DICP OpenIR
Subject Area物理化学
The role of serum albumin in the metabolism of Boc5: Molecular identification, species differences and contribution to plasma metabolism
Ge, Guang-Bo1; Ai, Chun-Zhi1; Hu, Wen-Bing2; Hou, Jie3; Zhu, Liang-Liang1; He, Gui-Yuan1; Fang, Zhong-Ze1; Liang, Si-Cheng1; Wang, Fu-Yi2; Yang, Ling1; Wang FY(汪福意); Yang L(杨凌)
KeywordBoc5 Albumin Pseudo-esterase Transesterification Species Differences
Source PublicationEUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
2013-01-23
DOI10.1016/j.ejps.2012.11.011
Volume48Issue:1-2Pages:360-369
Indexed BySCI
Cooperation Status
SubtypeArticle
Department18
Funding Project1806
Contribution Rank待补充
WOS HeadingsScience & Technology ; Life Sciences & Biomedicine
Funding Organization1,1 ; 1,1 ; 1,1 ; 1,1
WOS SubjectPharmacology & Pharmacy
WOS Research AreaPharmacology & Pharmacy
WOS KeywordGLUCAGON-LIKE PEPTIDE-1 ; ESTERASE-LIKE ACTIVITY ; FREE FATTY-ACIDS ; TYPE-2 DIABETES-MELLITUS ; RECEPTOR AGONIST ; SUBSTITUTED ASPIRINS ; CRYSTAL-STRUCTURES ; GLYCEMIC CONTROL ; DRUG DISCOVERY ; BETA-CELL
AbstractBoc5, the first nonpeptidic agonist of Glucagon-like peptide-1 receptor, has been recognized as a potential candidate for treatment of diabetes. However, the metabolic behaviors of this novel molecule in both human and experimental animals remain unclear. This study aimed to explore the metabolic behaviors of Boc5 in biological preparations from human, pig and rat. Boc5 was found to be very stable in liver microsomes of human, pig and rat, but it can be degraded to two metabolites in plasma from all three species, via the successive hydrolysis of the C-22 esters. Chemical inhibition studies using selective esterase inhibitors and assays with purified enzymes suggested that Boc5 hydrolysis in human was totally mediated by human serum albumin (HSA) rather than esterases. ESI-TOF-MS/MS analysis revealed that Lys525 of HSA could be modified by treatment with Boc5, strongly suggesting the pseudo-esterase activity of albumin. Studies on species differences in this albumin-mediated metabolism showed large species differences in degradation rate of Boc5, the half lives of Boc5 in plasma from three various species varied from 23.5 h to 83.1 h, but they were much closer to the half lives of Boc5 in corresponding serum albumins, implying the predominant role of serum albumin in plasma metabolism of Boc5. Additionally, the effects of various ligands including fatty acids and several drugs with unambiguous binding sites on HSA, on the pseudo-esterase activity of HSA, were also investigated using both experimental and molecular modelling studies. These results showed that the binding of various ligands to HSA could significantly affect the pseudo-esterase activity of HSA towards Boc5, due to the ligand-induced conformation changes of HSA. (c) 2012 Elsevier B.V. All rights reserved.
Language英语
Funding Organization1,1 ; 1,1 ; 1,1 ; 1,1
URL查看原文
WOS IDWOS:000315613500040
Citation statistics
Cited Times:13[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://cas-ir.dicp.ac.cn/handle/321008/119127
Collection中国科学院大连化学物理研究所
Corresponding AuthorWang FY(汪福意); Yang L(杨凌)
Affiliation1.Chinese Acad Sci, Dalian Inst Chem Phys, Lab Pharmaceut Resource Discovery, Dalian, Peoples R China
2.Chinese Acad Sci, Inst Chem, Beijing Natl Lab Mol Sci, Beijing 100080, Peoples R China
3.Dalian Med Univ, Dept Biotechnol, Dalian, Peoples R China
Recommended Citation
GB/T 7714
Ge, Guang-Bo,Ai, Chun-Zhi,Hu, Wen-Bing,et al. The role of serum albumin in the metabolism of Boc5: Molecular identification, species differences and contribution to plasma metabolism[J]. EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES,2013,48(1-2):360-369.
APA Ge, Guang-Bo.,Ai, Chun-Zhi.,Hu, Wen-Bing.,Hou, Jie.,Zhu, Liang-Liang.,...&杨凌.(2013).The role of serum albumin in the metabolism of Boc5: Molecular identification, species differences and contribution to plasma metabolism.EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES,48(1-2),360-369.
MLA Ge, Guang-Bo,et al."The role of serum albumin in the metabolism of Boc5: Molecular identification, species differences and contribution to plasma metabolism".EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES 48.1-2(2013):360-369.
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