Major generation route of cytotoxic protein adducts derived from acetaldehyde, a metabolite of alcohol

Abstract

The habitual excessive consumption of alcohol has been implicated in the onset and/or progression of alcoholic-associated liver/brain diseases (ALD/ABD), lung disease, rheumatoid arthritis, and cardiac tissue injury. Alcohol (ethanol) is metabolized to acetaldehyde (AA), a two-carbon carbonyl compound that reacts with proteins to form covalent AA-protein adducts (AAPAs). We herein propose that AA reacts with liver and/or brain proteins to generate AAPAs, which contribute to alcohol-induced liver injury and neurotoxicity in vivo, respectively. The viability of hepatocytes was significantly lower in a culture treated with AAPAs than in a culture treated with Nε-(ethyl)lysine (NEL), the reduced form of Schiff bases, or a control culture. Furthermore, a correlation was observed between staining for AAPA and 4-hydroxy-2-nonenal in the liver and the severity of ALD in both rats and humans. The chronic consumption of alcohol produces AAPAs and reactive oxygen species, both of which have been implicated in the pathogenesis of ALD. Moreover, a dose-dependent increase in neuronal cell death was noted in cortical neurons incubated with AAPAs, the neurotoxicity of which was completely suppressed by an anti-AAPA antibody, but not an anti-NEL antibody. AAPA epitopes have been detected in the brains of individuals withalcohol-related brain damage. AAPAs have also been shown to contribute to the pathogenesis of ABD. The hypothesis proposed herein is that strongly cytotoxic AAPAs are iminobutane structures, which differ from the known structures of NEL. We suggest the importance of structural epitope AAPAs as toxic moieties for hepatocytes and neuronal cells in alcoholism.