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学科主题: 物理化学
题名: Deoxyschizandrin, a Naturally Occurring Lignan, Is a Specific Probe Substrate of Human Cytochrome P450 3A
作者: Wu, Jingjing1, 3;  Cao, Yunfeng1, 4;  Zhang, Yanyan1;  Liu, Yong1;  Hong, James Y.2;  Zhu, Liangliang1, 3;  Ge, Guangbo1;  Yang, Ling1
通讯作者: 杨凌
刊名: DRUG METABOLISM AND DISPOSITION
发表日期: 2014
DOI: 10.1124/dmd.113.053884
卷: 42, 期:1, 页:94-104
收录类别: SCI
合作性质: 
文章类型: Article
部门归属: 18
项目归属: 1806
产权排名: 待补充
WOS标题词: Science & Technology ;  Life Sciences & Biomedicine
类目[WOS]: Pharmacology & Pharmacy
资助者: 1,1
研究领域[WOS]: Pharmacology & Pharmacy
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.
关键词[WOS]: DRUG-DRUG INTERACTIONS ;  HUMAN LIVER-MICROSOMES ;  IN-VITRO METABOLISM ;  TESTOSTERONE-METABOLISM ;  DEPENDENT MODULATION ;  CATALYTIC-ACTIVITY ;  CYP3A4 ;  MIDAZOLAM ;  INHIBITION ;  RAT
语种: 英语
原文出处: 查看原文
WOS记录号: WOS:000329502200012
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/119724
Appears in Collections:中国科学院大连化学物理研究所_期刊论文

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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

Recommended Citation:
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.
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