Metabolism of vitamin A and its active metabolite all-trans retinoic acid in small intestinal enterocytes

Retinol and its metabolites (retinoids) are essential for growth and cell d ifferentiation, particularly of epithelial tissue. Retinoids mediate most o f their function via interaction with retinoid receptors (retinoic acid rec eptors and retinoid X receptors), which act as ligand-activated transcripti on factors controlling the expression of a number of target genes. We have investigated whether retinoid receptor ligands such as all-trans-retinoic a cid (RA) are formed in the human intestinal epithelium from dietary vitamin A. We show here that retinol was metabolized to its active metabolite, all -trans-RA, by isolated cytosolic fractions of human small intestinal entero cytes and by human Caco-2 cells. All-trans-RA was metabolized by human smal l intestinal microsomes to at least two metabolites (all-trans-4-hydroxy-RA and all-trans-4-oxo-RA). When Caco-2 cells were incubated with all-trans-R A, at least three major polar metabolites (all-trans-4-hydroxy-RA, all-tran s-4-oxo-RA, and 13-cis-4-hydroxy-RA) were identified by HPLC-UV. The cytoch rome P450 (CYP)1A1 inhibitor alpha -naphthoflavone inhibited the metabolism of all-trans-RA, whereas the CYP1A1 inducer beta -naphthoflavone induced t he metabolism of all-trans-RA, suggesting that CYP1A1 is involved. The indu ction of CYP3A by rifampicin enhanced the metabolism, and the induction of all-trans-RA metabolism was also observed after preincubation of the cells with all-trans-RA. Liarozole almost completely inhibited the RA metabolism. The specific retinoic acid metabolizing CYP26 was induced after RA treatme nt in Caco-2 cells. It is concluded that in addition to CYP1A1 and CYP3A, C YP26 may be the main CYP enzyme responsible for the metabolism of all-trans -RA in enterocytes. Active ligands such as all-trans-RA are formed in intes tinal epithelial cells.