摘要
目的研究五味子和五味子科8种木脂素成分对大鼠肝CYP3A1/2活性和人肝CYP3A4活性的影响。方法在体外大鼠及健康人肝微粒体孵育体系中加入底物睾酮和不同浓度的五味子或木脂素成分,甲醇终止反应,用高效液相色谱仪检测睾酮的羟化代谢产物6β羟基睾酮的生成量反映CYP3A酶活性。人原代肝细胞和五味子水提物共同培养3 d后同法测定CYP3A酶活性的变化。结果大鼠肝微粒体孵育体系中,五味子水提物和醇提物对CYP3A1/2酶活性有浓度依赖性抑制作用,IC_(50)分别为487.8和175.7 mg·L^(-1),五味子酯甲、南五味子素、异南五味子素、内南五味子素和angeloyl binankadsurina A的IC_(50)分别为3.77、6.18、20.67、16.43和23.07μmol·L^(-1);人肝微粒体孵育体系中,五味子水提物抑制CYP3A4酶活性的IC_(50)为317.3 mg·L^(-1),8种木脂素成分对酶活性的抑制作用与大鼠微粒体结果相似;人原代肝细胞培养中,五味子水提物(1500 mg·L^(-1))浓度可以抑制50%以上的CYP3A4酶活性。结论体外给药五味子和五种木脂素成分对大鼠肝CYP3A1/2活性和人肝CYP3A4活性有浓度依赖性抑制作用。
A/M To evaluate the effects of Schisandra Chinensis Baill （WWZ） and eight lignans of Schisandraceae plant on the enzyme activities of rat hepatic CYP3A1/2 and human hepatic CYP3A4. METHODS WWZ and eight lignans were incubated with microsomes obtained from rat and human at various concentrations, and the effect upon the rate of testosterone metabolism was determined. Micosomal CYP3A activity was determined by measuring the amount of 613 - hydroxytestosterone by HPLC. Hepatocytes from two human donors were treated with aqueous extract of WWZ for 3 d before the addition of testosterone. After the incubation, aliquots of medium were analyzed for 613-hydroxytestosterone by HPLC. RESULTS Aqueous and ethanolic extracts of WWZ showed dose-dependent inhibition of the formation of 613- hydroxytestosterone from testosterone （ IC50 of 487.8 and 175.7 mg· L^- 1 ） in rat liver microsomes. The most pronounced effects were observed with gomisin C, kadsurin, heterolitin D, interiorin and angeloyl binankadsurina A which inhibited CYP3A1/2-mediated testosterone 613-hydroxylation （IC60 of 3.77, 6.18, 20.67, 16.43 and 23.07 μmol· L^- 1, respec- tively）. The IC50 of aqueous extract of WWZ for the inhibition of human microsomal CYP3A4 activity was 317.3 mg^- 1 and the effects of eight lignans were similar for the inhibition of CYP3A in human and rat. In human hepatocytes chronically exposed to WWZ （ 1 500 mg·L^- 1 ） , CYP3A4 enzyme activity decreased by more than 50%. CONCLUSION WWZ and 5 of 8 lignans tested show dose-dependent inhibition of the enzyme activity of hepatic CYP3A.
出处
《中国临床药学杂志》
CAS
2007年第5期267-271,共5页
Chinese Journal of Clinical Pharmacy
关键词
五味子
木脂素
CYP3A
肝微粒体
肝细胞
大鼠
人
Schisandra Chinensis Baill
lignan
CYP3A
hepatic microsome
hepatic hepatocyte
rat
human
