DICP OpenIR
Subject Area物理化学
Deoxyschizandrin, a Naturally Occurring Lignan, Is a Specific Probe Substrate of Human Cytochrome P450 3A
Wu, Jingjing1,3; Cao, Yunfeng1,4; Zhang, Yanyan1; Liu, Yong1; Hong, James Y.2; Zhu, Liangliang1,3; Ge, Guangbo1; Yang, Ling1; Yang L(杨凌)
Source PublicationDRUG METABOLISM AND DISPOSITION
2014
DOI10.1124/dmd.113.053884
Volume42Issue:1Pages:94-104
Indexed BySCI
Cooperation Status
SubtypeArticle
Department18
Funding Project1806
Contribution Rank待补充
WOS HeadingsScience & Technology ; Life Sciences & Biomedicine
Funding Organization1,1 ; 1,1 ; 1,1 ; 1,1
WOS SubjectPharmacology & Pharmacy
WOS Research AreaPharmacology & Pharmacy
WOS KeywordDRUG-DRUG INTERACTIONS ; HUMAN LIVER-MICROSOMES ; IN-VITRO METABOLISM ; TESTOSTERONE-METABOLISM ; DEPENDENT MODULATION ; CATALYTIC-ACTIVITY ; CYP3A4 ; MIDAZOLAM ; INHIBITION ; RAT
AbstractTo 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.
Language英语
Funding Organization1,1 ; 1,1 ; 1,1 ; 1,1
URL查看原文
WOS IDWOS:000329502200012
Citation statistics
Cited Times:16[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://cas-ir.dicp.ac.cn/handle/321008/119724
Collection中国科学院大连化学物理研究所
Corresponding AuthorYang L(杨凌)
Affiliation1.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
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..,...&杨凌.(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.
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