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题名: In Vitro Evaluation of the Effect of 7-Methyl Substitution on Glucuronidation of Daphnetin: Metabolic Stability, Isoform Selectivity, and Bioactivity Analysis
作者: Liang, Si-Cheng1, 2, 3;  Ge, Guang-Bo2;  Xia, Yang-Liu2, 3;  Zhang, Jiang-Wei2;  Qi, Xiao-Yi1;  Tu, Cai-Xia1;  Yang, Ling2
关键词: daphnetin ;  glucuronidation ;  methyl substitution ;  structural modification ;  metabolic stability ;  phase II enzymes ;  glucuronosyltransferases ;  human liver microsomes ;  enzyme kinetics ;  metabolic clearance
刊名: JOURNAL OF PHARMACEUTICAL SCIENCES
发表日期: 2015-10-01
DOI: 10.1002/jps.24538
卷: 104, 期:10, 页:3557-3564
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology ;  Life Sciences & Biomedicine ;  Physical Sciences
类目[WOS]: Chemistry, Medicinal ;  Chemistry, Multidisciplinary ;  Pharmacology & Pharmacy
研究领域[WOS]: Pharmacology & Pharmacy ;  Chemistry
英文摘要: The C-8 phenol group is essential to exert the bioactivities of daphnetin, but it is readily conjugated with glucuronic acid prior to excretion. In this study, daphnetin-7-methylether (7M-DNP) was used to investigate the effect of 7-methyl substitution on daphnetin glucuronidation in human/rat liver (HLM/RLM) and intestine (HIM/RIM) microsomes, and recombinant UDP-glucuronosyltransferases (UGTs). Compared with daphnetin, the V-max/K-m values of 7M-DNP via 8-O-glucuronidation were 2.1-fold lower in HLM, 1.7-fold lower in HIM, and 2.4-fold lower in RLM, suggesting an improvement in metabolic stability. Different from daphnetin 8-O-glucuronidation exclusively catalyzed by UGT1A6 and UGT1A9, UGT1A1, -1A3, -1A7, -1A8, and -1A9 showed glucuronidation activity toward 7M-DNP. Kinetics studies, chemical inhibition, and the relative activity factor approach were used to demonstrate that UGT1A9 was mainly responsible for the reaction in HLM, whereas UGT1A1 was a primary contributor in HIM. The V-max/K-m values of 7M-DNP glucuronidation in HLM and HIM were 0.61-0.74-fold lower than those of rat, suggesting the differences between the two species. The bioactivity analysis demonstrated that 7M-DNP had an anti-inflammatory activity comparable to that of daphnetin. These findings indicated that the outcomes of 7-methyl substitution on daphnetin might be positive, but this should be confirmed in future in vivo studies. (c) 2015 Wiley Periodicals, Inc.
关键词[WOS]: HUMAN UDP-GLUCURONOSYLTRANSFERASES ;  TANDEM MASS-SPECTROMETRY ;  COUMARIN DERIVATIVES ;  BIOLOGICAL-ACTIVITY ;  LIVER-MICROSOMES ;  PROTEIN-KINASE ;  IDENTIFICATION ;  INHIBITOR ;  EXPRESSION ;  ACID
语种: 英语
WOS记录号: WOS:000360991400028
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/146525
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.Dalian Med Univ, Affiliated Hosp 2, Dalian, Peoples R China
2.Chinese Acad Sci, Dalian Inst Chem Phys, Lab Pharmaceut Resource Discovery, Dalian, Peoples R China
3.Univ Chinese Acad Sci, Beijing, Peoples R China

Recommended Citation:
Liang, Si-Cheng,Ge, Guang-Bo,Xia, Yang-Liu,et al. In Vitro Evaluation of the Effect of 7-Methyl Substitution on Glucuronidation of Daphnetin: Metabolic Stability, Isoform Selectivity, and Bioactivity Analysis[J]. JOURNAL OF PHARMACEUTICAL SCIENCES,2015,104(10):3557-3564.
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