DICP OpenIR
学科主题物理化学
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)
关键词Boc5 Albumin Pseudo-esterase Transesterification Species Differences
刊名EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
2013-01-23
DOI10.1016/j.ejps.2012.11.011
48期:1-2页:360-369
收录类别SCI
合作性质
文章类型Article
部门归属18
项目归属1806
产权排名待补充
WOS标题词Science & Technology ; Life Sciences & Biomedicine
资助者1,1 ; 1,1 ; 1,1 ; 1,1
类目[WOS]Pharmacology & Pharmacy
研究领域[WOS]Pharmacology & Pharmacy
关键词[WOS]GLUCAGON-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
英文摘要Boc5, 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.
语种英语
资助者1,1 ; 1,1 ; 1,1 ; 1,1
原文出处查看原文
WOS记录号WOS:000315613500040
引用统计
被引频次:12[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://cas-ir.dicp.ac.cn/handle/321008/119127
专题中国科学院大连化学物理研究所
通讯作者Wang FY(汪福意); Yang L(杨凌)
作者单位1.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
推荐引用方式
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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