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学科主题: 物理化学
题名: The role of serum albumin in the metabolism of Boc5: Molecular identification, species differences and contribution to plasma metabolism
作者: 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
通讯作者: 汪福意 ;  杨凌
关键词: Boc5 ;  Albumin ;  Pseudo-esterase ;  Transesterification ;  Species differences
刊名: EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
发表日期: 2013-01-23
DOI: 10.1016/j.ejps.2012.11.011
卷: 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
类目[WOS]: Pharmacology & Pharmacy
资助者: 1,1
研究领域[WOS]: Pharmacology & Pharmacy
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.
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
语种: 英语
原文出处: 查看原文
WOS记录号: WOS:000315613500040
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/119127
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.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:
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.
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