ANTIBODY-MEDIATED HEPATOTOXICITY OF ETHANOL

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The principle metabolite of ethanol, acetaldehyde, has been shown to react with amino groups on proteins and phospholipids to yield secondary N-ethylamine adducts. In the case of protein adducts formed during metabolism of ethanol, these amines have been shown to act as neoantigens and generate an immune response. Previous studies have shown a correlation between the presence in the serum of antibodies that bind to these adducts and alcohol-related hepatotoxicity. We have recently shown that some of the polyclonal IgG antibodies raised in rabbits against protein adducts of acetaldehyde cross-react with synthetic acetaldehyde-phosphatidylethanolamine adducts (N-ethyl-PE). If N-ethyl-PE adducts are formed in vivo during metabolism of alcohol, then binding of cross-reactive antibodies to these adducts exposed on the surface of hepatocytes could contribute to alcohol-related hepatotoxicity. The aims of this proposal are to determine if acetaldehyde adducts of phospholipids appear on the surface of alcohol-exposed hepatocytes and if binding of antibodies to them results in lysis of hepatocytes as a consequence of activation of neutrophils or complement. A sequence of steps is described that will determine whether acetaldehyde adducts of phospholipids are formed in vivo, measure the binding of antibodies to hepatocytes that have N-ethyl-phosphatidylethanolamine incorporated into their surface using flow cytometry, and measure the immune-mediated cytotoxicity that could result from binding of neutrophils or complement to antibodies on the hepatocyte surface. These studies may be significant in two ways: First, measurement of the appearance of acetaldehyde-phospholipid adducts may add an important additional component to existing assays for markers of alcohol exposure. Second, the additional haptenic epitopes provided by acetaldehyde-phospholipid adducts on the hepatocyte surface may be a contributing factor in binding of neutrophils or complement that results in immune-mediated hepatotoxicity.