Deoxyschizandrin, a Naturally Occurring Lignan, Is a Specific Probe Substrate of Human Cytochrome P450 3A

	Deoxyschizandrin, a Naturally Occurring Lignan, Is a Specific Probe Substrate of Human Cytochrome P450 3A
	Wu, Jingjing 1,3; Cao, Yunfeng 1,4; Zhang, Yanyan 1; Liu, Yong 1; Hong, James Y.2; Zhu, Liangliang 1,3; Ge, Guangbo 1; Yang, Ling 1
刊名	drug metabolism and disposition
	2014
卷号	42 期号:1 页码:94-104
通讯作者	杨凌
产权排序	待补充
合作状况	英
英文摘要	to accurately predict the modifications done during metabolic processes by cytochrome p450 (p450) 3a enzyme, selecting substrates that best represent a broad range of substrate substitutions and that follow the michaelis-menten kinetic properties is highly necessary. in the present study, the oxidative pathways of deoxyschizandrin (ds), the most abundant lignan in fructus schisandrae fruit extract, were characterized with liver microsomes from human (hlm) and rat (rlm). only one monohydroxylated metabolite 7(s)-hydroxylated metabolite (isoschizandrin, isz), was identified using liquid chromatography-mass spectrometry and nuclear magnetic resonance techniques. cyp3a4 and cyp3a5 were found to be the major isoforms involved in the monohydroxylation of ds. also, the kinetic studies showed that ds hydroxylation obeyed michaelis-menten kinetics both in hlm and in rlm. however, the subsequent metabolism of isz was nearly nonexistent when ds was present. more importantly, the interactions between ds and three well characterized cyp3a probe substrates, testosterone (tst), midazolam (mdz), and nifedipine (nif), were studied. tst and mdz were shown to compete with ds for the mutual binding site, causing k-m to be increased. the presence of ds also lowered the binding affinities for mdz and tst. however, ds showed only slight inhibitory effects on nifedipine (nif) oxidation even though nif was able to inhibit ds hydroxylation in a noncompetitive fashion. these results show that ds is a good representative substrate of mdz and tst primarily due to their shared, large binding regions on cyp3a. therefore, ds is an attractive candidate as a novel cyp3a probe substrate for predicting the metabolic modifications in cyp3a activity.
学科主题	物理化学
WOS标题词	science & technology ; life sciences & biomedicine
类目[WOS]	pharmacology & pharmacy
研究领域[WOS]	pharmacology & pharmacy
关键词[WOS]	drug-drug interactions ; human liver-microsomes ; in-vitro metabolism ; testosterone-metabolism ; dependent modulation ; catalytic-activity ; cyp3a4 ; midazolam ; inhibition ; rat
收录类别	SCI
资助信息	1，1
原文出处	104
语种	英语
WOS记录号	WOS:000329502200012
公开日期	2014-09-11
内容类型	期刊论文
源URL	[http://159.226.238.44/handle/321008/119724]
专题	大连化学物理研究所_中国科学院大连化学物理研究所
作者单位	1.Chinese Acad Sci, Dalian Inst Chem Phys, Lab Pharmaceut Resource Discovery, Dalian, Peoples R China 2.Univ Illinois, Dept Biopharmaceut Sci, Chicago, IL USA 3.Chinese Acad Sci, Grad Univ, Beijing, Peoples R China 4.Shanghai Inst Planned Parenthood Res, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	Wu, Jingjing,Cao, Yunfeng,Zhang, Yanyan,et al. Deoxyschizandrin, a Naturally Occurring Lignan, Is a Specific Probe Substrate of Human Cytochrome P450 3A[J]. drug metabolism and disposition,2014,42(1):94-104.
APA	Wu, Jingjing.,Cao, Yunfeng.,Zhang, Yanyan.,Liu, Yong.,Hong, James Y..,...&Yang, Ling.(2014).Deoxyschizandrin, a Naturally Occurring Lignan, Is a Specific Probe Substrate of Human Cytochrome P450 3A.drug metabolism and disposition,42(1),94-104.
MLA	Wu, Jingjing,et al."Deoxyschizandrin, a Naturally Occurring Lignan, Is a Specific Probe Substrate of Human Cytochrome P450 3A".drug metabolism and disposition 42.1(2014):94-104.