Retinoic acid hydroxylase (CYP26) is a key enzyme in neuronal differentiation of embryonal carcinoma cells

Besides nuclear retinoid receptors and cellular retinoid binding proteins a lso retinoic acid (RA)-synthesizing enzymes (using all-trans-retinal as sub strate) and RA-catabolizing enzymes (producing hydroxylated products) may e xplain the specific effects of retinoids. In the past we have established a n active role for 4-hydroxy-RA and 4-oxo-RA, which originally were consider ed to be inactive retinoids, but in fact are highly active modulators of po sitional specification in Xenopus development. Here we present evidence for a specific role of hydroxylated RA metabolites in the onset of neuronal di fferentiation. 4-Hydroxy- and 18-hydroxy-RA are products of the hydroxylati on of RA by a novel cytochrome P450 (CYP)-type of enzyme, CYP26, expression of which is rapidly induced by RA. P19 embryonal carcinoma (EC) cell lines stably expressing hCYP26 undergo extensive and rapid neuronal differentiat ion in monolayer at already low concentrations of RA, while normally P19 ce lls under these conditions differentiate only in endoderm-like cells. Our r esults indicate that the effects on growth inhibition and RAR beta transact ivation of P19 EC cells are mediated directly by RA, while the onset of neu ronal differentiation and the subsequent expression of neuronal markers is mediated by hCYP26 via the conversion of RA to its hydroxylated products. ( C) 1999 Academie Press.