ABSTRACT
T'ne enzymology described above has left a somewhat confusing story for under~ standing what enzymes play physiologically significant roles in retinoic acid synthesis. Analysis of ADH gene expression has, however, provided additional information which strongly implicates ADH as a physiological retinol dehy~
~.-.6vu~··~ for retinoic acid synthesis. Recent experiments in this have indicated that expression of the human class ADH gene ADH3 is regulated transcriptionally by retinoic acid (93). Class I ADH mRNA has been shown to be induced by retinoic acid in human HepG2 hepatocellular carcinoma cells and mouse F9 embryonal carcinoma cells (84). Between positions -300 and -284 base pairs relative to the transcription start site, the human ADH3 promoter contains two directly repeated copies of the nucleotide sequence 5'-AGGTCA~3' spaced by five base pairs, which is sufficient to act as retinoic acid response element
This motif was also noticed as an essential DNA sequence for retinoic add response elements present in the control regions of the genes encoding laminin Bl (95) and the retinoic acid receptor~ (96). These findings indicate that retinoic acid can potentially stimulate its own synthesis via a positive feedback loop effectingADH3 transcription, hence production of class I ADH known to use retinol as a substrate. Ff'llis argues strongly that dass I ADH activity, in particular the activity of the isozyme encooeo ADH3, plays a physiologically significant role in human retinoic acid synthesis. Purified y-ADH has been shown to function as a retinol dehydrogenase (53).
