Acetaldehyde Enhances Alcohol Sensitivity and Protects against Alcoholism: Evidence from Alcohol Metabolism in Subjects with Variant <i>ALDH2*2</i> Gene Allele

Alcoholism is a complex behavior trait influenced by multiple genes as well as by sociocultural factors. Alcohol metabolism is one of the biological determinants that can significantly influence drinking behaviors. Alcohol sensitivity is thought to be a behavioral trait marker for susceptibility to develop alcoholism. The subjective perceptions would be an indicator for the alcohol preference. To investigate alcohol sensitivity for the variants <i>ADH1B*2</i> and <i>ALDH2*2</i>, sixty healthy young males with different combinatory <i>ADH1B</i> and <i>ALDH2</i> genotypes, <i>ADH1B*2/*2–ALDH2*1/*1</i> (<i>n</i> = 23), <i>ADH1B*2/*2–ALDH2*1/*2</i> (<i>n</i> = 27), and <i>ADH1B*1/*1–ALDH2*1/*1</i> (<i>n</i> = 10), participated in the study. The subjective perceptions were assessed by a structured scale, and blood ethanol and acetaldehyde were determined by GC and HPLC after an alcohol challenge in two dose sessions (0.3 g/kg or 0.5 g/kg ethanol). The principal findings are (1) dose-dependent increase of blood ethanol concentration, unaffected by <i>ADH1B</i> or <i>ALDH2</i>; (2) significant build-up of blood acetaldehyde, strikingly influenced by the <i>ALDH2*2</i> gene allele and correlated with the dose of ingested alcohol; (3) the increased heart rate and subjective sensations caused by acetaldehyde accumulation in the <i>ALDH2*2</i> heterozygotes; (4) no significant effect of <i>ADH1B</i> polymorphism in alcohol metabolism or producing the psychological responses. The study findings provide the evidence of acetaldehyde potentiating the alcohol sensitivity and feedback to self-control the drinking amount. The results indicate that <i>ALDH2*2</i> plays a major role for acetaldehyde-related physiological negative responses and prove the genetic protection against development of alcoholism in East Asians.