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学科主题: 物理化学
题名: Characterization of human metabolic pathway of daphnetin: UDP-glucuronosyltransferase involved in the methylated daphnetin
作者: Liang SC(梁思成) ;  Ge GB(葛广波) ;  Liu HX(刘慧鑫) ;  Zhang JW(张江伟) ;  Yang L(杨凌)
会议名称: 16th North American Regional ISSX Meeting
会议日期: 2009-10-18
出版日期: 2009-10-18
会议地点: 美国
通讯作者: 杨凌
部门归属: 十八室
主办者: The International Society for the Study of Xenobiotics (ISSX)
摘要: Daphnetin (7, 8-dihydroxycoumarin) was used for treatment against coagulation disorders and Burger’s since 1980s. Like other coumarin analogs, daphnetin has been found to exhibit broad biological effects including anti-inflammatory, antimicrobial, anti-malarial, anti-cancer activities. Previous studies indicated that daphnetin was metabolized rapidly in vivo. However its metabolic pathway in human is still unknown. According to the structure of daphnetin, there are two phenolic hydroxyl groups in the coumarin skeleton, indicating the potential phase II enzymes mediated clearance. Our previous study revealed that the UGT1A9 and UGT1A6 involved in the glucuronidation of daphnetin. In this study, we investigated other phase II metabolic pathway of daphnetin. One metabolite (M-1) was detected when daphnetin was incubated with human liver S9 in the presence of 3’-phosphoadenosine 5’-phosphosulfate, indicating the existence of methylation pathway of daphnetin by Catechol-O-methyltransferase (COMT). M-1 was indentified as the C-7 methylated daphnetin by liquid chromatography/mass spectrometry (LC/MS) and nuclear magnetic resonance (NMR). Notably, M-1 was found can be glucuronidated in human liver microsomes (HLMs) in the presence of UDPGA. Further study showed that UGT1A1, UGT1A3, UGT1A7, UGT1A8, UGT1A9 and UGT1A10 involved in M-1 glucuronidation by using 12 commercially available recombinant human UGTs. These results indicated that daphnetin can be metabolized by COMT and the methylated metabolite (M-1) can be further metabolized by several UGTs, which revealed that the phase II metabolic pathway plays a crucial role in metabolic clearance of daphnetin.
语种: 中文
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内容类型: 会议论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/113672
Appears in Collections:中国科学院大连化学物理研究所_会议论文

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Recommended Citation:
Liang SC,Ge GB,Liu HX,et al. Characterization of human metabolic pathway of daphnetin: UDP-glucuronosyltransferase involved in the methylated daphnetin[C]. 见:16th North American Regional ISSX Meeting. 美国. 2009-10-18.
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