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Protein Adduct-Trapping by Hydrazinophthalazine Drugs: Mechanisms of Cytoprotection Against Acrolein-Mediated Toxicity

Molecular Toxicology Research Group, Department of Clinical & Experimental Pharmacology (P.C.B., F.R.F., L.M.K.), and Department of Chemistry (L.M.K., S.M.P.), the University of Adelaide, Adelaide, South Australia, Australia; and Department of Pharmaceutical Sciences, the University of Colorado Health Science Center, Denver, Colorado (D.R.P.)

Acrolein is a highly toxic aldehyde involved in a number of diseases as well as drug-induced toxicities. Its pronounced toxicity reflects the readiness with which it forms adducts in proteins and DNA. As a bifunctional electrophile, initial reactions between acrolein and protein generate adducts containing an electrophilic center that can participate in secondary deleterious reactions (e.g., cross-linking). We hypothesize that inactivation of these reactive protein adducts with nucleophilic drugs may counteract acrolein toxicity. Because we previously observed that 1-hydrazinophthalazine (hydralazine) strongly diminishes the toxicity of the acrolein precursor allyl alcohol, we explored the possibility that hydralazine targets reactive acrolein adducts in proteins. We report that hydralazine abolished the immunoreactivity of an acrolein-modified model protein (bovine serum albumin), but only if the drug was added to the protein within 30 min of commencing modification by acrolein. The ability of a range of carbonyl-trapping drugs to interfere with "early" events in protein modification strongly correlated with their protective potencies against allyl alcohol toxicity in hepatocytes. In mass spectrometry studies using a model lysine-containing peptide, hydralazine rapidly formed hydrazones with Michael adducts generated by acrolein. Using an antibody raised against such ternary drug-acrolein-protein complexes in Western blotting experiments, clear adduct-trapping was evident in acrolein-preloaded hepatocytes exposed to cytoprotective concentrations of hydralazine ranging from 2 to 50 µM. These novel findings begin to reveal the molecular mechanisms whereby hydralazine functions as an efficient "protein adduct-trapping" drug.

Received September 15, 2003; accepted November 20, 2003.

Address correspondence to: Dr. Philip C Burcham, Molecular Toxicology Research Group, Department of Clinical and Experimental Pharmacology, The University of Adelaide, Adelaide, SA 5005, Australia. E-mail: philip.burcham{at}adelaide.edu.au

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