普萘洛尔对映异构体诱导HUVEC细胞的蛋白质表达谱差异

Differences in Protein Expression Profiles of HUVEC Exposed to Two Propranolol Enantiomers

手性药物只能通过严格的手性识别才能选择性地与特定生物大分子相互作用,在药动学、药效学等方面上表现出手性特征.以非选择性β肾上腺素能受体阻滞剂普萘洛尔(PRO)的对映异构体R(+)/S(-)-PRO为模型药物,分别作用于人脐静脉内皮细胞(HUVEC),提取全细胞蛋白质,经双向电泳、MALDI-TOF-MS、SWISSPROT数据库分析鉴定差异表达蛋白质;共筛选出22个差异表达蛋白质点,鉴定了HSP86、HSP84、GRP75、KLC18、KBTB2、TGM2、GBLP、GCNT2、RAB36、KLH34等10种蛋白质.研究表明,PRO对映异构体可引起广泛的基因表达改变,涉及信号分子、代谢酶、骨架蛋白、伴侣蛋白等,且具有显著的手性特征,这可能与PRO显著的手性生物学特征有紧密联系,但仍需开展进一步深入研究,以明确产生PRO手性生物学特征的多种途径和机制.蛋白质组学技术为深入了解药物的手性生物学特征及其作用机制提供了新的思路和策略,对手性药物开发和临床合理用药有着重要的意义.

Chiral medicines selectively interact with biological macromolecules through strict chiral recognition and demonstrate different pharmacokinetic characteristics and drug effects. Two propranolol （PRO） enantiomers （R（ ＋ ）/S（ - ）-PRO）, nonselective β-adrenergic receptor （β-AR） antagonists, were used to treat the human umbilical vein endothelial cell（ HUVEC）. The total proteins from treated cells were extracted and separated by two-dimensional gel electrophoresis （2-DE）, the acquired images were analyzed using PDQuest software. A total of 22 differentially expressed proteins were identified by matrix-assisted laser desorption ionization time of flight mass spectrometry （MALDI-TOF MS）. 10 of them were identified following SWISSPROT database queries, which are HSP86, HSP84, GRP75, KLC18, KBTB2, TGM2, GBLP, GCNT2, RAB36 and KLH34. The data indicated that PRO enantiomers could introduce extensive changes in gene expressions in signaling molecules, metabolic enzymes, skeleton proteins, chaperonin proteins and so on, which might be specific to the chiral characteristics of PRO. Further studies would focused to clarify the roles of several candidate channels and the possible mechanisms involved in the functions of chiral PRO enantiomers. Our results demonstrated that proteomics approaches could provide new strategies for the deeper understanding of chiral drugs and their biological characteristics, which might be significant to improve the development and rationalized clinical administration of chiral drugs.