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Research ArticleTOXICOLOGY

Strong Protein Adduct Trapping Accompanies Abolition of Acrolein-Mediated Hepatotoxicity by Hydralazine in Mice

Lisa M. Kaminskas, Simon M. Pyke and Philip C. Burcham
Journal of Pharmacology and Experimental Therapeutics September 2004, 310 (3) 1003-1010; DOI: https://doi.org/10.1124/jpet.104.067330
Lisa M. Kaminskas
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Simon M. Pyke
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Philip C. Burcham
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Abstract

Acrolein is a highly reactive α,β-unsaturated aldehyde that readily alkylates nucleophilic centers in cell macromolecules. Typically, such reactions proceed via Michael addition chemistry, forming adducts that retain an electrophilic carbonyl group. Since these species participate in secondary deleterious reactions, we hypothesize that inactivation of carbonyl adducts may attenuate acrolein toxicity. Indeed, we recently established that the nucleophilic antihypertensive drug hydralazine readily “traps” acrolein adducts in cell proteins and strongly suppresses acrolein-mediated toxicity in isolated hepatocytes. This work sought to determine whether hydralazine prevents the in vivo hepatotoxicity of the acrolein precursor allyl alcohol in whole mice and whether adduct trapping accompanies any such hepatoprotection. Mice received allyl alcohol alone or in conjunction with several doses of hydralazine. Four hours later, mice were sacrificed to allow for the determination of liver enzymes in plasma as markers of hepatic injury, whereas livers were assessed for glutathione and hydralazine-stabilized protein adducts. Hydralazine afforded strong, dose-dependent protection against the increases in plasma marker enzymes but not the hepatic glutathione depletion produced by allyl alcohol. Western blotting revealed intense, dose-dependent adduct trapping by hydralazine in numerous liver proteins over a broad 26- to 200-kDA mass range. In keeping with these findings, immunohistochemical analysis of liver slices indicated diffuse, extranuclear adduct trapping by hydralazine that was uniformly distributed across the liver lobule, with partial localization in parenchymal cell membranes. These findings concur with our hypothesis that hydralazine readily inactivates reactive carbonyl-retaining protein adducts formed by acrolein, thereby preventing secondary reactions that trigger cellular death.

Footnotes

  • This research was supported by the Research Committee of the Faculty of Health Sciences at the University of Adelaide. The work forms part of the Ph.D. thesis of L.M.K and was presented at the 2003 Annual Scientific Meeting of the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists in Sydney, New South Wales, Australia.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.104.067330.

  • ABBREVIATIONS: AA, allyl alcohol; GSH, glutathione; HYD, hydralazine; PBS, phosphate-buffered saline; SDH, sorbitol dehydrogenase; GPT, glutamate pyruvate transaminase; KLH, keyhole limpet hemocyanin; ANOVA, analysis of variance.

    • Received February 20, 2004.
    • Accepted May 6, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 310 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 310, Issue 3
1 Sep 2004
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Research ArticleTOXICOLOGY

Strong Protein Adduct Trapping Accompanies Abolition of Acrolein-Mediated Hepatotoxicity by Hydralazine in Mice

Lisa M. Kaminskas, Simon M. Pyke and Philip C. Burcham
Journal of Pharmacology and Experimental Therapeutics September 1, 2004, 310 (3) 1003-1010; DOI: https://doi.org/10.1124/jpet.104.067330

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Research ArticleTOXICOLOGY

Strong Protein Adduct Trapping Accompanies Abolition of Acrolein-Mediated Hepatotoxicity by Hydralazine in Mice

Lisa M. Kaminskas, Simon M. Pyke and Philip C. Burcham
Journal of Pharmacology and Experimental Therapeutics September 1, 2004, 310 (3) 1003-1010; DOI: https://doi.org/10.1124/jpet.104.067330
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