RT Journal Article SR Electronic T1 R115866 Inhibits All-trans-Retinoic Acid Metabolism and Exerts Retinoidal Effects in Rodents JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 304 OP 312 VO 293 IS 1 A1 Paul Stoppie A1 Marcel Borgers A1 Peter Borghgraef A1 Lieve Dillen A1 Jan Goossens A1 Gerard Sanz A1 Heidi Szel A1 Carl Van Hove A1 Greta Van Nyen A1 Geert Nobels A1 Hugo Vanden Bossche A1 Marc Venet A1 Gustaaf Willemsens A1 Jean Van Wauwe YR 2000 UL http://jpet.aspetjournals.org/content/293/1/304.abstract AB All-trans-retinoic acid (RA) regulates epithelial differentiation and growth through activation of specific nuclear RA receptors (RARs). Because high-rate metabolism largely impairs the biological efficacy of RA, we have sought for compounds capable of inhibiting the metabolic breakdown of the retinoid. This study identifies R115866 as a novel inhibitor of the cytochrome P450 (CYP)-mediated metabolism of RA. In vitro, nanomolar concentrations of R115866 inhibited the conversion of RA by CYP26, a RA-inducible RA metabolizing enzyme. In vivo, oral administration of R115866 (2.5 mg/kg) to rats induced marked and transient increases of endogenous RA levels in plasma, skin, fat, kidney, and testis. Consistent with its ability to enhance endogenous RA content in tissues, R115866 was found to exert retinoidal activities. Like RA, the title compound: 1) inhibited vaginal keratinization in estrogen-stimulated rats; 2) induced epidermal hyperplasia in mouse ear skin; 3) transformed mouse tail epidermis from a para- to an orthokeratotic skin type; and 4) up-regulated the CYP26 mRNA expression in rat liver. Furthermore, we found that the keratinization-suppressive and CYP26-inducing activities of R115866 could be reversed by concomitant administration of the RAR antagonist, AGN193109. Our data characterize R115866 as a potent, orally active inhibitor of RA metabolism, capable of enhancing RA levels and displaying retinoidal actions. These activities are reversed by RAR antagonism, supporting the idea that the actions of R115866 result from increased availability of endogenous RA and improved RAR triggering. The American Society for Pharmacology and Experimental Therapeutics