Acetaminophen Toxicity in Isolated Hepatocytes

  • D. S. Davies
  • L. B. G. Tee
  • C. Hampden
  • A. R. Boobis
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 197)


Acetaminophen is an analgesic and antipyretic agent which is readily available and extensively used throughout the world. Therapeutic doses of up to 4g daily produce few side-effects but doses in excess of 10–15g can cause hepatic necrosis whilst larger doses are often fatal 1.


Covalent Binding Reactive Metabolite Mercapturic Acid Butyl Hydroperoxide Acetaminophen Toxicity 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    J. L. Davidson, and W. N. Eastham, Acute liver necrosis following overdose of paracetamol, Brit. Med. J. 2: 497–499 (1966).CrossRefGoogle Scholar
  2. 2.
    J. R. Mitchell, D. J. Jollow, W. Z. Potter, D. C. Davis, J. R. Gillette, and B. B. Brodie, Acetaminophen-induced hepatic necrosis I. Role of drug metabolism, J. Pharmacol. Exp. Ther. 187: 185–194 (1973).PubMedGoogle Scholar
  3. 3.
    J. R. Mitchell, D. J. Jollow, W. Z. Potter, J. R. Gillette, and B. B. Brodie, Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione, J. Pharmacol. Exp. Ther. 187: 211–217 (1973).PubMedGoogle Scholar
  4. 4.
    D. J. Jollow, J. R. Mithcell, W. Z. Potter, D. C. Davis, J. R. Gillette, and B. B. Brodie, Acetaminophen-induced hepatic necrosis. II. Role of covalent binding in vivo, J. Pharmacol. Exp. Ther. 187: 195–202 (1973).PubMedGoogle Scholar
  5. 5.
    D. J. Jollow, S. S. Thorgeirsson, W. Z. Potter, M. Hashimoto, and J. R. Mitchell, Acetaminophen-induced hepatic necrosis. VI. Metabolism disposition of toxic and nontoxic doses of acetaminophen, Pharmacology 12: 251–271 (1974).PubMedCrossRefGoogle Scholar
  6. 6.
    W. Z. Potter, S. S. Thorgeirsson, D. J. Jollow, and J. R. Mitchell, Acetaminophen-induced hepatic necrosis. V. Correlation of hepatic necrosis, covalent binding and glutathione depletion in hamsters. Pharmacology 12: 129–143 (1974).PubMedCrossRefGoogle Scholar
  7. 7.
    D. J. Miner, and P. T. Kissinger, Evidence for the involvement of N-acetyl-p-quinoneimine in acetaminophen metabolism, Biochem. Pharmcol. 28: 3285–3291 (1979).CrossRefGoogle Scholar
  8. 8.
    I. A. Blair, A. R. Boobis, D. S. Davies, and T. M. Cresp, Paracetamol oxidation: synthesis and reactivity of N-acetyl-p-benzoquinoneimine, Tetrahedron Lett. 21: 4947–4950 (1980).CrossRefGoogle Scholar
  9. 9.
    J. A. Hinson, L. R. Pohl, and J. R. Gillette, N-Hydroxyacetaminophen: a microsomal metabolite of N-hydroxyphenacetin but apparently not of acetaminophen, Life Sci. 24: 2133–2138 (1979).PubMedCrossRefGoogle Scholar
  10. 10.
    D. C. Dahlin, G. T. Miwa, A. Y. H. Lu, and S. D. Nelson, N-Acetyl-p-benzoquinoneimine: A cytochrome P-450-mediated oxidation product of acetaminophen. Proc. Natl. Acad. Sci. USA 81: 1327–1331 (1984).PubMedCrossRefGoogle Scholar
  11. 11.
    D. S. Davies, Drug hepatotoxicity: formation and importance of reactive metabolites, in: “Drug Reactions and the liver”, M. Davis, J. M. Tredger, and R. Williams, eds, Pitman Medical, London, (1981).Google Scholar
  12. 12.
    A. C. Huggett, The Mechanism of Paracetamol Toxicity, PhD Thesis, University of London.Google Scholar
  13. 13.
    G. Bellomo, H. Thor, and S. Orrenius, Increase in cytosolic Ca2+ concentration during t-butyl hydroperoxide metabolism by isolated hepatocytes involves NADPH oxidation and mobilization of intracellular Ca2+ stores, FEBS Letts 168: 38–42 (1984).CrossRefGoogle Scholar
  14. 14.
    S. A. Jewell, G. Bellomo, H. Thor, S. Orrenius, and M. T. Smith, Bleb formation in hepatocytes during drug metabolism is caused by disturbances in thiol and calcium ion homeostasis, Science 217: 1257–1259 (1982).PubMedCrossRefGoogle Scholar
  15. 15.
    L. B. G. Tee, A. R. Boobis, A. C. Huggett, and D. S. Davies, Reversal of paracetamol toxicity in isolated hepatocytes by dithiothreitol, (Submitted for publication 1985 ).Google Scholar
  16. 16.
    L. F. Prescott, Glutathione: a protective mechanism against hepatotoxicity, Biochem, Soc. Trans. 10: 84–85 (1982).Google Scholar
  17. 17.
    S. Kashiwamata, and D. M. Greenberg, Studies on cystathionine synthase of rat liver properties of the highly purified enzyme, Biochim. et Biophys. acta 212: 488–500 (1979).Google Scholar
  18. 18.
    D. Deme, 0. Durieu-Trautmann, and F. Chatagner, The thiol groups of rat liver cystathionas: Influence of pyridoxal phosphate,l-homoserine and l-alanine on the effect of p-chloromercuribenzoate and 5,5’-Dithiobis-(2-nitrobenzoate) on the enzyme, Eur. J. Biochem. 20: 269–274 (1971).Google Scholar
  19. 19.
    G. F. Seeling, and A. Meister, a-Glutamylcysteine synthetase. Interactions of an essential sulfhydryl group. J. Biol. Chem. 259: 3534–3538 (1984).Google Scholar
  20. 20.
    L. B. G. Tee, T. Seddon, A. R. Boobis, and D. S. Davies, Drug metabolising activity of freshly isolated human hepatocytes, Brit. J. Clin. Pharmac. 19: 279–294 (1985).Google Scholar

Copyright information

© Plenum Press, New York 1986

Authors and Affiliations

  • D. S. Davies
    • 1
  • L. B. G. Tee
    • 1
  • C. Hampden
    • 1
  • A. R. Boobis
    • 1
  1. 1.Department of Clinical PharmacologyRoyal Postgraduate Medical SchoolLondon W12UK

Personalised recommendations