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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。
OBJECTIVE To study the metabolic transformation of 1-hydroxy-2,3,5-trimethoxysilyl ketone (HM-1) in rat liver microsomes and to identify the molecular mechanisms involved in the metabolism of 1-hydroxy- CYP450 enzyme subtype of 5-trimethoxy metabolism. Methods The rat liver microsomal incubation system was used to determine the concentration of 1-hydroxy-2,3,5-trimethoxyside in large Metabolic pathway in rat liver microsomes and identify the major CYP450 enzyme subtypes involved in the metabolism of 1-hydroxy-2,3,5-trimethoxyketone in rat liver microsomes by addition of specific chemical inhibitors. Results Six major metabolites were detected in rat liver microsomes. The structural elucidation of unknown metabolites showed that the phase I metabolic reaction of 1-hydroxy-2,3,5-trimethoxystrone was mainly demethylated CYP1A2, CYP2C6 / 11, CYP2D2, CYP2E1 and CYP3A2 are all involved in the metabolism of 1-hydroxy-2,3,5-trimethoxystrone in rat liver microsomes, of which CYP2C6 / 11 is more involved with CYP3A2. Conclusion The metabolic pathway of 1-hydroxy-2,3,5-trimethoxysilfenone in rat microsomes was further improved. It was identified that the participation of 1-hydroxy-2,3,5-trimethoxysilane in rats In metabolic CYP450 enzyme subtypes, which will provide a reference for the drug-drug interaction studies of 1-hydroxy-2,3,5-trimethoxysilane and provide guidance for the rational use of drug anchors.