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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on May 6, 2004; DOI: 10.1124/jpet.104.067330

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Simon M Pyke
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Received for publication February 20, 2004.
Revised May 5, 2004.
Accepted for publication May 6, 2004.

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

Lisa M Kaminskas 1, Simon M Pyke 1, Philip C Burcham 1*

1 The University of Adelaide

* Address correspondence to: E-mail: philip.burcham{at}adelaide.edu.au

Abstract

Acrolein is a highly reactive {alpha},{beta}-unsaturated aldehyde that readily alkylates nucleophilic centers in cell macromolecules. Typically, such reactions proceed via Michael addition pathways, forming adducts that retain an electrophilic carbonyl group. Since these species participate in secondary deleterious reactions, we hypothesise 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 determination of liver enzymes in plasma as markers of hepatic injury, while 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. Immunohistochemical analysis revealed 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.


Key words: acrolein, adduct-trapping, allyl alcohol, hepatoprotection, hydralazine, protein adducts


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