Eliciting the low-activity aldehyde dehydrogenase Asian phenotype by an antisense mechanism results in an aversion to ethanol

A mutation in the gene encoding for the liver mitochondrial aldehyde dehydr ogenase (ALDH2-2), present in some Asian populations, lowers or abolishes t he activity of this enzyme and results in elevations in blood acetaldehyde upon ethanol consumption, a phenotype that greatly protects against alcohol abuse and alcoholism. We have determined whether the administration of ant isense phosphorothioate oligonucleotides (ASOs) can mimic the low-activity ALDH2-2 Asian phenotype. Rat hepatoma cells incubated for 24 h with an anti sense oligonucleotide (ASO-9) showed reductions in ALDH2 mRNA levels of 85% and ALDH2 (half-life of 22 h) activity of 55% equivalent to a >90% inhibit ion in ALDH2 synthesis. Glutamate dehydrogenase mRNA and activity remained unchanged. Base mismatches in the oligonucleotide rendered ASO-9 virtually inactive, confirming an antisense effect. Administration of ASO-9 (20 mg/kg /day for 4 d) to rats resulted in a 50% reduction in liver ALDH2 mRNA, a 40 % inhibition in ALDH2 activity, and a fourfold (P < 0.001) increase in circ ulating plasma acetaldehyde levels after ethanol (1 g/kg) administration. A dministration of ASO-9 to rats by osmotic pumps led to an aversion (-61%, P < 0.02) to ethanol. These studies provide a proof of principle that specif ic inhibition of gene expression can be used to mimic the protective effect s afforded by the ALDH2-2 phenotype.