RGD Reference Report - Eliciting the low-activity aldehyde dehydrogenase Asian phenotype by an antisense mechanism results in an aversion to ethanol. - Rat Genome Database

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

Authors: Garver, E  Tu Gc,   Cao, Q N  Aini, M  Zhou, F  Israel, Y 
Citation: Garver E, etal., J Exp Med. 2001 Sep 3;194(5):571-80. doi: 10.1084/jem.194.5.571.
RGD ID: 15036815
Pubmed: PMID:11535626   (View Abstract at PubMed)
PMCID: PMC2195938   (View Article at PubMed Central)
DOI: DOI:10.1084/jem.194.5.571   (Journal Full-text)

A mutation in the gene encoding for the liver mitochondrial aldehyde dehydrogenase (ALDH2-2), present in some Asian populations, lowers or abolishes the 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 antisense phosphorothioate oligonucleotides (ASOs) can mimic the low-activity ALDH2-2 Asian phenotype. Rat hepatoma cells incubated for 24 h with an antisense 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% inhibition 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 circulating plasma acetaldehyde levels after ethanol (1 g/kg) administration. Administration 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 specific inhibition of gene expression can be used to mimic the protective effects afforded by the ALDH2-2 phenotype.



Gene-Chemical Interaction Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
ALDH2Humanphosphorothioate oligonucleotide decreases expressionISOAldh2 (Rattus norvegicus)phosphorothioate oligonucleotide decreased mRNA and activity of ALDH2 in rat liverRGD 
Aldh2Mousephosphorothioate oligonucleotide decreases expressionISOAldh2 (Rattus norvegicus)phosphorothioate oligonucleotide decreased mRNA and activity of ALDH2 in rat liverRGD 
Aldh2Ratphosphorothioate oligonucleotide decreases expressionEXP phosphorothioate oligonucleotide decreased mRNA and activity of ALDH2 in rat liverRGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Aldh2Ratacetaldehyde metabolic process  IMP  RGD 
Aldh2Ratbehavioral response to ethanol  IMP  RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Aldh2Ratalcohol aversion  IMP  RGD 
Objects Annotated

Genes (Rattus norvegicus)
Aldh2  (aldehyde dehydrogenase 2 family member)

Genes (Mus musculus)
Aldh2  (aldehyde dehydrogenase 2, mitochondrial)

Genes (Homo sapiens)
ALDH2  (aldehyde dehydrogenase 2 family member)


Additional Information