Overview of the role of alcohol dehydrogenase and aldehyde dehydrogenase and their variants in the genesis of alcohol-related pathology

Abstract

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 β2, 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.

Genetic polymorphism of alcohol-metabolizing enzyme and alcohol dependence in Polish men

“…Hence, these investigators emphasize the importance of ADH1B*2 protection against developing alcohol dependence (3,24,(30)(31)(32)(33)(34)(35)(36)(37). Our results agree with those of other studies presented above and disagree with the study by Vidal et al (38) on the Spanish population.…”

“…Studies regarding ADH1C*1 among whites are more contradictory and show ambiguous findings: no correlation (13,22,23), protection against alcohol dependence (3) or inconclusive results (24,25). Borras at al.…”

Emerging Associations of the ALDH2*2 Polymorphism with Disease Susceptibility

“…The authors admit, however, that stratification according to drinking status was impossible due to inconsistencies in data collection among studies. More convincing data regarding ethanol consumption, ALDH2 genotype, and cancer risk has been documented in in vitro studies and mouse models [52][53][54][55][56][57][58]. ALDH2*2 and osteoporosis: Osteoporosis is characterized by a decrease in bone mineral density, bone mass, and bone strength, which ultimately leads to an increased risk of fracture [59].…”

Proteomic Analysis of Membrane-Associated Proteins from Rat Liver Autophagosomes

“…5 Alcohol dehydrogenase (ADH1; spot no. 45; 3x enriched) 199 probably evolved as a protective measure against toxic xenobiotic alcohols, 200 and is capable of metabolizing a variety of alcoholic drugs. 201 Although alcohol oxidation by ADH generates toxic aldehydes, 202 the reaction is actually kinetically favoured in the opposite direction, 203 indicating that ADH may protect against aldehydes generated by bacteria 204 or by microsomal oxidation.…”