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

Abstract	Humans who carry a point mutation in the gene coding for alcohol dehydrogenase-1B (ADH1B2; 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 ADH1B2 allele are protected against alcoholism.
Authors	Mario Rivera-Meza, María Elena Quintanilla, Lutske Tampier, Casilda V Mura, Amalia Sapag, Yedy Israel
Journal	FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 24 Issue 1 Pg. 266-74 (Jan 2010) ISSN: 1530-6860 [Electronic] United States
PMID	19710201 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	DNA Primers Recombinant Proteins Ethanol ADH1B protein, human Alcohol Dehydrogenase Acetaldehyde
Topics	Acetaldehyde (blood) Adenoviridae (genetics) Alcohol Dehydrogenase (genetics, metabolism) Alcoholism (enzymology, genetics, prevention & control) Alleles Amino Acid Substitution Animals Animals, Genetically Modified Base Sequence Cell Line DNA Primers (genetics) Disease Models, Animal Ethanol (administration & dosage) Genetic Vectors Humans Kinetics Mutagenesis, Site-Directed Point Mutation Polymorphism, Genetic Rats Recombinant Proteins (genetics, metabolism) Transduction, Genetic Transfection

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