Chen Qian, Wu Yu-jing, Cheng Neng-neng, Li Ya-lin, Wang Yong-ming
Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China.
Yao Xue Xue Bao. 2010 Sep;45(9):1194-8.
This study is to investigate the effects of aqueous extract of Schisandra chinensis Baill (WWZ), kadsurin, schisandrin A, schisandrin B and schisandrol B on rat hepatic CYP3A. Rats received a daily gavage of aqueous extract of WWZ for different times. The livers were harvested after gavage and subjected to microsome preparation. Microsomal CYP3A activity was determined by measuring the amount of the metabolite of testosterone (6 beta-hydroxytestosterone) with HPLC. Aqueous extract of WWZ, kadsurin and schisandrin A were incubated with microsomes obtained from rat. Microsomal CYP3A activity was determined by HPLC. Primary hepatocytes were separated and extracted from rat, then were treated with aqueous extract of WWZ, schisandrin A, schisandrin B and schisandrol B. Then, the expression of CYP3A1 mRNA was analyzed by RT-PCR. As for the in vivo assay, aqueous extract of WWZ significantly inhibited the enzyme activity of CYP3A after 12 h gavage. The inhibitory effect was converted to inductive effect after 3-day gavage. Aqueous extract of WWZ could induce the enzyme activity of CYP3A after 6-day gavage. Aqueous extract of WWZ and kadsurin showed a dose-dependent inhibition of CYP3A (IC50 of 487.8 microg mL(-1) and 6.2 micromol L(-1), separately). In rat primary hepatocytes, aqueous extract of WWZ (2.5 mg mL(-1)), schisandrin A (0.1 micromol L(-1)), schisandrin B (0.1 micromol L(-1)) and schisandrol B (10 micromol L(-1)) increased significantly the expression of CYP3A1 mRNA by 23%, 55%, 42% and 27%, respectively. Aqueous extract of WWZ could show dual effect on the enzyme activity of CYP3A in rat in vivo. Meanwhile, kadsurin showed a dose-dependent inhibition of the enzyme activity of hepatic CYP3A in vitro. And schisandrin A, schisandrin B and schisandrol B showed significant inductive effect on the expression of rat CYP3A1 mRNA.
本研究旨在探讨五味子水提取物（WWZ）、南五味子酸、五味子醇甲、五味子醇乙和五味子酯甲对大鼠肝脏CYP3A的影响。大鼠每日接受不同时间的WWZ水提取物灌胃。灌胃后取肝脏并进行微粒体制备。通过高效液相色谱法（HPLC）测定睾酮代谢产物（6β-羟基睾酮）的量来确定微粒体CYP3A活性。将WWZ水提取物、南五味子酸和五味子醇甲与大鼠来源的微粒体一起孵育。通过HPLC测定微粒体CYP3A活性。从大鼠分离并提取原代肝细胞，然后用WWZ水提取物、五味子醇甲、五味子醇乙和五味子酯甲进行处理。然后，通过逆转录聚合酶链反应（RT-PCR）分析CYP3A1 mRNA的表达。在体内试验中，WWZ水提取物灌胃12小时后显著抑制CYP3A的酶活性。灌胃3天后抑制作用转变为诱导作用。灌胃6天后，WWZ水提取物可诱导CYP3A的酶活性。WWZ水提取物和南五味子酸对CYP3A表现出剂量依赖性抑制（IC50分别为487.8μg mL(-1)和6.2μmol L(-1)）。在大鼠原代肝细胞中，WWZ水提取物（2.5mg mL(-1)）、五味子醇甲（0.1μmol L(-1)）、五味子醇乙（0.1μmol L(-1)）和五味子酯甲（10μmol L(-1)）分别使CYP3A1 mRNA的表达显著增加23%、55%、42%和27%。WWZ水提取物对大鼠体内CYP3A的酶活性可表现出双重作用。同时，南五味子酸在体外对肝脏CYP3A的酶活性表现出剂量依赖性抑制。而五味子醇甲、五味子醇乙和五味子酯甲对大鼠CYP3A1 mRNA的表达表现出显著的诱导作用。
