DICP OpenIR
In Vitro Evaluation of the Effect of 7-Methyl Substitution on Glucuronidation of Daphnetin: Metabolic Stability, Isoform Selectivity, and Bioactivity Analysis
Liang, Si-Cheng1,2,3; Ge, Guang-Bo2; Xia, Yang-Liu2,3; Zhang, Jiang-Wei2; Qi, Xiao-Yi1; Tu, Cai-Xia1; Yang, Ling2
KeywordDaphnetin Glucuronidation Methyl Substitution Structural Modification Metabolic Stability Phase Ii Enzymes Glucuronosyltransferases Human Liver Microsomes Enzyme Kinetics Metabolic Clearance
Source PublicationJOURNAL OF PHARMACEUTICAL SCIENCES
2015-10-01
DOI10.1002/jps.24538
Volume104Issue:10Pages:3557-3564
Indexed BySCI
SubtypeArticle
WOS HeadingsScience & Technology ; Life Sciences & Biomedicine ; Physical Sciences
WOS SubjectChemistry, Medicinal ; Chemistry, Multidisciplinary ; Pharmacology & Pharmacy
WOS Research AreaPharmacology & Pharmacy ; Chemistry
WOS KeywordHUMAN UDP-GLUCURONOSYLTRANSFERASES ; TANDEM MASS-SPECTROMETRY ; COUMARIN DERIVATIVES ; BIOLOGICAL-ACTIVITY ; LIVER-MICROSOMES ; PROTEIN-KINASE ; IDENTIFICATION ; INHIBITOR ; EXPRESSION ; ACID
AbstractThe 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.
Language英语
WOS IDWOS:000360991400028
Citation statistics
Document Type期刊论文
Identifierhttp://cas-ir.dicp.ac.cn/handle/321008/146525
Collection中国科学院大连化学物理研究所
Affiliation1.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
GB/T 7714
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.
APA Liang, Si-Cheng.,Ge, Guang-Bo.,Xia, Yang-Liu.,Zhang, Jiang-Wei.,Qi, Xiao-Yi.,...&Yang, Ling.(2015).In Vitro Evaluation of the Effect of 7-Methyl Substitution on Glucuronidation of Daphnetin: Metabolic Stability, Isoform Selectivity, and Bioactivity Analysis.JOURNAL OF PHARMACEUTICAL SCIENCES,104(10),3557-3564.
MLA Liang, Si-Cheng,et al."In Vitro Evaluation of the Effect of 7-Methyl Substitution on Glucuronidation of Daphnetin: Metabolic Stability, Isoform Selectivity, and Bioactivity Analysis".JOURNAL OF PHARMACEUTICAL SCIENCES 104.10(2015):3557-3564.
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