Israel Y, Rivera-Meza M, Karahanian E, Quintanilla ME, Tampier L, Morales P, Herrera-Marschitz M. Gene specific modifications unravel ethanol and acetaldehyde actions. Front Behav Neurosci 2013;7:80.doi:10.3389/fnbeh.2013.00080
Ethanol is metabolized into acetaldehyde mainly by the action of alcohol dehydrogenase in the liver, while mainly by the action of catalase in the brain. Aldehyde dehydrogenase-2 metabolizes acetaldehyde into acetate in both organs. Gene specific modifications reviewed here show that an increased liver generation of acetaldehyde (by transduction of a gene coding for a high-activity liver alcohol dehydrogenase ADH1*B2) leads to increased blood acetaldehyde levels and aversion to ethanol in animals. Similarly aversive is an increased acetaldehyde level resulting from the inhibition of liver aldehyde dehydrogenase-2 (ALDH2) synthesis (by an antisense coding gene against aldh2 mRNA).
The situation is diametrically different when acetaldehyde is generated in the brain. When the brain ventral tegmental area (VTA) is endowed with an increased ability to generate acetaldehyde (by transfection of liver rADH) the reinforcing effects of ethanol are increased, while a highly specific inhibition of catalase synthesis (by transduction of a shRNA anti catalase mRNA) virtually abolishes the reinforcing effects of ethanol as seen by a complete abolition of ethanol intake in rats bred for generations as high ethanol drinkers. Data shows two divergent effects of increases in acetaldehyde generation: aversive in the periphery but reinforcing in the brain.
This paper presents an excellent summary of the effects of genetically determined enzymes that affect the metabolism of alcohol; such factors relate strongly to both the rewarding and the aversive effects of alcohol. Of almost 100 genes that have been found to relate to alcohol metabolism, the two major ones appear to be alcohol dehydrogenase and aldehyde dehydrogenase. The authors describe the metabolism of alcohol into acetaldehyde by alcohol dehydrogenase, and then focus especially on the metabolism of acetaldehyde by aldehyde dehydrogenase-2.
Previous studies have shown that 20-40% of individuals of East Asian origin have a point mutation in the genes that code for high affinity aldehyde dehydrogenase-2; such people tend to show high levels of acetaldehyde and develop flushing, tachycardia, headache, nausea, and emesis from even small amounts of alcohol. Being very intolerant of alcohol, they are at very low risk of alcohol abuse. This mutation is much less common among European and North American populations.
Most of the studies described in this paper were carried out in Wistar-derived rats selectively bred for over 80 generations, which led to two lines of rats: the UChA (abstainer) and the UShB (bibulous). Other data suggest similar relationships among humans for the activity of liver-generated aldehyde dehydrogenase. However, some Forum reviewers stressed that there are limitations in our current knowledge about the metabolism of alcohol or acetaldehyde in the brain among humans, indicating the need for further research in humans.
The authors summarize their extensive review of the literature by stating: “An increased liver generation of acetaldehyde, leading to increased blood acetaldehyde levels, results in aversion to ethanol in animals. Similarly, aversion to ethanol results from an increased acetaldehyde level resulting from the inhibition of liver aldehyde dehydrogenase-2 synthesis.” They go on to indicate that the situation is different when acetaldehyde is generated in the brain, stating that there are “two divergent effects of increases in acetaldehyde generation: aversive in the periphery but reinforcing in the brain.” As alcohol dehydrogenase in not expressed in the brain, interactions of alcohol and acetaldehyde in the brain may result primarily by a catalase mechanism.
The authors also describe what is known as the “alcohol deprivation effect,” in which animals given alcohol over a period of time, then deprived of alcohol, tend to drink excessively when alcohol is reintroduced. Drugs given to inhibit catalase activity block the excessive drinking when alcohol is reintroduced. The authors state that this suggests possible therapeutic avenues in the treatment of alcoholism, although extensive further research is needed.
Importance of these findings in relation to alcohol abuse: As pointed out by Forum reviewers Van Velden and Kotze, “Alcoholism is a huge problem worldwide, and we need to understand this addiction better if we want to combat this negative effect of alcohol consumption in humans. Alcohol use disorders (AUD) involving hazardous, harmful, and addictive misuse of alcohol are widespread in most parts of the world. This paper highlights the molecular understanding of alcoholism, and may contribute to the therapeutic armamentarium of the physician in treating and preventing alcoholism.
“This paper summarizes research indicating that individuals carrying the ALDH2*2 allele are protected between 66% (heterozygous ALDH2*1/ ALDH2*2) and 99% (homozygous ALDH2*2/ ALDH2*2) against alcoholism. These studies indicate that humans carrying the ADH1B*2 (ADH-47His) gene are protected against alcoholism. These studies strongly suggest possible therapeutic avenues in the treatment of alcoholism. The paper contributes to a better understanding of the genetic polymorphisms leading to alcohol abuse, and this can be of great value.”
A summary paper on genetically determined mechanisms related to the metabolism of alcohol and acetaldehyde describes numerous ways that the metabolism, especially of acetaldehyde, may be modified, both in the periphery of the body and in the brain. Individuals with a mutation of the aldehyde dehydrogenase gene (the ALDH2*2 allele), and certain other genetically determined enzymes, do not tolerate alcohol and are much less likely to become alcohol abusers. The authors state that their studies suggest possible therapeutic avenues in the treatment of alcoholism.
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Comments on this paper have been provided by the following members of the International Scientific Forum on Alcohol Research:
David Van Velden, MD, Dept. of Pathology, Stellenbosch University, Stellenbosch, South Africa
Harvey Finkel, MD, Hematology/Oncology,
Dag S. Thelle, MD, PhD, Senior Professor of Cardiovascular Epidemiology and Prevention, University of Gothenburg, Sweden; Senior Professor of Quantitative Medicine at the University of Oslo, Norway
Maritha J. Kotze, PhD, Human Genetics, Dept of Pathology, University of Stellenbosch, Tygerberg, South Africa
R. Curtis Ellison, MD, Section of Preventive Medicine & Epidemiology, Boston University School of Medicine, Boston, MA, USA
Arne Svilaas, MD, PhD, general practice and lipidology, Oslo University Hospital, Oslo, Norway