欧前胡素和异欧前胡素对体外细胞色素P450酶活性的-中国中药杂志.docVIP

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 曹 艳1,2，钟玉环1，原 梅1，李 桦1*，赵春杰2 (1. 军事医学科学院 毒物药物研究所，北京 100850； 2. 沈阳药科大学，辽宁 沈阳 110016) [摘要] 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。本文研究了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值，评价两药对人肝CYP1A2、2B6、2C9、2C19、2D6和3A4酶，以及大鼠肝CYP1A2、2B6、2D2和3A1/20.05和0.20 μmol·L-1；抑制2B6 的IC50分别为0.18和1.07 μmol·L-1。两药还是2C19的中等抑制剂，以及2C9、2D6和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和2.98 μmol·L-1。它们分别是2B6 的中等和弱抑制剂，IC50为6.22和21.71 μmol·L-1。两药还是2D2和3A1/2的弱抑制剂。结果表明，IM和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。 关键词：欧前胡素；异欧前胡素；细胞色素P450酶；肝微粒体；药物相互作用Inhibitory effects of imperatorin and isoimperatorin on cytochrome P450 enzymes in human and rat liver microsomes CAO Yan1,2, ZHONG Yu-Huan1, YUAN Mei1, LI Hua1*, ZHAO Chun-Jie2 (1. Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing 100850, China; 2. Shenyang Pharmaceutical University, Shenyang 110016, China) [Abstract] Imperatorin (IM) and isoimperatorin (ISOIM) are major active components of the herb medicines from Umbelliferae plants. They have been widely used to treat various diseases. In the present study, the inhibitory effects of IM and ISOIM on cytochrome P450 (CYP) isoforms were evaluated in vitro to assess their potential drug-drug interaction. IM and ISOIM were incubated separately with human or rat liver microsomes for 30 min, in the presence of NADPH and a group of CYP probe substrates. The activities of the CYP isoforms were determined by LC-MS/MS analysis of the metabolites of the CYP probe substrates, including phenacetin, bupropion, tolbutamide, S-mephenytoin, dextromethorphan and midazolam. IC50 values were calculated to grade the inhibitory potencies of the drugs on human CYP1A2, 2B6, 2C9, 2C19, 2D6 and 3A4, as well as on rat CYP1A2, 2B6, 2D2 and 3A1/2. In human liver microsomes, IM and ISOIM showed differ