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Structural Modifications at the C-4 Position Strongly Affect the Glucuronidation of 6,7-Dihydroxycoumarins
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
Source PublicationDRUG METABOLISM AND DISPOSITION
2015-04-01
DOI10.1124/dmd.114.060681
Volume43Issue:4Pages:553-560
Indexed BySCI
SubtypeArticle
WOS HeadingsScience & Technology ; Life Sciences & Biomedicine
WOS SubjectPharmacology & Pharmacy
WOS Research AreaPharmacology & Pharmacy
WOS KeywordTANDEM MASS-SPECTROMETRY ; HUMAN UDP-GLUCURONOSYLTRANSFERASES ; RADICAL-SCAVENGING ACTIVITIES ; TUMOR-CELL LINES ; ANTIINFLAMMATORY ACTIVITY ; LIPOXYGENASE INHIBITOR ; COUMARIN DERIVATIVES ; BIOLOGICAL-ACTIVITY ; TRANSFERASE 1A ; ESCULETIN
AbstractEsculetin (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.
Language英语
WOS IDWOS:000352002400013
Citation statistics
Cited Times:7[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://cas-ir.dicp.ac.cn/handle/321008/146144
Collection中国科学院大连化学物理研究所
Affiliation1.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
GB/T 7714
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.
APA Xia, Yang-Liu.,Ge, Guang-Bo.,Wang, Ping.,Liang, Si-Cheng.,He, Yu-Qi.,...&Yang, Ling.(2015).Structural Modifications at the C-4 Position Strongly Affect the Glucuronidation of 6,7-Dihydroxycoumarins.DRUG METABOLISM AND DISPOSITION,43(4),553-560.
MLA Xia, Yang-Liu,et al."Structural Modifications at the C-4 Position Strongly Affect the Glucuronidation of 6,7-Dihydroxycoumarins".DRUG METABOLISM AND DISPOSITION 43.4(2015):553-560.
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