Toward a Molecular Basis of Alcohol Use and Abuse

Gregg Duester, Duester, Gregg

Alcohol dehydrogenase (ADH) is best known as the enzyme which catalyzes the reversible oxidation/reduction of ethanol/acetaldehyde. However, mammalian ADH has also been shown to function in vitro as a retinol dehydrogenase in the conversion of retinol (vitamin A alcohol) to retinoic acid, a hormone which regulates gene expression at the transcriptional level. It is clear that retinol must be converted to more active retinoid forms in order to fulfill its roles in growth, development, and cellular differentiation. An important unsolved issue in retinoid research is the control of retinoic acid synthesis from retinol during differentiation. Several enzymes which participate in the conversion of retinol to retinoic acid in vitro have been isolated, but more information on their relative importance is needed. Human ADH exists as a family of isozymes encoded by seven genes which are differentially expressed in adult and fetal mammalian tissues, being found preferentially in the epithelial cells which are known to synthesize and respond to retinoic acid. Retinoic acid is also known to play a role in neural tube development in vertebrate embryos. Excessive doses of retinoic acid or ethanol are both teratogenic for neural tube development. A relationship may exist between these two types of teratogenesis due to the role of ADH in both retinol and ethanol metabolism and the ability of ethanol to competitively inhibit retinol oxidation. There is a lack of information on the expression patterns of ADH genes in early embryos, but transgenic mouse studies are presented here which show that the human ADH3 gene can be expressed in several mouse embryonic tissues including the neural tube. Thus, ethanol-induced neural tube defects seen in cases of fetal alcohol syndrome may be due to ethanol inhibition of retinol oxidation catalyzed by an embryonic ADH. This could potentially lower retinoic acid levels in the neural tube to the extent that gene expression is not properly regulated, resulting in morphological defects.