The majority of the ethanol consumed by individuals is metabolized to acetaldehyde by cytosolic alcohol dehydrogenase (ADH) and acetaldehyde is subsequently converted to acetate by mitochondrial aldehyde dehydrogenase (ALDH2-1) in liver. Both ADH and ALDH2 have been reported to be polymorphic in nature with functionally variant alleles of different kinetic properties. Therefore, it was proposed that the individual differences in the biological response to ethanol consumption may be genetically controlled. The most extensively studied ALDH enzyme is the so-called Oriental variant of ALDH (ALDH2-2). The cDNA sequence coding for this variant has been found to contain a point mutation (nucleotide G to A) changing one amino acid at Glu 487 to Lys 487. The liver ALDH2 is a tetrameric enzyme. In vitro studies revealed that the ALDH2-2 homotetramer has a higher Km toward NAD+ as compared to ALDH2-1, and this leads to reduced ALDH2-2 activity under physiological conditions. However, many questions remain unclear, including the natural metabolic role of ALDH2. An animal model for ALDH2-2 would allow the effect of the amino acid difference in ALDH2-2 to be determined apart from other complicated variables such as the social, cultural, and environmental influences in human life. Therefore, transgenic mice line with the human ALDH2-2 and ALDH2-1 alleles and the ALDH2 knock-out mice will be produced and used as animal models to study the physiological effects of mutations which are naturally occurring in the human.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Intramural Research (Z01)
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National Institute on Alcohol Abuse and Alcoholism
United States
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