DICP OpenIR
Methylation, Glucuronidation, and Sulfonation of Daphnetin in Human Hepatic Preparations In Vitro: Metabolic Profiling, Pathway Comparison, and Bioactivity Analysis
Liang, Si-Cheng1,2,3; Xia, Yang-Liu1,2; Hou, Jie4; Ge, Guang-Bo1; Zhang, Jiang-Wei1; He, Yu-Qi1; Wang, Jia-Yue1,2; Qi, Xiao-Yi1,2; Yang, Ling1
KeywordDaphnetin Methylation Glucuronidation Sulfonation 8-o-methyldaphnetin Anti-inflammatory Activity
Source PublicationJOURNAL OF PHARMACEUTICAL SCIENCES
2016-02-01
ISSN0022-3549
DOI10.1016/j.xphs.2015.10.010
Volume105Issue:2Pages:808-816
Indexed BySCI
SubtypeArticle
WOS HeadingsScience & Technology ; Life Sciences & Biomedicine ; Physical Sciences
WOS SubjectChemistry, Medicinal ; Chemistry, Multidisciplinary ; Pharmacology & Pharmacy
WOS Research AreaPharmacology & Pharmacy ; Chemistry
WOS KeywordCATECHOL-O-METHYLTRANSFERASE ; MOLECULAR MECHANISMS ; COUMARIN DERIVATIVES ; DRUG DISCOVERY ; IDENTIFICATION ; EXPRESSION ; CELLS ; LIVER ; RAT ; QUERCETIN
AbstractOur previous study demonstrated that daphnetin is subject to glucuronidation in vitro. However, daphnetin metabolism is still poorly documented. This study aimed to investigate daphnetin metabolism and its consequent effect on the bioactivity. Metabolic profiles obtained by human liver S9 fractions and human hepatocytes showed that daphnetin was metabolized by glucuronidation, sulfonation, and methylation to form 6 conjugates which were synthesized and identified as 7-O-glucuronide, 8-O-glucuronide, 7-O-sulfate and 8-O-sulfate, 8-O-methylate, and 7-O-suflo-8-O-methylate. Regioselective 8-O-methylation of daphnetin was investigated using in silico docking calculations, and the results suggested that a close proximity (2.03 A) of 8-OH to the critical residue Lysine 144 might be the responsible mechanism. Compared with glucuronidation and sulfonation pathways, the methylation of daphnetin had a high clearance rate (470 mu L/min/mg) in human liver S9 fractions and contributed to a large amount (37.3%) of the methyl-derived metabolites in human hepatocyte. Reaction phenotyping studies showed the major role of SULT1A1, -1A2, and -1A3 in daphnetin sulfonation, and soluble COMT in daphnetin 8-O-methylation. Of the metabolites, only 8-O-methyldaphnetin exhibited an inhibitory activity on lymphocyte proliferation comparable to that of daphnetin. In conclusion, methylation is a crucial pathway for daphnetin clearance and might be involved in pharmacologic actions of daphnetin in humans. (C) 2016 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.
Language英语
WOS IDWOS:000381768500047
PublisherWILEY-BLACKWELL
Citation statistics
Cited Times:8[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://cas-ir.dicp.ac.cn/handle/321008/170019
Collection中国科学院大连化学物理研究所
Corresponding AuthorGe, Guang-Bo; Qi, Xiao-Yi
Affiliation1.Chinese Acad Sci, Dalian Inst Chem Phys, Lab Pharmaceut Resource Discovery, Dalian, Peoples R China
2.Dalian Med Univ, Affiliated Hosp 2, Dalian, Peoples R China
3.Univ Chinese Acad Sci, Beijing, Peoples R China
4.Dalian Med Univ, Dalian, Peoples R China
Recommended Citation
GB/T 7714
Liang, Si-Cheng,Xia, Yang-Liu,Hou, Jie,et al. Methylation, Glucuronidation, and Sulfonation of Daphnetin in Human Hepatic Preparations In Vitro: Metabolic Profiling, Pathway Comparison, and Bioactivity Analysis[J]. JOURNAL OF PHARMACEUTICAL SCIENCES,2016,105(2):808-816.
APA Liang, Si-Cheng.,Xia, Yang-Liu.,Hou, Jie.,Ge, Guang-Bo.,Zhang, Jiang-Wei.,...&Yang, Ling.(2016).Methylation, Glucuronidation, and Sulfonation of Daphnetin in Human Hepatic Preparations In Vitro: Metabolic Profiling, Pathway Comparison, and Bioactivity Analysis.JOURNAL OF PHARMACEUTICAL SCIENCES,105(2),808-816.
MLA Liang, Si-Cheng,et al."Methylation, Glucuronidation, and Sulfonation of Daphnetin in Human Hepatic Preparations In Vitro: Metabolic Profiling, Pathway Comparison, and Bioactivity Analysis".JOURNAL OF PHARMACEUTICAL SCIENCES 105.2(2016):808-816.
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