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题名: Identification and Characterization of Human UDP-Glucuronosyltransferases Responsible for the In Vitro Glucuronidation of Daphnetin
作者: Liang, Si-Cheng1, 2;  Ge, Guang-Bo1;  Liu, Hui-Xin1, 2;  Zhang, Yan-Yan1;  Wang, Li-Ming3;  Zhang, Jiang-Wei1;  Yin, Lu1;  Li, Wei1, 2;  Fang, Zhong-Ze1, 2;  Wu, Jing-Jing1;  Li, Guo-Hui1;  Yang, Ling1
通讯作者: 杨凌
刊名: DRUG METABOLISM AND DISPOSITION
发表日期: 2010-06-01
DOI: 10.1124/dmd.109.030734
卷: 38, 期:6, 页:973-980
收录类别: SCI
文章类型: Article
部门归属: 18
项目归属: 1806
产权排名: 1;1
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: Daphnetin has been developed as an oral medicine for treatment of coagulation disorders and rheumatoid arthritis in China, but its in vitro metabolism remains unknown. In the present study, the UDP-glucuronosyltransferase (UGT) conjugation pathways of daphnetin were characterized. Two metabolites, 7-O-monoglucuronide daphnetin (M-1) and 8-O-monoglucuronide daphnetin (M-2), were identified by liquid chromatography/mass spectrometry and NMR when daphnetin was incubated, respectively, with liver microsomes from human (HLM), rat (RLM), and minipig (PLM) and human intestinal microsomes (HIM) in the presence of UDP-glucuronic acid. Screening assays with 12 human recombinant UGTs demonstrated that the formations of M-1 and M-2 were almost exclusively catalyzed by UGT1A9 and UGT1A6, whereas M-1 was formed to a minor extent by UGT1A3, 1A4, 1A7, 1A8, and 1A10 at a high substrate concentration. Kinetics studies, chemical inhibition, and correlation analysis were used to demonstrate that human UGT1A9 and UGT1A6 were major isoforms involved in the daphnetin glucuronidations in HLM and HIM. By in vitro-in vivo extrapolation of the kinetic data measured in HLM, the hepatic clearance and the corresponding hepatic extraction ratio were estimated to be 19.3 ml/min/kg b.wt. and 0.93, respectively, suggesting that human clearance of daphnetin via the glucuronidation is extensive. Chemical inhibition of daphnetin glucuronidation in HLM, RLM, and PLM showed large species differences although the metabolites were formed similarly among the species. In conclusion, the UGT conjugation pathways of daphnetin were fully elucidated and its C-8 phenol group was more selectively catalyzed by UGTs than by the C-7 phenol.
关键词[WOS]: HUMAN LIVER-MICROSOMES ;  DRUG GLUCURONIDATION ;  COUMARIN DERIVATIVES ;  SPECIES-DIFFERENCES ;  PROTEIN-KINASE ;  UGT 1A9 ;  METABOLISM ;  PREDICTION ;  CLEARANCE ;  INHIBITOR
语种: 英语
原文出处: 查看原文
WOS记录号: WOS:000277620200012
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/103151
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.Chinese Acad Sci, Grad Sch, Beijing, Peoples R China
3.Dalian Med Univ, Affiliated Hosp 2, Dalian, Peoples R China

Recommended Citation:
Liang, Si-Cheng,Ge, Guang-Bo,Liu, Hui-Xin,et al. Identification and Characterization of Human UDP-Glucuronosyltransferases Responsible for the In Vitro Glucuronidation of Daphnetin[J]. DRUG METABOLISM AND DISPOSITION,2010,38(6):973-980.
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