Methylation, Glucuronidation, and Sulfonation of Daphnetin in Human Hepatic Preparations In Vitro: Metabolic Profiling, Pathway Comparison, and Bioactivity Analysis
文献类型：期刊论文
| 作者 | Zhang, Jiang-Wei1; He, Yu-Qi1; Wang, Jia-Yue1,2; Liang, Si-Cheng1,2,3; Yang, Ling1; Qi, Xiao-Yi1,2; Xia, Yang-Liu1,2; Hou, Jie4; Ge, Guang-Bo1 |
| 刊名 | JOURNAL OF PHARMACEUTICAL SCIENCES
 |
| 出版日期 | 2016-02-01 |
| 卷号 | 105期号:2页码:808-816 |
| 关键词 | Daphnetin Methylation Glucuronidation Sulfonation 8-o-methyldaphnetin Anti-inflammatory Activity |
| ISSN号 | 0022-3549 |
| DOI | 10.1016/j.xphs.2015.10.010 |
| 文献子类 | Article |
| 英文摘要 | Our 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. |
| WOS关键词 | CATECHOL-O-METHYLTRANSFERASE ; MOLECULAR MECHANISMS ; COUMARIN DERIVATIVES ; DRUG DISCOVERY ; IDENTIFICATION ; EXPRESSION ; CELLS ; LIVER ; RAT ; QUERCETIN |
| WOS研究方向 | Pharmacology & Pharmacy ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000381768500047 |
| 出版者 | WILEY-BLACKWELL |
| 源URL | [http://cas-ir.dicp.ac.cn/handle/321008/170018]  |
| 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 |
| 通讯作者 | Qi, Xiao-Yi; Ge, Guang-Bo |
| 作者单位 | 1.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 |
| 推荐引用方式 GB/T 7714 | Zhang, Jiang-Wei,He, Yu-Qi,Wang, Jia-Yue,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 | Zhang, Jiang-Wei.,He, Yu-Qi.,Wang, Jia-Yue.,Liang, Si-Cheng.,Yang, Ling.,...&Ge, Guang-Bo.(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 | Zhang, Jiang-Wei,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. |
入库方式： OAI收割
来源：大连化学物理研究所
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