ORIGINAL ARTICLESPolymorphisms in the mitochondrial aldehyde dehydrogenase gene (Aldh2) determine peak blood acetaldehyde levels and voluntary ethanol consumption in ratsQuintanilla, María Elenaa; Tampier, Lutskea; Sapag, Amaliab; Israel, Yedya b cAuthor Information aProgram of Molecular and Clinical Pharmacology, Faculty of Medicine bLaboratory of Gene Therapy, Department of Pharmacological and Toxicological Chemistry, Faculty of Chemical and Pharmaceutical Sciences and Millennium Institute for Advanced Studies in Cell Biology and Biotechnology, University of Chile, Santiago, Chile cDepartment of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA Sponsorship: This study was supported by FONDECYT-Chile (1010873 and 1040555), The Millennium Initiative (ICM-P 99-031F) and NIAAA (AA-10630). Correspondence and requests for reprints to Yedy Israel, Laboratory of Gene Therapy, University of Chile, Olivos 1007, Independencia, Santiago, Chile Tel: +562 678 2944; fax: +562 737 7231; e-mail: [email protected] Received 13 January 2005 Accepted 21 March 2005 Pharmacogenetics and Genomics: June 2005 - Volume 15 - Issue 6 - p 427-431 Buy 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 F0Aldh22/Aldh22 rats were crossed with high-drinker F0Aldh21/Aldh21 rats to obtain an F1 generation, which was intercrossed to obtain an 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, F2Aldh21/Aldh21 rats voluntarily consume 65% more alcohol (P<0.01) than F2Aldh22/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 F2Aldh22/Aldh22 compared to the higher drinker F2Aldh21/Aldh21 animals, despite the existence of identical steady-state levels of blood acetaldehyde in animals of both genotypes. Polymorphisms in Aldh2 play an important role in: (i) determining peak blood acetaldehyde levels and (ii) modulating voluntary ethanol consumption. We postulate that the markedly higher peak of blood acetaldehyde generated in Aldh22/Aldh22 animals is aversive, leading to a reduced alcohol intake in Aldh22/Aldh22 versus that in Aldh21/Aldh21 animals. © 2005 Lippincott Williams & Wilkins, Inc.