Comparative Activation of Paracetamol in the Rat, Mouse and Man

  • C. E. Seddon
  • A. R. Bobois
  • D. S. Davies
Conference paper
Part of the Archives of Toxicology, Supplement book series (TOXICOLOGY, volume 11)

Abstract

The minor analgesic paracetamol is relatively non-toxic at normal therapeutic doses. In overdose it is hepatotoxic in a number of species, including man, due to its conversion to a highly reactive intermediate, N-acetyl-p-benzoquinoneimine (NABQI), by the hepatic mixed function oxidase system (reviewed in Prescott 1983). There are marked differences in susceptibility to the hepato toxicity of paracetamol, both within and between species (Davis et al. 1974). The causes of this variation are largely attributable to differences in the extent to which paracetamol is converted to NABQI, i.e. to differences in the activity of cytochrome P450 (Davis et al. 1974; Green et al. 1984). However, the factors responsible for regulating the forms of cytochrome P450 involved in this reaction have yet to be identified. Certainly, environmental factors play some role. For example, chronic ingestion of ethanol alters the activation and hence the toxicity of paracetamol in laboratory animals (Peterson 1983) and possibly in man (Prescott 1983). The extent to which genetic factors contribute to interindividual differences in this reaction is still far from clear. The present study was conducted to investigate some of the possible causes of inter- and intraspecies differences in paracetamol activation and also to attempt to identify the specific forms of cytochrome P450 involved.

Keywords

Adduct Histamine Cane Aniline Cimetidine 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Boobis AR, Brodie MJ, Khan GC, Fletcher DR, Saunders JH, Davies DS (1980) Monooxygenase activity of human liver in microsomal fractions of needle biopsy specimens. Br J Clin Pharmacol 9:11–19PubMedGoogle Scholar
  2. Boobis AR, Tee LBG, Hampden CE, Davies DS (1986) Freshly isolated hepatocytes as a model in which to study the toxicity of paracetamol. Food Chem Toxicol 24:731–736PubMedCrossRefGoogle Scholar
  3. Davis DC, Potter WZ, Jollow DJ, Mitchell JR (1974) Species differences in hepatic glutathione depletion, covalent binding and hepatic necrosis after acetaminophen. Life Sci 14:2099–2109PubMedCrossRefGoogle Scholar
  4. Green CE, Dabbs JE, Tyson CA (1984) Metabolism and cytotoxicity of acetaminophen in hepatocytes isolated from resistant and susceptible species. Toxicol Appl Pharmacol 76:139–149PubMedCrossRefGoogle Scholar
  5. Mitchell MC, Schenker S, Speeg KV (1984) Selective inhibition of acetaminophen oxidation and toxicity by cimetidine and other histamine H2-receptor antagonists in vivo and in vitro in the rat and in man. J Clin Invest 73:383–391PubMedCrossRefGoogle Scholar
  6. Morgan ET, Koop DR, Coon MJ (1983) Comparison of six rabbit liver cytochrome P-450 isozymes in formation of a reactive metabolite of acetaminophen. Biochem Biophys Res Commun 112:8–13PubMedCrossRefGoogle Scholar
  7. Peterson FJ, Holloway DE, Erickson RR, Duquette PH, McClain CJ, Holtzman JL (1980) Ethanol induction of acetaminophen toxicity and metabolism. Life Sci 27:1701–1711Google Scholar
  8. Prescott LF (1983) Paracetamol overdosage. Pharmacological considerations and clinical management. Drugs 25:290–314PubMedCrossRefGoogle Scholar
  9. Rudd GD, Donn KH, Grisham JW (1980) Prevention of acetaminophen-induced necrosis by cimetidine in mice. Res Commun Chem Pathol Pharmacol 32:369–372Google Scholar
  10. Ryan DE, Koop DR, Thomas PE, Coon MJ, Levin W (1986) Evidence that isoniazid and ethanol induce the same microsomal cytochrome P-450 in rat liver, an isozyme homologous to rabbit liver cytochrome P-450 isozyme 3a. Arch Biochem Biophys 246:633–644PubMedCrossRefGoogle Scholar
  11. Sesardic D, Boobis AR, McQuade J, Baker S, Lock EA, Elcombe CR, Robson RT, Hayward C, Davies DS (1986) Inter-relatedness of some isozymes of cytochrome P-450 from rat, rabbit and human determined with monoclonal antibodies. Biochem J 236:569–577PubMedGoogle Scholar
  12. Tee LBG, Davies DS, Seddon CE, Boobis AR (1986) Species differences in the hepatotoxicity of paracetamol are due to differences in the rate of conversion to its cytotoxic metabolite. Biochem Pharmacol 36:1041–1052CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 1987

Authors and Affiliations

  • C. E. Seddon
    • 1
  • A. R. Bobois
    • 1
  • D. S. Davies
    • 1
  1. 1.Department of Clinical PharmacologyRoyal Postgraduate Medical SchoolLondonUK

Personalised recommendations