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-1B (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
Mario
M
Laboratory of Gene Therapy, Department of Pharmacological and Toxicological Chemistry, University of Chile, Olivos 1007, Independencia, Santiago, Chile.
Quintanilla
María Elena
ME
Tampier
Lutske
L
Mura
Casilda V
CV
Sapag
Amalia
A
Israel
Yedy
Y
D000079:Acetaldehyde / Q000097:blood; D000256:Adenoviridae / Q000235:genetics; D000426:Alcohol Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D000437:Alcoholism / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control*; D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D000431:Ethanol / Q000008:administration & dosage; D005822:Genetic Vectors; D006801:Humans; D007700:Kinetics; D016297:Mutagenesis, Site-Directed; D017354:Point Mutation; D011110:Polymorphism, Genetic; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic; D014162:Transfection
D017931:DNA Primers; D011994:Recombinant Proteins; D000431:Ethanol; C489332:ADH1B protein, human; D000426:Alcohol Dehydrogenase; D000079:Acetaldehyde