Mechanism of protection against alcoholism by an alcohol dehydrogenase polymorphism: development of an animal model

Humans who carry a point mutation in the gene coding for alcohol dehydrogenase‐lB (ADH1B*2; Arg47His) are markedly protected against alcoholism. Although this mutation results in a 100‐fold increase in enzyme activity, it has not been reported to cause higher levels of acetaldehyde, a metabolite of ethanol known to deter alcohol intake. Hence, the mechanism by which this mutation confers protection against alcoholism is unknown. To study this protective effect, the wild‐type rat cDNA encoding rADH‐47Arg was mutated to encode rADH‐47His, mimicking the human mutation. The mutated cDNA was incorporated into an adenoviral vector and administered to genetically selected alcohol‐preferring rats. The V max of rADH‐47His was 6‐fold higher ( P <0.001) than that of the wild‐type rADH‐47Arg. Animals transduced with rAdh‐47His showed a 90% ( P <0.01) increase in liver ADH activity and a 50% reduction (P< 0.001) in voluntary ethanol intake. In animals transduced with rAdh‐47His, administration of ethanol (1g/kg) produced a short‐lived increase of arterial blood acetaldehyde concentration to levels that were 3.5‐ to 5‐fold greater than those in animals transduced with the wild‐type rAdh‐47Arg vector or with a noncoding vector. This brief increase (burst) in arterial acetaldehyde concentration after ethanol ingestion may constitute the mechanism by which humans carrying the ADH1B*2 allele are protected against alcoholism.—Rivera‐Meza, M., Quin‐tanilla, M. E., Tampier, L., Mura, C. V., Sapag, A., Israel, Y. Mechanism of protection against alcoholism by an alcohol dehydrogenase polymorphism: development of an animal model. FASEB J . 24, 266–274 (2010). www.fasebj.org