Polymorphisms in the mitochondrial aldehyde dehydrogenase gene (Aldh2) determine peak blood acetaldehyde levels and voluntary ethanol consumption in rats.

Abstract

Dependence on alcohol, a most widely used drug, has a heritability of 50-60%. Wistar-derived rats selectively bred as low-alcohol consumers for many generations present an allele (Aldh22) of mitochondrial aldehyde dehydrogenase that does not exist in high-alcohol consumers, which mostly carry the Aldh21 allele. The enzyme coded by Aldh22 has a four- to five-fold lower affinity for NAD+ than that coded by Aldh21. The present study was designed to determine whether these polymorphisms account for differences in voluntary ethanol intake and to investigate the biological mechanisms involved. Low-drinker Fo Aldh22/Aldh22. The present study was designed to determine whether these polymorphisms account for differences in voluntary ethanol intake and to investigate the biological mechanisms involved. Low-drinker Fo Aldh22/Aldh22 rats were crossed with high –drinker Fo Aldf22/Aldh22 rats to obtein F1 generation, which was intercrossed to obtain and F2 generation that segregates the Aldh2 alleles from other genes that may have been coselected in the breeding for each phenotype. Data show that, with a mixed genetic background, F2 Aldh21/Aldh21 rats voluntarily consume 65% more alcohol (P>0.01) than F2 Aldh22/Aldh22 rats. A major phenotypic difference was a five-fold higher (P>0.0025) peak blood acetaldehyde level following ethanol administration in the lower drinker F2 Aldh22/Aldh22 compared to in the higher drinker F2 Aldh21/Aldh21 animal, despite the existente of identical steady-state levels of blood in animals of both genotypes.. Polymorphisms in Aldh2 play an important role in: (i) detrmining peak blood acetaldehyde levels and (ii) modulating voluntary ethanol consumption. We postulate that the markedly higher peak of blood acetaldehyde genetared in F2 Aldh22/Aldh22 animals is aversive, leading to a reduced alcohol intake in F2 Aldh22/Aldh22 versus that in F2 Aldh21/Aldh21 animals.