R115866 inhibits all-trans-retinoic acid metabolism and exerts retinoidal effects in rodents

All-trans-retinoic acid (RA) regulates epithelial differentiation and growt h through activation of specific nuclear RA receptors (RARs). Because high- rate metabolism largely impairs the biological efficacy of RA, we have soug ht for compounds capable of inhibiting the metabolic breakdown of the retin oid. This study identifies R115866 as a novel inhibitor of the cytochrome P 450 (CYP)-mediated metabolism of RA. In vitro, nanomolar concentrations of R115866 inhibited the conversion of RA by CYP26, a RA-inducible RA metaboli zing enzyme. in vivo, oral administration of R115866 (2.5 mg/kg) to rats in duced marked and transient increases of endogenous RA levels in plasma, ski n, fat, kidney, and testis. Consistent with its ability to enhance endogeno us RA content in tissues, R115866 was found to exert retinoidal activities. Like RA, the title compound: 1) inhibited vaginal keratinization in estrog en-stimulated rats; 2) induced epidermal hyperplasia in mouse ear skin; 3) transformed mouse tail epidermis from a para- to an orthokeratotic skin typ e; 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 anta gonist, 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, suppor ting the idea that the actions of R115866 result from increased availabilit y of endogenous RA and improved RAR triggering.