远志寡糖酯类化合物及远志酮Ⅲ对CYP450酶的活性影响研究

Effect of oligosaccharide esters and polygalaxanthone Ⅲ from Polygala tenuifolia willd towards cytochrome P450

该研究采用人肝微粒体体外孵育的方法,通过特异性探针反应评价从远志中分离得到的寡糖酯类化合物tenuifoliside C,tenuifoliside D,telephiose A,telephiose C和远志酮Ⅲ对8个CYP450酶亚型的抑制作用。分别以非那西丁(CYP1A2)、香豆素(CYP2A6)、紫杉醇(CYP2C8)、双氯芬酸(CYP2C9)、右美沙芬(CYP2D6)、氯唑沙宗(CYP2E1)、咪达唑仑(CYP3A4)、S-美芬妥因(CYP2C19)作为评价CYP450酶活性的体外探针药物,以高效液相色谱法(HPLC)分别测定其代谢产物对乙酰氨基酚、7-羟基香豆素、6α-羟基紫杉醇、4'-羟基双氯芬酸、右啡烷、6-羟基氯唑沙宗、1'-羟基咪达唑仑、4'-羟基美芬妥因的生成量,评价5个单体化合物对CYP450酶活性的影响。研究结果表明,4个寡糖酯类化合物和远志酮Ⅲ对CYP2E1有显著的抑制作用(抑制率>50%),对其他7个亚型CYP1A2,CYP2A6,CYP2C8,CYP2C9,CYP2C19,CYP2D6,CYP3A没有明显抑制作用。IC50分别为38.73,54.14,61.77,62.22,50.56μmol·L-1。

Five compounds（ tenuifoliside C,tenuifoliside D,telephiose A,telephiose C and polygalaxanthone Ⅲ） from polygala tenuifolia willd were incubated together with CYP probe substrate in human liver microsomes to investigate the inhibitory effect towards CYP450 enzyme. Phenacetin（ CYP1A2）,coumarin（ CYP2A6）,paclitaxel（ CYP2C8）,diclofenac（ CYP2C9）,S-mephenytoin（ CYP2C19）,dextromethorphan（ CYP2D6）,chlorzoxazone（ CYP2E1）,midazolam（ CYP3A） were selected as the isoform specific substrate. And the formation of paracetamol,7-hydroxycoumarin,6α-hydroxy paclitaxel,4＇-hydroxydiclofenac,dextrorphan,6-hydro xychlorzoxazone,1＇-hydroxymidazolam,4＇-hydroxymephenytoin were detected respectively to measure the effect towards CYP450 by high-pressure liquid chromatography（ HPLC）. The result shows that five compounds from polygala tenuifolia willd significantly inhibit chlorzoxazone 6-hydroxylation catalyzed by CYP2E1,while showed no effect towards CYP1A2,CYP2A6,CYP2C8,CYP2C9,CYP2C19,CYP2D6,CYP3 A. And IC50 value was 38. 73,54. 14,61. 77,62. 22,50. 56 μmol·L^-1,respectively.