欧前胡素和异欧前胡素对人和大鼠肝微粒体细胞色素P450酶活性的抑制作用

Inhibitory effect of imperatorin and isoimperatorin on activity of cytochrome P450 enzyme in human and rat liver microsomes

欧前胡素(IM)和异欧前胡素(ISOIM)是伞形科常用中药的主要有效成分,在临床上广泛应用。该文研究了IM和ISOIM对人和大鼠肝微粒体细胞色素P450酶(CYP)活性的抑制作用,并评价它们的相互作用潜能。在体外将系列浓度的IM和ISOIM与人和大鼠肝微粒体孵育30 min,以非那西丁、安非他酮、甲苯磺丁脲、S-美芬妥英、右美沙芬和咪达唑仑为CYP探针底物,应用LC-MS/MS定量检测各探针底物的代谢产物生成量,计算得到的IC50,评价两药对人肝CYP1A2,2B6,2C9,2C19,2D6,3A4酶,以及大鼠肝CYP1A2,2B6,2D2,3A1/2酶的抑制活性,并对抑制强度进行分级。在人肝微粒体中,IM和ISOIM对6个CYP同工酶均有不同程度的抑制作用。它们是1A2和2B6的强抑制剂,抑制1A2的IC50分别为0.05,0.20μmol.L-1;抑制2B6的IC50分别为0.18,1.07μmol.L-1。两药还是2C19的中等抑制剂,以及2C9,2D6,3A4的弱抑制剂。在大鼠肝微粒体中,IM和ISOIM是1A2的中等抑制剂,IC50分别为1.95,2.98μmol.L-1。它们分别是2B6的中等和弱抑制剂,IC50为6.22,21.71μmol.L-1。两药还是2D2,3A1/2的弱抑制剂。结果表明IM,ISOIM对人肝CYP酶有广泛的抑制作用,它们是CYP1A2和2B6酶的强抑制剂,临床用药时应注意因CYP酶抑制引起的相互作用。

Imperatorin （IM） and isoimperatorin （ISOIM） are major active components of common herbal medicines from Um- belliferae plants, and widely used in clinic. This article studies the inhibitory effect of IM and ISOIM on the activity of cytochrome P450 （CYP） enzyme, and assesses their potential drug-drug interaction. IM and ISOIM were incubated separately with human or rat liver microsomes for 30 rain, with phenacetin, bupropion, tolbutamide, S-mephenytoin, dextormethorphan and midazolam as probe sub- strates. Metabolites of the CYP probe substrates were determined by LC-MS/MS, and ICs0values were calculated to assess the inhibito- ry effect of the two drugs on human CYP1A2, 2B6, 2C9, 2C19, 2D6 and 3A4 enzymes, as well as on rat CYP1A2, 2B6, 2D2 and 3A1/2, and grade their inhibitory intensity. In human liver microsomes, IM and ISOIM showed different inhibitory effects on all of the six CYP isoenzymes. They were strong inhibitors for 1A2 and 2B6. The ICso values were 0. 05 and 0. 20 μg·L^-1 for IA2, and 0. 18 and 1.07 μg·L^-1 for 2B6, respectively. They also showed moderate inhibitory effect on 2C19, and weak effect on 2C9, 2D6 and 3A4. In rat liver microsomes, IM and ISOIM were identified as moderate inhibitors for 1A2, with ICs0 values of 1.95 and 2. 98μg·L^-1. They were moderate and weak inhibitors for 2B6, with IC50 values of 6. 22 and 21.71 μg·L^-1 , respectively. They also had weaker inhibitory effect on 2D2 and 3A1/2. The results indicated that IM and ISOIM had extensive inhibitory effects on human CYP enzymes. They are strong inhibitors of CYP1A2 and 2B6 enzymes. However, it is worth noting the interaction arising from the inhibito- ry effect of CYP enzymes in clinic.