The Journal of Experimental Medicine
IN Cell Analyzer 2000
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Published online 3 September 2001. doi:10.1084/jem.194.5.571
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© The Rockefeller University Press, 0022-1007/2001/9/571/ $5.00
The Journal of Experimental Medicine, Volume 194, Number 5, September 3, 2001 571-580

Original Article

Eliciting the Low-Activity Aldehyde Dehydrogenase Asian Phenotype by an Antisense Mechanism Results in an Aversion to Ethanol

Eric Garvera, Guang-chou Tua, Qing-Na Caoa, Maria Ainia, Feng Zhoua, and Yedy Israela,b

a Department of Pathology, Anatomy and Cell Biology, and the Alcohol Research Center, Thomas Jefferson University, Philadelphia PA 19107
b Laboratory of Gene Therapy and Millennium Institute, University of Chile, 11111 Santiago, Chile
Department of Pathology and Cell Biology, Thomas Jefferson University, 1020 Locust St., Rm. 275, Philadelphia, PA 19107.215-923-9263215-503-5063

emg002{at}jefferson.edu

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.

Key Words: alcoholism • disulfiram • ALDH2-2 • acetaldehyde • treatment

Abbreviations used in this paper: ALDH2, aldehyde dehydrogenase; ASO, antisense phosphorothioate oligonucleotide; CHX, cycloheximide; GDH, glutamate dehydrogenase; RT, reverse transcriptase.

© 2001 The Rockefeller University Press


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