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Research ArticleArticle

Immunochemical Comparison of 3′-Hydroxyacetanilide and Acetaminophen Binding in Mouse Liver

William F. Salminen Jr., Stephen M. Roberts, Neil R. Pumford and Jack A. Hinson
Drug Metabolism and Disposition March 1998, 26 (3) 267-271;
William F. Salminen Jr.
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Stephen M. Roberts
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Neil R. Pumford
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Jack A. Hinson
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Abstract

The hepatotoxicity of the analgesic acetaminophen is believed to be mediated by covalent binding to critical proteins. Radiolabeled 3′-hydroxyacetanilide, a regioisomer of acetaminophen, covalently binds to proteins at levels similar to those of acetaminophen, but without toxicity. Covalent binding has recently been detected by Western blot to a 50-kDa microsomal protein that comigrated with CYP2E1 and was accompanied by a loss of the CYP2E1 activity. However, radiolabel studies previously indicated that a significant amount of the radiolabel is lost during electrophoresis. In the present study, 3′-hydroxyacetanilide covalent binding was detected immunohistochemically in liver using an anti-acetaminophen antiserum. 3′-Hydroxyacetanilide (1000 mg/kg, ip) administration to mice resulted in panlobular immunostaining in liver, with the single layer of hepatocytes surrounding the central veins having the greatest intensity of staining. Staining was most intense at 1 hr and somewhat decreased at 3 and 6 hr. In contrast, immunochemical staining indicated that covalent binding of acetaminophen (250 mg/kg, ip) was confined to the centrilobular hepatocytes, the area of the ensuing necrosis. Cobaltous chloride pretreatment decreased the total intensity of the panlobular immunostaining following 3′-hydroxyacetanilide. The CYP2E1 inhibitor diallyl sulfide decreased the intensity of immunostaining in the central vein area only. Western blot analysis indicated diallyl sulfide also eliminated binding to the microsomal 50-kDa protein. These data are consistent with centrilobular binding of 3′-hydroxyacetanilide, mediated in part by CYP2E1, and panlobular binding, mediated by other P450 enzymes.

Footnotes

  • Send reprint requests to: Dr. Stephen M. Roberts, Center for Environmental & Human Toxicology, University of Florida, Box 110885, Gainesville, FL 32611.

  • W.F.S. and S.M.R. were supported in part by National Institute for Environmental Health Sciences Grant ES 07213.

  • N.R.P. and J.A.H. were supported in part by National Institute of General Medical Sciences Grant GM 48749.

  • Abbreviations used are::
    APAP
    acetaminophen
    NAPQI
    N-acetyl-p-quinone imine
    AMAP
    3′-hydroxyacetanilide
    SDS-PAGE
    sodium dodecyl sulfate-polyacrylamide gel electrophoresis
    DAB
    3,3′-diaminobenzidine
    DAS
    diallyl sulfide
    • Received May 30, 1997.
    • Accepted October 6, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 26, Issue 3
1 Mar 1998
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Research ArticleArticle

Immunochemical Comparison of 3′-Hydroxyacetanilide and Acetaminophen Binding in Mouse Liver

William F. Salminen, Stephen M. Roberts, Neil R. Pumford and Jack A. Hinson
Drug Metabolism and Disposition March 1, 1998, 26 (3) 267-271;

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Research ArticleArticle

Immunochemical Comparison of 3′-Hydroxyacetanilide and Acetaminophen Binding in Mouse Liver

William F. Salminen, Stephen M. Roberts, Neil R. Pumford and Jack A. Hinson
Drug Metabolism and Disposition March 1, 1998, 26 (3) 267-271;
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