The Mechanism of Phenobarbitone Potentiation of Centrilobular Hepatic Necrosis

  • Martyn T. Smith
  • Eric D. Wills
Part of the Advances in Experimental Medicine and Biology book series (AEMB)

Abstract

The pre-treatment of rats with phenobarbitone markedly potentiates both the incidence and severity of the centrilobular hepatic necrosis caused by reactive intermediates of foreign compounds such as paracetamol, phenacetin and halogenated aromatic hydrocarbons (Brodie et al.,1971; Mitchell et al.,1976) These reactive intermediates are formed mainly as a result of mixed function oxidase activity, involving cytochrome P-450, and the liver is normally protected against their toxicity by reduced glutathione (GSH) (Mitchell et al.,1973). Phenobarbitone could therefore potentiate the level of centrilobular hepatic necrosis by:
  1. (a)

    selectively increasing the concentration of cytochrome P-450 and the activity of the mixed-function oxidase in the centrilobular hepatocytes, or

     
  2. (b)

    selectively lowering the concentration of GSH in the centrilobular hepatocytes.

     

Keywords

Toxic Metabolite G6PD Activity Foreign Compound Periportal Hepatocyte Periportal Region 
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. Altman, F.P., 1972, Quantitative dehydrogenase histochemistry with special reference to the pentose shunt dehydrogenases, Progr. Histochem. Cytochem., 4: 225.CrossRefGoogle Scholar
  2. Bitensky, L., 1980, Microdensitometry, in: “Trends in Enzyme Histochemistry and Cytochemistry”, Ciba Foundation Symp. 73, Excerpta Medica, Amsterdam.Google Scholar
  3. Brodie, B.B., Reid, W.D., Cho, A.K., Sipes, G., Krishna, G. and Gillette, J.R., 1971, Possible mechanism of liver necrosis caused by aromatic organic compounds, Proc. Nat. Acad. Sci., USA, 68: 160.CrossRefGoogle Scholar
  4. Chayen, J., Altman, F.P. and Butcher, R.G., 1973, The effect of certain drugs on the production and possible utilization of reducing equivalents outside the mitochondrion, in: “Fundamentals of Cell Pharmacology”, S. Dikstein, ed., Charles C. Thomas, Springfield, Illinois, U.S.A.Google Scholar
  5. Gooding, P. E., Chayen, J., Sawyer, B. and Slater, T. F., 1978, Cytochrome P-450 distribution in rat liver and the effect of sodium phenobarbitone administration, Chem. -Biol. Interact. 20: 299.PubMedCrossRefGoogle Scholar
  6. Gumucio, J. J., DeMason, L. J., Miller, D. L., Krezoski, S. O. and Keener, M., 1978, Induction of cytochrome P-450 in a selective subpopulation of hepatocytes, Am. J. Physiol., 234: C102.PubMedGoogle Scholar
  7. Mitchell, J. R.,Jollow, D.J., Potter, W. Z., Davis, D.C., Gillette, J.R. and Brodie, B. B., 1973, Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione, J.Pharmacol. exp. Ther., 187: 211.Google Scholar
  8. Mitchell, J.R., Nelson, S.D., Thorgeirsson, S. S., McMurty, R. J. and Dybing, E., 1976, Metabolic activation: Biochemical basis for many drug-induced liver injuries, Progr. Liver Dis., 5: 259.PubMedGoogle Scholar
  9. Smith, M. T., Loveridge, N., Wills, E.D. and Chayen, J., 1979, The distribution of glutathione in the rat liver lobule, Biochem. J., 182: 103.PubMedGoogle Scholar
  10. Smith, M. T. and Wills, E.D., 1980, The effect of dietary lipid on the distribution of cytochrome P-450 in rat liver, Proc. VIth Int. Congr. Histochem. Cytochem., Brighton.Google Scholar

Copyright information

© Springer Science+Business Media New York 1982

Authors and Affiliations

  • Martyn T. Smith
    • 1
  • Eric D. Wills
    • 1
  1. 1.Biochemistry DepartmentThe Medical College of St. Bartholomew’s HospitalLondonUK

Personalised recommendations