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题名: Structural Modifications at the C-4 Position Strongly Affect the Glucuronidation of 6,7-Dihydroxycoumarins
作者: Xia, Yang-Liu1, 2;  Ge, Guang-Bo1;  Wang, Ping1;  Liang, Si-Cheng1, 2;  He, Yu-Qi1;  Ning, Jing1, 3;  Qian, Xing-Kai1, 3;  Li, Yan1;  Yang, Ling1
刊名: DRUG METABOLISM AND DISPOSITION
发表日期: 2015-04-01
DOI: 10.1124/dmd.114.060681
卷: 43, 期:4, 页:553-560
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: Esculetin (6,7-dihydroxycoumarin) and its C-4 derivatives have multiple pharmacologic activities, but the poor metabolic stability of these catechols has severely restricted their application in the clinic. Glucuronidation plays important roles in catechols elimination, although thus far the effects of structural modifications on the metabolic selectivity and the catalytic efficacy of the human UDP-glucuronosyltransferase (UGT) enzymes remain unclear. This study was aimed at exploring the structure-glucuronidation relationship of esculetin and its C-4 derivatives, including 4-methyl esculetin, 4-phenyl esculetin, and 4-hydroxymethyl esculetin as well as 4-acetic acid esculetin. It was achieved by identifying the main human UGTs responsible for the different reactions and by careful characterization of the reactions kinetics. These catechols, with the exception of 4-acetic acid esculetin, are selectively metabolized to the corresponding 7-O-glucuronides. UGT1A6 and UGT1A9 are the two major UGTs involved in the 7-O-glucuronidation of 4-methyl esculetin and esculetin. UGT1A6 was the major contributor for 7-O-glucuronidation of 4-hydroxymethyl esculetin, and UGT1A9 played a significant role in the 7-O-glucuronidation of 4-phenyl esculetin. The results of the kinetic analyses revealed that the K-m values of the compounds, in both UGT1A9 and human liver microsomes, decreased with increasing hydrophobicity of the C-4 substitutions. The outcome of this was that C-4 hydrophobic and hydrophilic groups on 6,7-dihydroxycoumarin exhibited contrasting effects on UGT affinity. All of these findings provide helpful guidance for further structural modification of 6,7-dihydroxycoumarins with improved metabolic stability.
关键词[WOS]: TANDEM MASS-SPECTROMETRY ;  HUMAN UDP-GLUCURONOSYLTRANSFERASES ;  RADICAL-SCAVENGING ACTIVITIES ;  TUMOR-CELL LINES ;  ANTIINFLAMMATORY ACTIVITY ;  LIPOXYGENASE INHIBITOR ;  COUMARIN DERIVATIVES ;  BIOLOGICAL-ACTIVITY ;  TRANSFERASE 1A ;  ESCULETIN
语种: 英语
WOS记录号: WOS:000352002400013
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/146144
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 116023, Peoples R China
2.Univ Chinese Acad Sci, Beijing, Peoples R China
3.Dalian Med Univ, Dalian, Peoples R China

Recommended Citation:
Xia, Yang-Liu,Ge, Guang-Bo,Wang, Ping,et al. Structural Modifications at the C-4 Position Strongly Affect the Glucuronidation of 6,7-Dihydroxycoumarins[J]. DRUG METABOLISM AND DISPOSITION,2015,43(4):553-560.
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