Inhibition of the Retinoic Acid (RA) Hydroxylases CYP26A1 and CYP26B1 Results in Dynamic, Tissue-Specific Changes in Endogenous RA Signaling.

retinoic acid (RA), the active metabolite of vitamin A, is a ligand for several nuclear receptors and acts as a critical regulator of many physiologic processes. The cytochrome P450 family 26 (CYP26) enzymes are responsible for RA clearance, and are potential drug targets to increase concentrations of endogenous RA in a tissue-specific manner. Talarozole is a potent inhibitor of CYP26A1 and CYP26B1, and has shown some success in clinical trials. However, it is not known what magnitude of change is needed in tissue RA concentrations to promote RA signaling changes. The aim of this study was to quantify the increase in endogenous RA concentrations necessary to alter RA signaling in target organs, and to establish the relationship between CYP26 inhibition and altered RA concentrations in tissues. Following a single 2.5-mg/kg dose of talarozole to mice, RA concentrations increased up to 5.7-, 2.7-, and 2.5-fold in serum, liver, and testis, respectively, resulting in induction of in the liver and testis and Rar and Pgc 1 in liver. The increase in RA concentrations was well predicted from talarozole pharmacokinetics and in vitro data of CYP26 inhibition. After multiple doses of talarozole, a significant increase in RA concentrations was observed in serum but not in liver or testis. This lack of increase in RA concentrations correlated with an increase in CYP26A1 expression in the liver. The increased RA concentrations in serum without a change in liver suggest that CYP26B1 in extrahepatic sites plays a key role in regulating systemic RA exposure.