Polymorphisms of human aldehyde dehydrogenases - Consequences for drug metabolism and disease

Aldehyde dehydrogenases (ALDHs), a superfamily of NAD(P)(+)-dependent enzym es with similar primary structures, catalyze the oxidation of a wide spectr um of endogenous and exogenous aliphatic and aromatic aldehydes, Thus far, 16 ALDH genes with distinct chromosomal locations have been identified in t he human genome. Polymorphism in ALDH2 is associated with altered acetaldeh yde metabolism, decreased risk of alcoholism and increased risk of ethanol- induced cancers. Polymorphisms in ALDH3A2, ALDH4A1, ALDH5A1 and ALDH6A1 are associated with metabolic diseases generally characterized by neurologic c omplications. Mutations in ALDH3A2 cause loss of enzymatic activity and are the molecular basis of Sjogren-Larsson syndrome. Mutations in ALDH4A1 are associated with type II hyperprolinemia, Deficiency in ALDH5A1 causes 4-hyd roxybutyric aciduria. Lack of ALDH6A1 appears to be associated with develop mental delay. Allelic variants of the ALDH1A1, ALDH1B1, ALDH3A1 and ALDH9A1 genes have also been observed but not yet characterized. This review descr ibes consequences of ALDH polymorphisms with respect to drug metabolism and disease. Copyright (C) 2000 S. Karger AG. Basel.