: 3745.PubMedCrossRefGoogle Scholar
  7. 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
  8. 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
  9. Gerber, J. G., MacDonald, J. S., Harbison, R. D.,Villeneuve, J.-P.,Wood, A. J. J., and Nies, A. S., 1977, Effect of N-acetylcysteine on hepatic covalent binding of paracetamol (acetaminophen), Lancet, 1: 657.PubMedCrossRefGoogle Scholar
  10. Hoffmann, K.-J., Streeter, A. J., Axworthy, D. B., and Baillie, T. A., 1985a, Structural characterization of the major covalent adduct formed in vitro between acetaminophen and bovine serum albumin, Chem.-Biol. Interact., 53: 155.PubMedCrossRefGoogle Scholar
  11. Hoffmann, K.-J., Streeter, A. J., Axworthy, D. B., and Baillie, T. A., 1985b, Identification of the major covalent adduct formed in vitro and in vivo between acetaminophen and mouse liver proteins, Mol. Pharmacol., 27: 566.PubMedGoogle Scholar
  12. Huggett, A., and Blair, I. A., 1983, The mechanism of paracetamol-induced hepatotoxicity: implications for therapy, Human Toxicol., 2: 399.CrossRefGoogle Scholar
  13. Labadarios, D., Davis, M., Portmann, B., and Williams, R., 1977, Paracetamol-induced hepatic necrosis in the mouse: relationship between covalent binding, hepatic glutathione depletion, and the protective effect of a-mercaptopropionylglycine, Biochem. Pharmacol., 26: 31.PubMedCrossRefGoogle Scholar
  14. Lowry, O. H., Rosebrough, N. J., Farr, A. L., and Randall, R. J., 1951, Protein measurement with the Folin phenol reagent, J. Biol. Chem., 193: 265.PubMedGoogle Scholar
  15. 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
  16. 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
  17. Pedersen, K. O., 1962, Exclusion chromatography, Arch.Biochem. Biophys.,suppl. 1: 157.Google Scholar
  18. 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
  19. Prescott, L. F., Wright, N., Roscoe, P., and Brown, S. S., 1971, Plasma paracetamol half-life and hepatic necrosis in patients with paracetamol overdosage, Lancet, 1: 519.PubMedCrossRefGoogle Scholar
  20. Roberts, S. A., and Jollow, D. J., 1978, Acetaminophen structure-toxicity relationships: why is 3-hydroxyacetanilide not hepatotoxic?, Pharmacologist, 20: 259.Google Scholar
  21. 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
  22. 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
  23. 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
  24. 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
  25. Streeter, A. J., Bjorge, S. M., Axworthy, D. B., Nelson, S. D., and Baillie, T. A., 1984a, The microsomal metabolism and site of covalent binding to protein of 3’-hydroxyacetanilide, a nonhepatotoxic positional isomer of acetaminophen, Drug Metab. Dispos., 12: 565.PubMedGoogle Scholar
  26. Streeter, A. J., Dahlin, D. C., Nelson, S. D., and Baillie, T. A., 1984b, The covalent binding of acetaminophen to protein. Evidence for cysteine residues as major sites of arylation in vitro, Chem.-Biol. Interact., 48: 349.PubMedCrossRefGoogle Scholar
  27. Wunderer, H., 1972, Darstellung und Eigenschaften von Jodamino-p-benzochinonen, Chem. Ber., 105: 3479.CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1986

Authors and Affiliations

  • Anthony J. Streeter
    • 1
  • Peter J. Harvison
    • 1
  • Sidney D. Nelson
    • 1
  • Thomas A. Baillie
    • 1
  1. 1.Department of Medicinal ChemistryBG-20 University of WashingtonSeattleUSA

Personalised recommendations