Wedelolactone metabolism in rats through regioselective glucuronidation catalyzed by uridine diphosphate-glucuronosyltransferases 1As (UGT1As)

doi:10.1016/j.phymed.2016.01.007

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	Wedelolactone metabolism in rats through regioselective glucuronidation catalyzed by uridine diphosphate-glucuronosyltransferases 1As (UGT1As)
	Li, Liang2 ; Huang, Xue-juan 1; Peng, Jian-long 2; Zheng, Ming-yue2 ; Zhong, Da-fang2 ; Zhang, Chao-feng 1; Chen, Xiao-yan2
刊名	PHYTOMEDICINE
	2016-04-15
卷号	23 期号:4 页码:340-349
关键词	Wedelolactone Metabolism Uridine diphosphate-glucuronosyltransferase (UGT) Molecular docking
ISSN号	0944-7113
DOI	10.1016/j.phymed.2016.01.007
文献子类	Article
英文摘要	Background: Wedelolactone (WEL), a medicinal plant-derived coumestan, has been reported to exhibit a diverse range of pharmacological activities. However, the metabolism and disposition of WEL remain unexplored. Purpose: The present study aims to investigate the metabolism of WEL in rats and identify the enzymes responsible for forming major WEL metabolites. Methods: Plasma, urine, feces, and bile samples were collected before and after 50 mg/kg WEL was orally administered to rats. Metabolites were profiled by ultrahigh performance liquid chromatography/quadrupole time-of-flight mass spectrometry and identified by high-performance liquid chromatography-solid-phase extraction-nuclear magnetic resonance spectroscopy. The in vitro WEL glucuronidation activities of human liver microsomes, human kidney microsomes, human intestine microsomes, and 12 recombinant human uridine diphosphate-glucuronosyltransferase (UGT) isoforms were screened. Molecular docking simulation of the interaction between WEL and UGT1A9 was conducted. Results: WEL underwent extensive metabolism, and 17 metabolites were identified. The major metabolic pathways observed were glucuronidation and methylation. Glucuronic acid was preferentially introduced into 5-OH, whereas no obvious regioselectivity was observed in the methylation of 11-OH and 12-OH. Multiple UGTs, including UGT1A1, UGT1A3, UGT1A6, UGT1A7, UGT1A8, UGT1A9, and UGT1A10, were involved in forming WEL glucuronides and O-methylated WEL glucuronides. Conclusion: The extensive glucuronidation and methylation is responsible for the low oral bioavailability of WEL in rats. UGT1A1 and UGT1A9 were the major enzymes involved in the glucuronidation of WEL and O-methylated WEL. Molecular docking studies revealed that 5-OH was accessible to the catalytic domain of UGT1As; therefore, 5-OH exhibited a high probability of glucuronidation. (C) 2016 Elsevier GmbH. All rights reserved.
资助项目	Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)[00000000] ; National Natural Science Foundation of China[81573553]
WOS关键词	UDP-GLUCURONOSYLTRANSFERASES ; PHYTOCHEMICALS ; PATHWAY ; CELLS
WOS研究方向	Plant Sciences ; Pharmacology & Pharmacy ; Integrative & Complementary Medicine
语种	英语
出版者	ELSEVIER GMBH, URBAN & FISCHER VERLAG
WOS记录号	WOS:000372355800002
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276074]
专题	上海药物代谢研究中心
通讯作者	Chen, Xiao-yan
作者单位	1.China Pharmaceut Univ, Res Dept Pharmacognosy, State Key Lab Nat Med, 639 Longmian Rd, Nanjing 211198, Jiangsu, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, 501 Haike Rd, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Li, Liang,Huang, Xue-juan,Peng, Jian-long,et al. Wedelolactone metabolism in rats through regioselective glucuronidation catalyzed by uridine diphosphate-glucuronosyltransferases 1As (UGT1As)[J]. PHYTOMEDICINE,2016,23(4):340-349.
APA	Li, Liang.,Huang, Xue-juan.,Peng, Jian-long.,Zheng, Ming-yue.,Zhong, Da-fang.,...&Chen, Xiao-yan.(2016).Wedelolactone metabolism in rats through regioselective glucuronidation catalyzed by uridine diphosphate-glucuronosyltransferases 1As (UGT1As).PHYTOMEDICINE,23(4),340-349.
MLA	Li, Liang,et al."Wedelolactone metabolism in rats through regioselective glucuronidation catalyzed by uridine diphosphate-glucuronosyltransferases 1As (UGT1As)".PHYTOMEDICINE 23.4(2016):340-349.