Effect of cellular retinol-binding protein on retinol oxidation by human class IV retinol/alcohol dehydrogenase and inhibition by ethanol.

All-trans retinoic acid (atRA) is a powerful morphogen synthesized in a variety of tissues. Oxidation of all-trans retinol to all-trans retinal determines the overall rate of atRA biosynthesis. This reaction is catalyzed by multiple dehydrogenases in vitro. In the cells, most all-trans retinol is bound to cellular retinol binding protein (CRBP). Whether retinoic acid is produced from the free or CRBP-bound retinol in vivo is not known. The current study investigated whether human medium-chain alcohol/retinol dehydrogenases (ADH) can oxidize the CRBP-bound retinol. The results of this study suggest that retinol bound to CRBP cannot be channeled to the active site of ADH. Thus, the contribution of ADH isozymes to retinoic acid biosynthesis will depend on the amount of free retinol in each cell. Physiological levels of ethanol will substantially inhibit the oxidation of free retinol by human ADHs: class I, alpha alpha and beta 2 beta 2; class II, pi pi; and class IV, sigma sigma.