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A Naturally Occurring Isoform-Specific Probe for Highly Selective and Sensitive Detection of Human Cytochrome P450 3A5
Wu, Jing-Jing1; Cao, Yun-Feng1,2; Feng, Liang1; He, Yu-Qi3; Hong, James Y.4; Dou, Tong-Yi1; Wang, Ping1; Hao, Da-Cheng5; Ge, Guang-Bo1; Yang, Ling6
刊名JOURNAL OF MEDICINAL CHEMISTRY
2017-05-11
DOI10.1021/acs.jmedchem.7b00001
60页:3804-3813
收录类别SCI
文章类型Article
WOS标题词Science & Technology ; Life Sciences & Biomedicine
类目[WOS]Chemistry, Medicinal
研究领域[WOS]Pharmacology & Pharmacy
关键词[WOS]HUMAN LIVER-MICROSOMES ; IN-VITRO METABOLISM ; CYP3A5 ; P450 ; EXPRESSION ; IDENTIFICATION ; INACTIVATION ; INHIBITION ; ENZYMES ; MARKERS
英文摘要Cytochrome P450 (CYP) 3A5 characterized with polymorphic and extensive expression in multiple tissues is the most important P450 enzyme among the minor CYP3A isoforms. However, a selective and sensitive probe for CYP3A5 remains unavailable. In this study, we identified and characterized a naturally occurring lignan 12 (schisantherin E) as an isoform-specific probe for selective detection of CYP3A5 activity in complex biological samples. With thorough characterization including LC-MS and NMR, we found that 12 can be metabolized by CYP3A5 to generate a major metabolite 2-O-demethylated 12. Meanwhile, both reaction phenotyping and chemical inhibition experiments further revealed that CYP3A5 selectively catalyzed the 2-O-demethylation of 12. Specifically, the interactions between the Phe210 residue of CYP3A5 and methyl benzoate of 12 might play key roles in 12-O-demethylation, which was revealed by docking simulation and site-directed mutagenesis studies. These findings are beneficial for exploring the role of CYP3A5 in drug metabolism and pathologic process.
语种英语
WOS记录号WOS:000401403100019
引用统计
文献类型期刊论文
条目标识符http://cas-ir.dicp.ac.cn/handle/321008/152282
专题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, Dalian 116023, Peoples R China
2.Key Lab Liaoning Tumor Clin Metabol, Jinzhou, Liaoning, Peoples R China
3.Zunyi Med Univ, Minist Educ, Key Lab Basic Pharmacol, Sch Pharm, Zunyi 563000, Guizhou, Peoples R China
4.Univ Illinois, Dept Biopharmaceut Sci, Chicago, IL 60612 USA
5.Dalian Jiaotong Univ, Sch Environm & Chem Engn, Dalian 116028, Peoples R China
6.Shanghai Univ Tradit Chinese Med, Shanghai 201203, Peoples R China
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Wu, Jing-Jing,Cao, Yun-Feng,Feng, Liang,et al. A Naturally Occurring Isoform-Specific Probe for Highly Selective and Sensitive Detection of Human Cytochrome P450 3A5[J]. JOURNAL OF MEDICINAL CHEMISTRY,2017,60:3804-3813.
APA Wu, Jing-Jing.,Cao, Yun-Feng.,Feng, Liang.,He, Yu-Qi.,Hong, James Y..,...&Yang, Ling.(2017).A Naturally Occurring Isoform-Specific Probe for Highly Selective and Sensitive Detection of Human Cytochrome P450 3A5.JOURNAL OF MEDICINAL CHEMISTRY,60,3804-3813.
MLA Wu, Jing-Jing,et al."A Naturally Occurring Isoform-Specific Probe for Highly Selective and Sensitive Detection of Human Cytochrome P450 3A5".JOURNAL OF MEDICINAL CHEMISTRY 60(2017):3804-3813.
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