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学科主题: 物理化学
题名: Identification and Characterization of Human UDP-glucuronosyltransferases Responsible for the Glucuronidation of Fraxetin
作者: Xia, Yang-Liu1, 2;  Liang, Si-Cheng1, 2;  Zhu, Liang-Liang1;  Ge, Guang-Bo1;  He, Gui-Yuan1, 2;  Ning, Jing1;  Lv, Xia1;  Ma, Xiao-Chi3;  Yang, Ling1;  Yang, Sheng-Li1
通讯作者: 葛广波
关键词: fraxetin ;  UDP-glucuronosyltransferases (UGTs) ;  UGT1A9 ;  glucuronidation ;  human liver microsomes (HLMs)
刊名: DRUG METABOLISM AND PHARMACOKINETICS
发表日期: 2014-04-25
DOI: 10.2133/dmpk.DMPK-13-RG-059
卷: 29, 期:2, 页:135-140
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology ;  Life Sciences & Biomedicine
类目[WOS]: Pharmacology & Pharmacy
研究领域[WOS]: Pharmacology & Pharmacy
英文摘要: Fraxetin, a major constituent of the traditional medicine plant Fraxinus rhynchophylla Hance (Oleaceae), has been found to possess multiple bioactivities. However, the metabolic pathway(s) of fraxetin in human tissues has not been reported yet. This study aimed to characterize the glucuronidation pathway(s) of fraxetin in human tissues. Fraxetin could be metabolized to two glucuronides in human liver microsomes (HLMs). These two glucuronides were biosynthesized and characterized as 7-O-glucuronide (7-O-G) and 8-O-glucuronide (8-O-G). UGT1A1, -1A6, -1A7, -1A8, -1A9 and -1A10 participated in the formation of 7-O-G, while the formation of 8-O-G was catalyzed selectively by UGT1A6 and UGT1A9. UGT1A9 showed the highest catalytic activities in the formation of 7-O-G and 8-O-G. Both kinetic characterization and inhibition assays demonstrated that UGT1A9 played important roles in fraxetin glucuronidations in HLMs, especially in the formation of the major metabolite 8-O-G. Furthermore, the intrinsic clearance of fraxetin in both human liver microsomes and UGT1A9 was greater than that of 7,8-dihydroxylcoumarin, revealing that the addition of a C-6 methoxy group led to the higher metabolic clearance. In summary, the glucuronidation pathways of fraxetin in human liver microsomes were well-characterized, and UGT1A9 was the major isoform responsible for the glucuronidations of fraxetin.
关键词[WOS]: HUMAN LIVER ;  RATS ;  CHROMATOGRAPHY ;  INHIBITION ;  METABOLISM ;  MICROSOMES ;  KIDNEY ;  MICE
语种: 英语
WOS记录号: WOS:000334596600005
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/144431
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.Chinese Acad Sci, Grad Univ, Beijing, Peoples R China
3.Dalian Med Univ, Dalian, Peoples R China

Recommended Citation:
Xia, Yang-Liu,Liang, Si-Cheng,Zhu, Liang-Liang,et al. Identification and Characterization of Human UDP-glucuronosyltransferases Responsible for the Glucuronidation of Fraxetin[J]. DRUG METABOLISM AND PHARMACOKINETICS,2014,29(2):135-140.
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