Recent studies have shown that acetaldehyde and the lipid peroxidation-derived aldehyde, malondialdehyde, can react together with proteins in a synergistic manner to form distinct hybrid adducts which have been designated as MAA adducts. MAA adducts are immunogenic, generating antibodies which recognize MAA epitopes on proteins. MAA adducts were shown to be formed in the lives of ethanol-fed rats. Because both the covalent binding of acetaldehyde to proteins and increased lipid peroxidation have been proposed as possible mechanisms of ethanol-induced liver injury. MAA protein-adduct formation represents an event dependent on both of these mechanisms, indicating a common or unifying process (i.e. MAA adduct formation) that may account for the hepatotoxic effects of alcohol. Therefore, the following hypothesis has been proposed. MAA adducts, resulting from the synergistic reaction of acetaldehyde an malondialdehyde with proteins, represent a major species of aldehyde adducts formed in the liver during ethanol oxidation. MAA adduct formation with specific target proteins results in selective functional impairment of thee proteins and ultimately leads to liver injury. The objectives of the proposed studies are to further characterize the chemistry of MAA adduct formation and develop sensitive and reliable immunochemical based assays for the detection of MAA adducts in biological samples. Further critical objectives include describing the functional consequences of MAA adduct formation in the liver and evaluating the role of MAA adduct in ethanol-induced liver injury. Therefore, to attain these objectives the following specific aims are proposed: 1) To further characterize the chemistry of MAA adduct formation and provide structural assignments for the major defined MAA adducts; 2) To generate and characterize specific antibodies against defined MAA adducts in order to develop immunological methods for MMA adduct detection and quantification; 3) To determine MAA protein adduct formation and identify target proteins in the liver and other organs during chronic ethanol administration; 4) To ascertain the role of MAA adducts in the ethanol-induced impairment of hepatic protein trafficking pathways; 5) To evaluate the relationship between MAA adducts and hepatotoxicity in combined models of chronic ethanol ingestion and administration of agents that induce lipid peroxidation. Overall, these proposed studies should provide valuable information concerning the basic molecular mechanisms of alcohol-induced hepatotoxicity.
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