"Although genetic factors are known to influence individual differences in alcohol metabolism," said John Crabbe, director of the Portland Alcohol Center and corresponding author for the study, "most of that knowledge is limited to alcohol or aldehyde dehydrogenases. This study used a mouse model to look for the locations of additional genes affecting alcohol metabolism. By studying many genetically different mouse strains, we found evidence for several genes that significantly affect how much alcohol reaches the brain, and how long it remains there. Our findings tell us approximately where in the genome of the mouse those genes are, for example, on which ends of which chromosomes, in this case chromosome 17. However, we have only a 'neighborhood' address now, and each neighborhood houses many specific genes. So, we need further studies to pinpoint which genes are actually responsible."
Alcohol is metabolized by the enzyme alcohol dehydrogenase to acetaldehyde. Acetaldehyde is a lot like formaldehyde, the chemical used to "pickle" organs for long-term storage; it is toxic, and when an individual has high acetaldehyde levels, they feel nauseated, flushed, hot, and dizzy. Fortunately, acetaldehyde is quickly converted into acetate and carbon dioxide by the enzyme aldehyde dehydrogenase (ALDH). However, if ALDH isn't doing its job efficiently, an individual who drinks alcohol will accumulate acetaldehyde in his or her blood and brain.
"We have known for a long time that individuals from East Asia often have a variant form of ALDH that works slowly to eliminate alcohol," said Crabbe, "and these individuals experience the bad side effects when they drink. As you can imagine, very few Asians with the variant ALDH become alcoholics. Because we inherit which form of ALDH we have from our parents, this is a very clear example of a gene that is protective against alcoholism."
Scientists have used this genetic knowledge to create at least one form of treatment for alcoholism, said Richard Deitrich, professor of pharmacology at the University of Colorado School of Medicine. "The drug Antabuse™ or disulfiram is used in alcoholics to inhibit aldehyde dehydrogenase, thereby achieving elevated levels of acetaldehyde, and thus deter these individuals from drinking," he said. "In short, about half of all Asians have a genetic deterrent to drinking, while Occidentals have to do it through chemistry."
Still, which variants of alcohol dehydrogenase or ALDH an individual has cannot explain all of the different rates of alcohol metabolism. Using mouse models - the genomes of mice and humans are likely more than 80% similar - researchers searched for additional genes of importance. They focused on two inbred mouse strains that have been used extensively to identify genes influencing traits associated with drug abuse and alcoholism. One was B6, known to prefer alcohol solutions to water, and the other was D2, known to avoid alcohol; additionally, they looked at 25 BXD RI strains, each of which is a cross between B6 and D2 mice. Following alcohol injections (of either 2 or 3 g/kg alcohol), blood alcohol concentrations and alcohol metabolism rates were measured in all 27 strains at several time points and then correlated with polymorphic markers.
"One interesting aspect of this paper is that they did not find any genetic 'hot spots' for either alcohol or aldehyde dehydrogenases," said Deitrich. "They found candidate genes for variations in alcohol metabolism that have never been suggested to have anything to do with alcohol metabolism, especially the superoxide dismutase enzyme. The implications are that it becomes increasingly important to do these kind of studies since they are continually turning up genes that apparently influence alcohol metabolism and alcohol's effects that we would never have considered as being important previously."
"Our job now is to home in on the specific genes," said Crabbe. "This requires making specific crosses between mouse strains and testing the offspring until we gradually get closer and closer to the actual genes involved. As these studies progress, we should be able to locate the relevant genes in humans as well, because knowing where the genes are in mice tells us where to look in humans. Potentially, finding additional genetic participants in alcohol metabolism could serve as sources of treatments in the future."
Co-authors of the Alcoholism: Clinical & Experimental Research paper included Judith E. Grisel (now at Furman University), Pamela Metten, Charlotte D. Wenger, and Catherine M. Merrill of the Portland Alcohol Research Center, the Department of Veterans Affairs Medical Center, and the Department of Behavioral Neuroscience at the Oregon Health & Science University. The study was funded by the National Institute on Alcohol Abuse and Alcoholism and the Department of Veterans Affairs.