花锚酮类化合物1-羟基-2,3,5-三甲氧基酮在大鼠肝脏微粒体中的代谢转化及CYP450酶亚型的鉴定  

Biotransformation and Involved CYP450 Isomers of Bioactive Xanthone HM-1 from Halenia elliptica,D.Don in Rat Liver Microsomes

作　　者：谭湘姗 冯茹 石建功 车镇涛 王琰 

机构地区：[1]中国医学科学院药物研究所,天然药物活性物质与功能国家重点实验室,北京100050 [2]Department of Medicinal Chemistry&Pharmacognosy(MC 781),UIC College of Pharmacy,Chicago,IL 60612-7231

出　　处：《中国药学杂志》2014年第19期1704-1709,共6页Chinese Pharmaceutical Journal

基　　金：“重大新药创制”科技重大专项(2012ZX09301-002-001,2012ZX09301-002-006);国家自然基金面上项目(30873115);中国医学科学院药物所基本科研业务费(2012CHX18)

摘　　要：目的研究花锚酮类化合物1-羟基-2,3,5-三甲氧基酮(HM-1)在大鼠肝脏微粒体中的代谢转化,并鉴定参与1-羟基-2,3,5-三甲氧基代谢的CYP450酶亚型。方法采用大鼠肝脏微粒体温孵体系,结合高效液相-离子阱-飞行时间质谱技术(LC/MSn-IT-TOF),确定1-羟基-2,3,5-三甲氧基酮在大鼠肝脏微粒中的代谢途径,并通过加入特异性化学抑制剂,鉴定参与1-羟基-2,3,5-三甲氧基酮在大鼠肝脏微粒体中代谢的主要CYP450酶亚型。结果在大鼠肝微粒体中主要检测到6个代谢产物,通过对未知代谢产物进行结构解析,表明1-羟基-2,3,5-三甲氧基酮的I相代谢反应主要是去甲基化或/和羟化反应;CYP1A2、CYP2C6/11、CYP2D2、CYP2E1、CYP3A2均参与了1-羟基-2,3,5-三甲氧基酮在大鼠肝脏微粒体中的代谢,其中CYP2C6/11与CYP3A2的参与程度较高。结论进一步完善了1-羟基-2,3,5-三甲氧基酮在大鼠微粒体中的代谢途径,鉴别了参与1-羟基-2,3,5-三甲氧基酮在大鼠中代谢的CYP450酶亚型,这将为1-羟基-2,3,5-三甲氧基酮的药物药物相互作用研究提供参考,也为花锚的临床合理用药提供指导。ABSTRACT：OBJECTIVE To study the biotransformation of bioactive xanthones 1- hydroxyl- 2, 3, 5- trimethoxyxanthone （ HM-1 ） from Halenia eUiptica, D. Don and five mostly common CYP450 isoforms involved of the its metabolism in rat liver microsomes （RLMs）. METHODS Using RLMs, combining high performance liquid chromatography coupled to ion trap time-of-flight mass spectrometry （LC/MS n-IT-TOF） , the metabolic pathway of HM-1 was profiled. CYP1A2, CYP2C6/11, CYP2D2, CYP2E1, CYP3A2 were studied to identify the involved isoforms by using specific chemical inhibitor of each isoform. RESULTS Six phase I metabo- lites were detected and identified in the metabolism of HM-1 in RLMs. Demethylation or/and hydroxylation were the major phase I metabolic reactions. By using specific chemical inhibitors with three different concentrations, CYP1A2, CYP2C6/11, CYP2D2, CYP2E1, CYP3A2 were all found to be involved in the metabolism of HM-1. By contrast, CYP2C6/11 and CYP3A2 were the most involved isoforms. CONCLUSION The metabolic profile of HM-1 is further improved, and CYP450 isomers involved in metablosm of HM-1 in RLMs is identified. This will provide a scientific reference for the drug-drug interaction of HM-1 and an instruction for the clinical use of Halenia elliptica, D. Don.

关 键 词：1-羟基-2 3 5-三甲氧基[口山]酮 CYP450 高效液相-离子阱-飞行时间质谱 特异性化学抑制剂 代谢转化 

分 类 号：R965[医药卫生—药理学]