Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (F.S., S.T., N.I.); and School of Molecular Biosciences and the Center for Reproductive Biology, Washington State University, Pullman, Washington (C.H., T.K.).
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (F.S., S.T., N.I.); and School of Molecular Biosciences and the Center for Reproductive Biology, Washington State University, Pullman, Washington (C.H., T.K.)
Drug Metab Dispos. 2017 Jul;45(7):846-854. doi: 10.1124/dmd.117.075341. Epub 2017 Apr 26.
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.
视黄酸（RA）是维生素 A 的活性代谢物，是几种核受体的配体，是许多生理过程的关键调节剂。细胞色素 P450 家族 26（CYP26）酶负责 RA 的清除，是增加组织中内源性 RA 浓度的潜在药物靶点。他拉唑唑是 CYP26A1 和 CYP26B1 的强效抑制剂，在临床试验中已取得一些成功。然而，尚不清楚需要改变组织 RA 浓度的幅度才能促进 RA 信号改变。本研究的目的是量化增加内源性 RA 浓度以改变靶器官中 RA 信号所需的幅度，并确定 CYP26 抑制与组织中改变的 RA 浓度之间的关系。给小鼠单次给予 2.5mg/kg 的他拉唑唑后，血清、肝脏和睾丸中的 RA 浓度分别增加了 5.7、2.7 和 2.5 倍，导致肝脏和睾丸中的 诱导，以及肝脏中的 Rar 和 Pgc1 诱导。RA 浓度的增加与他拉唑唑药代动力学和 CYP26 抑制的体外数据非常吻合。给予他拉唑唑多次剂量后，血清中 RA 浓度显著增加，但肝脏或睾丸中没有增加。这种 RA 浓度的增加与肝脏中 CYP26A1 表达的增加相关。血清中 RA 浓度增加而肝脏中没有变化表明，肝外部位的 CYP26B1 在调节全身 RA 暴露中发挥关键作用。
