Identification and Characterization of Human UDP-Glucuronosyltransferases Responsible for the In Vitro Glucuronidation of Daphnetin

	Identification and Characterization of Human UDP-Glucuronosyltransferases Responsible for the In Vitro Glucuronidation of Daphnetin
	Liang, Si-Cheng 1,2; Ge, Guang-Bo 1; Liu, Hui-Xin 1,2; Zhang, Yan-Yan 1; Wang, Li-Ming 3; Zhang, Jiang-Wei 1; Yin, Lu 1; Li, Wei 1,2; Fang, Zhong-Ze 1,2; Wu, Jing-Jing 1
刊名	drug metabolism and disposition
	2010-06-01
卷号	38 期号:6 页码:973-980
ISSN号	0090-9556
通讯作者	杨凌
产权排序	1;1
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.
WOS标题词	science & technology ; life sciences & biomedicine
类目[WOS]	pharmacology & pharmacy
研究领域[WOS]	pharmacology & pharmacy
关键词[WOS]	human liver-microsomes ; drug glucuronidation ; coumarin derivatives ; species-differences ; protein-kinase ; ugt 1a9 ; metabolism ; prediction ; clearance ; inhibitor
收录类别	SCI
原文出处	false
语种	英语
WOS记录号	WOS:000277620200012
公开日期	2010-11-30
内容类型	期刊论文
源URL	[http://159.226.238.44/handle/321008/103151]
专题	大连化学物理研究所_中国科学院大连化学物理研究所
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
推荐引用方式 GB/T 7714	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.
APA	Liang, Si-Cheng.,Ge, Guang-Bo.,Liu, Hui-Xin.,Zhang, Yan-Yan.,Wang, Li-Ming.,...&Yang, Ling.(2010).Identification and Characterization of Human UDP-Glucuronosyltransferases Responsible for the In Vitro Glucuronidation of Daphnetin.drug metabolism and disposition,38(6),973-980.
MLA	Liang, Si-Cheng,et al."Identification and Characterization of Human UDP-Glucuronosyltransferases Responsible for the In Vitro Glucuronidation of Daphnetin".drug metabolism and disposition 38.6(2010):973-980.