Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland 20892.
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21201.
Toxicol Sci. 2019 Jan 1;167(1):282-292. doi: 10.1093/toxsci/kfy242.
The constitutive androstane receptor (CAR; NR1I3) is a nuclear receptor involved in all phases of drug metabolism and disposition. However, recently it's been implicated in energy metabolism, tumor progression, and cancer therapy as well. It is, therefore, important to identify compounds that induce human CAR (hCAR) activation to predict drug-drug interactions and potential therapeutic usage. In this study, we screen the Tox21 10,000 compound collection to characterize hCAR activators. A potential novel structural cluster of compounds was identified, which included nitazoxanide and tenonitrozole, whereas known structural clusters, such as flavones and prazoles, were also detected. Four compounds, neticonazole, diphenamid, phenothrin, and rimcazole, have been identified as novel hCAR activators, one of which, rimcazole, shows potential selectivity toward hCAR over its sister receptor, the pregnane X receptor (PXR). All 4 compounds translocated hCAR from the cytoplasm into the nucleus demonstrating the first step to CAR activation. Profiling these compounds as hCAR activators would enable an estimation of drug-drug interactions, as well as identify prospective therapeutically beneficial drugs.
组成型雄烷受体（CAR；NR1I3）是一种参与药物代谢和处置所有阶段的核受体。然而，最近它也与能量代谢、肿瘤进展和癌症治疗有关。因此，识别能够诱导人 CAR（hCAR）激活的化合物对于预测药物相互作用和潜在的治疗用途非常重要。在这项研究中，我们筛选了 Tox21 一万种化合物库，以鉴定 hCAR 激活剂。确定了一个潜在的新型化合物结构簇，其中包括硝唑尼特和替硝唑，而黄酮类和苯并咪唑类等已知结构簇也被检测到。鉴定了四种化合物，即奈替康唑、双苯酰胺、苯醚菊酯和里姆唑，它们是新型 hCAR 激活剂，其中一种，里姆唑，对 hCAR 表现出相对于其姊妹受体孕烷 X 受体（PXR）的潜在选择性。所有 4 种化合物均将 hCAR 从细胞质转位到细胞核，证明了 CAR 激活的第一步。将这些化合物鉴定为 hCAR 激活剂可以估计药物相互作用，并确定有潜在治疗益处的药物。
