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学科主题: 物理化学
题名: The role of the phase II enzymes in the metabolic elimination of daphnetin
作者: Liang SC(梁思成) ;  Liu HX(刘慧鑫) ;  Ge GB(葛广波) ;  Yang L(杨凌)
会议名称: 18th international symposium on microsomes and drug oxidations
会议日期: 2010-5-16
出版日期: 2010-05-16
会议地点: 中国
通讯作者: 杨凌
部门归属: 十八室
主办者: 上海药物所&北京大学
摘要: Abstract As a catechol-containing compound, daphnetin (7, 8-dihydroxycoumarin) has been developed as an oral medicine for treatment of coagulation disorders and rheumatoid arthritis in China. Our previous studies revealed that daphnetin can be potently metabolized by UDP-glucuronosyltransferases (UGTs) [1]. However, the role of other phase II enzymes such as sulfotransferase (SULT) and catechol-O-methyltransferase (COMT) in the metabolic elimination of daphnetin have not been well described. This study was intended to profile the phase II metabolites of daphnetin and compare the contribution of three conjugation pathways, namely sulfation, methylation and glucuronidation to daphnetin metabolism. In the presence of UDPGA, SAM and PAPS, five metabolites named M-1, M-2, M-3, M-4 and M-5 were detected in the pooled human liver S9 and were identified as 7-O-methyl-8-hydroxycoumarin glucuronide, 7-O-methyl-8-hydroxycoumarin sulfate, 7-O-glucuronide daphnetin, 8-O-glucuronide daphnetin and 7-O-methyl-8-hydroxycoumarin, respectively by liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR). At low substrate concentration of 4 µM, 7-O-methyl-8-hydroxycoumarin sulfate (M-2) was found to be the major metabolite in the incubation systems as described above, followed by two mono-glucuronides (M-3 and M-4), but the situation was opposite at high substrate concentration (20 µM), which suggested that methylation and sulfation can be the major pathways in daphnetin metabolism at low substrate concentration, while the UGT conjugation pathway play a primary role at high substrate concentration. In accordance, the kinetic studies showed that the Km values for daphnetin methylation were lower than its glucuronidation; for example, with human liver S9 supplied with SAM or UDPGA, the Km was 1.8 versus 100 µM. These findings indicated that the metabolism of daphnetin might be concentration-depended and thus it should be important to select administration does and frequency in the clinical applications of daphnetin. References Liang SC, Ge GB, Liu HX, Zhang YY et. al (2010) Identification and Characterization of Human UDP-Glucuronosyltransferases responsible for the in vitro Glucuronidation of Daphnetin, Drug Metab Dispos, 2010; 38:973-980.
语种: 中文
内容类型: 会议论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/114350
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,Liu HX,Ge GB,et al. The role of the phase II enzymes in the metabolic elimination of daphnetin[C]. 见:18th international symposium on microsomes and drug oxidations. 中国. 2010-5-16.
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