针对从椭圆叶花锚中提取的1-羟基-2,3,5-三甲氧基山山酮与人细胞色素P450酶的模型探针基质之间代谢性相互作用的酶动力学与分子嵌合研究

Wang, Y.; State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing 100050, China; email:wangyan@imm.ac.cn

Halenia elliptica D. Don is a Tibetan herb and medicinal preparations containing Halenia elliptica have been commonly used for the treatment of hepatitis B virus infection in China. The metabolism of 1-hydroxy-2,3,5- trimethoxy-xanthone (HM-1) to its metabolites is mediated through cytochrome P450 enzymes. This study aimed to investigate the herb-drug interaction potential of HM-1 by studying its effects on the metabolism of model probe substrates of five major CYP450 isoforms in human liver microsomes. HM-1 showed moderate inhibitory effects on CYP1A2 (IC 50 = 1.06 μM) and CYP2C9 (IC 50 = 3.89 μM), minimal inhibition on CYP3A4 (IC 20 = 11.94 μM), but no inhibition on model CYP2D6 (dextromethorphan) and CYP2E1 (chlorzoxazone) probe substrates. Inhibition kinetic studies showed that the K i values of HM-1 on CYP1A2, CYP2C9 and CYP3A4 were 5.12 μM, 2.00 μM and 95.03 μM, respectively. HM-1 competitively inhibited testosterone 6β-hydroxylation (CYP3A4) but displayed mixed type inhibitions for phenacetin O-deethylation (CYP1A2) and tolbutamide 4-hydroxylation (CYP2C9). Molecular docking study confirmed the inhibition modes of HM-1 on these human CYP isoforms. © 2012 Elsevier GmbH. All rights reserved.

State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing 100050, China