Reduction of ethanol consumption in alcohol-preferring rats by dual expression gene transfer.
OBJECTIVE
To mimic, in an animal model of alcoholism, the protective phenotype against alcohol consumption observed in humans carrying a fast alcohol dehydrogenase (ADH1B*2) and an inactive aldehyde dehydrogenase (ALDH2*2).


METHODS
We developed a multiple expression cassette adenoviral vector (AdV-ADH/asALDH2) encoding both a fast rat ADH and an antisense RNA against rat ALDH2. A control adenoviral vector (AdV-C) containing intronic non-coding DNA was also developed. These adenoviral vectors were administered intravenously to rats bred as high alcohol-drinkers (University of Chile bibulous) that were previously rendered alcohol dependent by a 75-day period of voluntary 10% ethanol intake.


RESULTS
Animals administered AdV-ADH/asALDH2 showed a 176% increase in liver ADH activity, whereas liver ALDH2 activity was reduced by 24%, and upon the administration of a dose of ethanol (1 g/kg, i.p.), these showed arterial acetaldehyde levels that were 400% higher than those of animals administered AdV-C. Rats that received the AdV-ADH/asALDH2 vector reduced by 60% their voluntary ethanol intake versus controls.


CONCLUSIONS
This study provides evidence that the simultaneous increase of liver ADH and a reduction of ALDH activity by gene transfer could constitute a potential therapeutic strategy for the treatment of alcoholism.
Faculty of Medicine, Institute of Biomedical Sciences, Program of Molecular and Clinical Pharmacology, Laboratory of Pharmacogenetics of Alcoholism, University of Chile, Av. Independencia 1027, Independencia, Santiago, Chile. mariorivera@med.uchile.cl
Mario
M
Rivera-Meza
María Elena
ME
Quintanilla
Lutske
L
Tampier
D000079:Acetaldehyde / Q000097:blood; D000256:Adenoviridae / Q000235:genetics; D000426:Alcohol Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D000428:Alcohol Drinking / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D000437:Alcoholism / Q000097:blood / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors* / Q000235:genetics; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D018014:Gene Transfer Techniques / Q000523:psychology*; D005822:Genetic Vectors / Q000627:therapeutic use*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D016372:RNA, Antisense / Q000235:genetics / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar
D007527:Isoenzymes; D024101:Mitochondrial Proteins; D016372:RNA, Antisense; D000426:Alcohol Dehydrogenase; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; C505112:Aldh2 protein, rat; D000079:Acetaldehyde