Inhibition of advanced glycation endproduct formation by acetaldehyde: Role in the cardioprotective effect of ethanol

Epidemiological studies suggest that there is a beneficial effect of modera te ethanol consumption on the incidence of cardiovascular disease. Ethanol is metabolized to acetaldehyde, a two-carbon carbonyl compound that can rea ct with nucleophiles to form covalent addition products. We have identified a biochemical modification produced by the reaction of acetaldehyde with p rotein-bound Amadori products. Amadori products typically arise from the no nenzymatic addition of reducing sugars (such as glucose) to protein amino g roups and are the precursors to irreversibly bound, crosslinking moieties c alled advanced glycation endproducts, or AGEs, AGEs accumulate over time on plasma lipoproteins and vascular wall components and play an important rol e in the development of diabetes- and age-related cardiovascular disease. T he attachment of acetaldehyde to a model Amadori product produces a chemica lly stabilized complex that cannot rearrange and progress to AGE formation. We tested the role of this reaction in preventing AGE formation in vivo by administering ethanol to diabetic rats, which normally exhibit increased A GE formation and high circulating levels of the hemoglobin Amadori product, HbA(1c), and the hemoglobin AGE product, Hb-AGE. In this model study, diab etic rats fed an ethanol diet for 4 weeks showed a 52% decrease in Hb-AGE w hen compared with diabetic controls (P < 0.001). Circulating levels of HbA( 1c) were unaffected by ethanol, pointing to the specificity of the acetalde hyde reaction for the post-Amadori, advanced glycation process; These data suggest a possible mechanism for the so-called "French paradox," (the cardi oprotection conferred by moderate ethanol ingestion) and may offer new stra tegies for inhibiting advanced glycation.