Xie Yiqiang, Li Yuhua, Huang Mianqing, Wu Qing, Liu Qibing, Zhang Junqing, Deng Huiming, Liu Mi, Huang Ling
The School of TCM of Hainan Medical University, Haikou, PR China.
Department of Pharmacy, the First Affiliated Hospital of Nanchang University, Nanchang, PR China.
Pak J Pharm Sci. 2018 Sep;31(5(Special)):2315-2321.
Feng-Liao-Chang-Wei-Kang (FLCWK), a traditional Chinese patent medicine, consists primarily of Polygonum hydropiper and Daphniphyllum calycinum roots. As a complex containing several kinds of flavonoids, FLCWK has the potential to impact the drug metabolism enzyme P450 3A4 (CYP3A4) and nuclear receptors. The purpose of this research was to probe the effects of FLCWK on CYP3A1, the homolog of CYP3A4 in rats, and to confirm whether FLCWK interferes with PXR and CAR-mediated transactivation of CYP3A4. The effects of FLCWK on Cyp3a1 mRNA, catalytic activity levels, and protein expression in Sprague-Dawley (SD) rat liver tissues were examined using real-time PCR, western blotting, and high-performance liquid chromatography (HPLC) assays, respectively. The efficacy of PXR and CAR on CYP3A4 transcriptional activity were detected using luciferase reporter assays and further research of the impact of FLCWK on CYP3A4 gene expression mediated by the PXR pathway was examined by transient transfection of PXR siRNA. FLCWK significantly increased Cyp3a1 mRNA, CYP3A1 activity, and protein expression levels in SD rats. FLCWK highly induced CYP3A4 luciferase activity mediated by PXR in PXRCYP3A4 co-transfected cells. A siRNA-mediated drop-off in PXR expression greatly cut the effect of FLCWK on CYP3A4 mRNA expression in HepG2 cells. These findings show that FLCWK up-regulates CYP3A4 levels via the PXR pathway. This effect should be considered being applied in clinical use as FLCWK has the potential to interact with other drugs.
枫蓼肠胃康，一种传统中成药，主要由水蓼和黄杨叶巴豆根组成。作为一种含有多种黄酮类化合物的复合物，枫蓼肠胃康有可能影响药物代谢酶P450 3A4（CYP3A4）和核受体。本研究的目的是探究枫蓼肠胃康对大鼠体内CYP3A4的同源物CYP3A1的影响，并确认枫蓼肠胃康是否干扰PXR和CAR介导的CYP3A4反式激活。分别使用实时PCR、蛋白质印迹法和高效液相色谱（HPLC）分析法检测枫蓼肠胃康对Sprague-Dawley（SD）大鼠肝脏组织中Cyp3a1 mRNA、催化活性水平和蛋白质表达的影响。使用荧光素酶报告基因检测法检测PXR和CAR对CYP3A4转录活性的作用，并通过瞬时转染PXR siRNA进一步研究枫蓼肠胃康对由PXR途径介导的CYP3A4基因表达的影响。枫蓼肠胃康显著增加了SD大鼠体内的Cyp3a1 mRNA、CYP3A1活性和蛋白质表达水平。在共转染PXRCYP3A4的细胞中，枫蓼肠胃康高度诱导了由PXR介导的CYP3A4荧光素酶活性。siRNA介导的PXR表达下降大大削弱了枫蓼肠胃康对HepG2细胞中CYP3A4 mRNA表达的影响。这些发现表明，枫蓼肠胃康通过PXR途径上调CYP3A4水平。由于枫蓼肠胃康有可能与其他药物相互作用，这种作用在临床应用中应予以考虑。
