Alcohol dehydrogenase (ADH) and
mitochondrial aldehyde dehydrogenase (ALDH2) are responsible for metabolizing the bulk of
ethanol consumed as part of the diet and their activities contribute to the rate of
ethanol elimination from the blood. They are expressed at highest levels in liver, but at lower levels in many tissues. This pathway probably evolved as a detoxification mechanism for environmental
alcohols. However, with the consumption of large amounts of
ethanol, the oxidation of
ethanol can become a major energy source and, particularly in the liver, interferes with the metabolism of other nutrients. Polymorphic variants of the genes for these
enzymes encode
enzymes with altered kinetic properties. The pathophysiological effects of these variants may be mediated by accumulation of
acetaldehyde; high-activity ADH variants are predicted to increase the rate of
acetaldehyde generation, while the low-activity ALDH2 variant is associated with an inability to metabolize this compound. The effects of
acetaldehyde may be expressed either in the cells generating it, or by delivery of
acetaldehyde to various tissues by the bloodstream or even saliva. Inheritance of the high-activity ADH beta2, encoded by the ADH2*2 gene, and the inactive ALDH2*2 gene product have been conclusively associated with reduced risk of
alcoholism. This association is influenced by gene-environment interactions, such as religion and national origin. The variants have also been studied for association with
alcoholic liver disease,
cancer,
fetal alcohol syndrome, CVD,
gout,
asthma and clearance of
xenobiotics. The strongest correlations found to date have been those between the ALDH2*2 allele and
cancers of the oro-pharynx and oesophagus. It will be important to replicate other interesting associations between these variants and other
cancers and
heart disease, and to determine the biochemical mechanisms underlying the associations.