Involvement of Alcohol-Metabolizing Enzymes in Retinoic Acid Synthesis and Inhibition by Ethanol

Abstract

Retinoic acid has recently been implicated as the active form of vitamin A involved in growth, development, and cellular differentiation. Retinoic acid has been implicated as a regulatory factor for some of the earliest events in vertebrate embryonic morphogenesis, including the development of the central nervous system. The mechanism of action of retinoic acid is that of a regulatory ligand for a family of retinoic acid receptors that directly modulate the transcriptional regulation of key genes involved in differentiation. Retinoic acid is derived from retinol (vitamin A alcohol) via two oxidation steps with retinal as the intermediate. Studies on the enzymology of retinoic acid synthesis have implicated alcohol dehydrogenase as a retinol dehydrogenase, and ethanol has been shown to inhibit this reaction competitively. Since ethanol is known to have teratogenic effects on central nervous system development (i.e., fetal alcohol syndrome), the mechanism of action may involve an inhibition of retinoic acid synthesis. Described here is the presently available evidence concerning the role of alcohol dehydrogenase in retinoic acid synthesis, the role of retinoic acid in neural tube development, and the role of ethanol as an agent that can disrupt both retinoic acid synthesis and neural tube development.