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Post-Treatment Protection with Piperonyl Butoxide Against Acetaminophen Hepatotoxicity is Associated with Changes in Selective but Not Total Covalent Binding

  • Joseph T. Brady
  • Raymond B. Birge
  • Edward A. Khairallah
  • Steven D. Cohen
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 283)

Abstract

Acetaminophen (APAP) induced hepatic centrilobular necrosis has been associated with cytochrome P-450-mediated generation of an electrophilic, reactive metabolite which covalently binds to cellular macromolecules as glutathione becomes depleted (Jollow, et al., 1973; Mitchell, et al., 1973a; 1973b; Potter, et al., 1973; 1974). Covalent binding has been well-correlated with the incidence and severity of liver necrosis and prior cytochrome P450 inhibition blocks both covalent binding and the atotoxicity (Jollow, et al., 1973; Potter, et al., 1973, 1974; Mitchell, et al., 1973a). In addition, administration of the cytochrome P-450 inhibitor, piperonyl butoxide (Pip B), 2 hrs after APAP, the time of maximal covalent binding (Jollow,et al., 1973, Ginsberg and Cohen, 1985) reduced the severity of liver damage (Brady, et al., 1988). The present study demonstrates that Pip B’s post-treatment protection is associated with alterations in selective protein arylation by APAP without a change in total covalent binding.

Keywords

Covalent Binding Reactive Metabolite Piperonyl Butoxide Benzoquinone Imine Acetaminophen Hepatotoxicity 
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.

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References

  1. Bartolone, J.B., Sparks, K., Cohen, S.D. and Khairallah, E.A. (1987). Immunochemical detection of acetaminophen bound liver proteins. Biochem. Pharmacol. 36, 1193–1196.CrossRefPubMedGoogle Scholar
  2. Bartolone, J.B., Birge, R.B., Sparks, K., Cohen, S.D. and Khairallah, E.A. (1988). Immunochemical analysis of acetaminophen covalent binding to proteins: Partial characterization of the major acetaminophen-binding liver proteins. Biochem. Pharmacol. 37, 4763–4774.CrossRefPubMedGoogle Scholar
  3. Bartolone, J.B., Beierschmitt, W.P., Birge, R.B., Emeigh, Hart, S.G., Wyand, D.S., Cohen, S.D. and Khairallah, E.A. (1989). Selective acetaminophen metabolite binding to extrahepatic proteins: An in vivo and in vitro analysis. Toxicol. Appl. Pharmacol. 99, 240–249.Google Scholar
  4. Beierschmitt, W.P., Brady, J.T., Bartolone, J.B., Wyand, D.S., Khairallah, E.A. and Cohen, S.D. (1989). Selective protein arylation and the age-dependency of acetaminophen hepatotoxicity in mice. Toxicol. Appl. Pharmacol. 98, 517–529.CrossRefPubMedGoogle Scholar
  5. Birge, R.B., Bartolone, J.B., McCann, D.J., Mangold, J.B., Cohen, S.D. and Khairallah, E.A. (1989). Selective protein arylation and 2,6-dimethyl acetaminophen in cultured mouse hepatocytes from phenobarbital-induced and uninduced mice: relationship to cytotoxicity. Biochem. Pharmacol. 31, 3745–3749.Google Scholar
  6. Birge, R.B., Bartolone, J.B., Nishanian, E.V., Bruno, M.K., Mangold, J.B., Cohen, S.D. and Khairallah, E.A. (1988). Dissociation of covalent binding from the oxidative effects of acetaminophen: studies using dimethylated acetaminophen derivatives. Biochem. Pharmacol. 38, 4429–4439.CrossRefGoogle Scholar
  7. Brady, J.T., Montelius, D.A., Beierschmitt, W.P., Wyand, D.S., Khairallah, E.A. and Cohen, S.D. (1988). The effect of piperonyl butoxide post-treatment on acetaminophen hepatotoxicity. Biochem. Pharmacol. 37, 2097–2099.Google Scholar
  8. Dahlin, D.C., Miwa, G.T., Lu, A.Y.H. and Nelson, S.D. (1984). N-acetyl-pbenzoquinone imine: a cytochrome P-450-mediated oxidation product of acetaminophen. Proc. Nat. Acad. Sci. 81, 1327–1331.Google Scholar
  9. Gillette, J.R. (1974). A perspective on the role of chemically reactive metabolites of foreign compounds in toxicity: I. Correlation of changes in covalent binding of reactive metabolites with changes in the incidence and severity of toxicity. Biochem. Pharmacol. 23 2785–2794.CrossRefPubMedGoogle Scholar
  10. Ginsberg, G.L. and Cohen,.SD. (1985). Plasma membrane alterations andcovalent binding to hepatic organelles after an hepatotoxicdose of acetaminophen (APAP). The Toxicologist 5, 154.Google Scholar
  11. Jollow, D.J., Mitchell, J.R., Potter, W.Z., Davis, D.C., Gillette, J.R. and Brodie, B.B. (1973). Acetaminophen-induced hepatic necrosis. II. Role of covalent binding in vivo. J. Pharmacol. Exp. Ther. 187, 185–194.Google Scholar
  12. Mitchell, J.R., Jollow, D.J., Potter, W.Z., Davis, D.C., Gillette, J.R., and Brodie, B.B. (1973a). Acetaminophen-induced hepatic necrosis. I. Role of drug metabolism. J. Pharmacol. Exp. Therap. 187, 185–194.Google Scholar
  13. Mitchell, J.R., Jollow, D.J., Potter, W.Z., Gillette, J.R. and Brodie, B.B. (1973b). Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione. J. Pharmacol. Exper. Therap. 187, 211–217.Google Scholar
  14. Placke, M.E., Wyand, D.S. and Cohen, S.D. (1987). Extrahepatic lesions induced by acetaminophen in the mouse. Toxicologic Pathol. 15, 381–387.CrossRefGoogle Scholar
  15. Potter, W.Z., Davis, D.C., Mitchell, J.R., Jollow, D.J., Gillette, J.R. and Brodie, B.B. (1973). Acetaminophen-induced hepatic necrosis. III. Cytochrome-P450 mediated covalent binding in vitro. J. Pharmacol. Exp. Ther. 187, 203–210.Google Scholar
  16. 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. Pharmacol. 12, 129–143.CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Joseph T. Brady
    • 1
  • Raymond B. Birge
    • 1
    • 2
  • Edward A. Khairallah
    • 2
  • Steven D. Cohen
    • 1
  1. 1.Toxicology Program: Departments of Pharmacology & ToxicologyUniversity of ConnecticutStorrsUSA
  2. 2.Toxicology Program: Departments of Molecular and Cell BiologyUniversity of ConnecticutStorrsUSA

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