Laboratory of Drug Metabolism and Pharmacokinetics, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
Drug Metab Pharmacokinet. 2011;26(4):331-40. doi: 10.2133/dmpk.dmpk-10-rg-115. Epub 2011 Mar 14.
The constitutive androstane receptor (CAR) is an orphan nuclear receptor which has been shown to participate in the activation of human CYP3A4, which metabolizes more than 50% of clinically used drugs. We investigated the effects of an array of compounds isolated from herbal medicines such as Rheum palmatum (Da Huang), Peucedanum praeruptorum Dunn (Qian Hu), Cortex Mori Radicis (Sang Bai Pi), Radix Asteris (Zi Wan), Salvia miltiorrhiza (Dan Shen), Polygonum cuspidatum Sieb. et Zucc (Hu Zhang), and Ginkgo biloba (Yin Xing) on the CAR-mediated transactivation of CYP3A4. The effect of herbal compounds on CYP3A4 expression was measured using a CYP3A4 luciferase reporter gene assay in transiently transfected human intestinal LS174T cells. The gene expression, protein expression, and catalytic activity of CYP3A4 in LS174T cells transfected with CAR were determined by using real-time PCR, Western blot analysis, and LC-MS/MS-based substrate assay. The study found that in CAR-transfected cells, praeruptorin A, C, and D significantly induced CYP3A4 luciferase activity, mRNA expression, and functional activity through the CAR-mediated pathway; conversely, induction was not found in untransfected cells. Our findings suggest that these herbal compounds can significantly up-regulate the CYP3A4 gene via the CAR-mediated pathway, which has important implications in herb-drug interactions.
组成型雄烷受体（CAR）是一种孤儿核受体，已被证明参与了人类 CYP3A4 的激活，CYP3A4 代谢了超过 50%的临床使用药物。我们研究了一系列从草药中分离得到的化合物对 CAR 介导的 CYP3A4 转录激活的影响，这些草药包括大黄（Rheum palmatum，Da Huang）、前胡（Peucedanum praeruptorum Dunn，Qian Hu）、桑白皮（Cortex Mori Radicis，Sang Bai Pi）、紫菀（Radix Asteris，Zi Wan）、丹参（Salvia miltiorrhiza，Dan Shen）、虎杖（Polygonum cuspidatum Sieb. et Zucc，Hu Zhang）和银杏（Ginkgo biloba，Yin Xing）。我们使用瞬时转染的人肠 LS174T 细胞中的 CYP3A4 荧光素酶报告基因测定来测量草药化合物对 CYP3A4 的影响。通过使用实时 PCR、Western blot 分析和基于 LC-MS/MS 的底物测定，在转染了 CAR 的 LS174T 细胞中测定 CYP3A4 的基因表达、蛋白表达和催化活性。研究发现，在 CAR 转染的细胞中，白花前胡甲素、白花前胡丙素和白花前胡丁素通过 CAR 介导的途径显著诱导 CYP3A4 荧光素酶活性、mRNA 表达和功能活性；而在未转染的细胞中则没有发现诱导作用。我们的研究结果表明，这些草药化合物可以通过 CAR 介导的途径显著上调 CYP3A4 基因，这对草药-药物相互作用具有重要意义。
