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题名: Structure-inhibition relationship of ginsenosides towards UDP-glucuronosyltransferases (UGTs)
作者: Fang, Zhong-Ze1, 3, 4, 5;  Cao, Yun-Feng2, 3, 4;  Hu, Cui-Min5;  Hong, Mo3, 4;  Sun, Xiao-Yu3, 4;  Ge, Guang-Bo6;  Liu, Yong6;  Zhang, Yan-Yan6;  Yang, Ling6;  Sun, Hong-Zhi1
关键词: Ginsenosides ;  UDP-glucuronosyltransferases (UGTs) ;  Ginseng-drug interaction
刊名: TOXICOLOGY AND APPLIED PHARMACOLOGY
发表日期: 2013-03-01
DOI: 10.1016/j.taap.2012.12.019
卷: 267, 期:2, 页:149-154
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology ;  Life Sciences & Biomedicine
类目[WOS]: Pharmacology & Pharmacy ;  Toxicology
研究领域[WOS]: Pharmacology & Pharmacy ;  Toxicology
英文摘要: The wide utilization of ginseng provides the high risk of herb-drug interaction (HDI) with many clinical drugs. The inhibition of ginsenosides towards drug-metabolizing enzymes (DMEs) has been regarded as an important reason for herb-drug interaction (HDI). Compared with the deep studies on the ginsenosides' inhibition towards cytochrome P450 (CYP), the inhibition of ginsenosides towards the important phase II enzymes UDP-glucuronosyltransferases (UGTs) remains to be unclear. The present study aims to evaluate the inhibition behavior of ginsenosides towards important UGT isoforms located in the liver and intestine using in vitro methods. The recombinant UGT isoform-catalyzed 4-methylumbelliferone (4-MU) glucuronidation reaction was employed as in vitro probe reaction. The results showed that structure-dependent inhibition existed for the inhibition of ginsenosides towards UGT isoforms. To clarify the possibility of in vivo herb-drug interaction induced by this kind of inhibition, the ginsenoside Rg(3) was selected as an example, and the inhibition kinetic type and parameters (IQ were determined. Rg(3) competitively inhibited UGT1A7, 2B7 and 2B15-catalyzed 4-MU glucuronidation reaction, and exerted noncompetitive inhibition towards UGT1A8-catalyzed 4-MU glucuronidation. The inhibition parameters (K-i values) were calculated to be 22.6, 7.9, 1.9, and 2.0 mu M for UGT1A7, 1A8, 2B7 and 2B15. Using human maximum plasma concentration of Rg(3) (400 ng/ml (0.5 mu M)) after intramuscular injection of 60 mg Rg(3), the area under the plasma concentration-time curve (AUC) was extrapolated to increase by 22%, 63%, 26.3%, and 25% for the co-administered drugs completely undergoing the metabolism catalyzed by UGT1A7, 1A8, 2B7 and 2B15, respectively. All these results indicated that the ginsenosides' inhibition towards UGT isoforms might be an important reason for ginseng-drug interaction. (C) 2013 Elsevier Inc. All rights reserved.
关键词[WOS]: DRUG-DRUG INTERACTIONS ;  HUMAN LIVER ;  GINSENG ;  WARFARIN ;  CYTOCHROME-P450 ;  GLUCURONIDATION ;  METABOLISM ;  CONSTITUENTS ;  CODEINE ;  HUMANS
语种: 英语
WOS记录号: WOS:000315366800002
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/137697
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.Liaoning Med Univ, Affiliated Hosp 1, Jinzhou 121001, Peoples R China
2.Shanghai Engineer & Technol Res Ctr Reprod Hlth D, Shanghai Inst Planned Parenthood Res, Key Lab Contracept & Devices Res NPFPC, Shanghai 200032, Peoples R China
3.Chinese Acad Sci, Dalian Inst Chem Phys, Joint Ctr Translat Med, Dalian 116023, Peoples R China
4.Liaoning Med Univ, Affiliated Hosp 1, Dalian 116023, Peoples R China
5.NCI, Lab Metab, Ctr Canc Res, Bethesda, MD 20892 USA
6.Chinese Acad Sci, Dalian Inst Chem Phys, Lab Pharmaceut Resource Discovery, Dalian 116023, Peoples R China

Recommended Citation:
Fang, Zhong-Ze,Cao, Yun-Feng,Hu, Cui-Min,et al. Structure-inhibition relationship of ginsenosides towards UDP-glucuronosyltransferases (UGTs)[J]. TOXICOLOGY AND APPLIED PHARMACOLOGY,2013,267(2):149-154.
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