摘要
为了明确速效救心丸中冰片“引经”作用机制,本研究首先建立外翻肠囊体外肠道吸收模型、小鼠在体药代模型和Caco-2细胞体外吸收模型,评价冰片促吸收作用。所有动物实验均符合南开大学伦理委员会的规定。结果显示,与不含冰片的速效救心丸组相比,含冰片的速效救心丸组的肠囊液中阿魏酸和藁本内酯的肠道累计吸收量和吸收渗透率显著增加;冰片可以增加阿魏酸和藁本内酯在血液及心脏等组织中的含量,显著降低Caco-2细胞的跨上皮电阻值,并显著增加辣根过氧化物酶透过量。为了进一步探究冰片促进药物肠道吸收的作用机制,本研究合成了冰片炔基光敏探针捕获其作用靶点,采用双荧光素酶报告系统评价其钙调控作用,发现冰片可以通过调控瞬时离子通道蛋白M8 (TrpM8)发挥升钙作用。通过质谱成像技术证明了冰片可以使阿魏酸在心脏的富集显著增加,进而显著增强大鼠胸主动脉的舒张效果。综上所述,速效救心丸中的冰片可以通过作用于TrpM8蛋白,扩大细胞间隙并增加肠道通透性,促进药物吸收和靶器官富集,最终实现药效增强的作用。
In order to research the mechanism of guiding action of borneol in Suxiaojiuxin pills, the model of in vitro intestinal absorption, in vivo drug metabolism of mice and cell in vitro absorption model of Caco-2 were established firstly. All animal experiments were in accordance with the regulations of the Animal Ethics Committee of Nankai University. The results showed that the cumulative absorption quantity and absorption permeability of ferulic acid and ligustilide in the intestinal juice of Suxiaojiuxin pills group were significantly increased comparing with fake Suxiaojiuxin pills group, which don’t contain borneol. By using borneol, the content of ferulic acid and ligustilide in the blood and tissues, such as heart, were added. The transepithelial resistance value and the content of horseradish peroxidase(HRP) in Caco-2 were rapidly decreased and increased, respectively. Due to further explore mechanism of promoting intestinal absorption of borneol for drugs, in this study, photosensitive probes of borneol were synthesized to capture its targets, and dual luciferase reporter system was used to evaluate its activity of calcium. It was found that it could make calcium overload by regulating transient receptor potential cation channel, subfamily M, member 8(TrpM8). Then, the results of mass spectrometry imaging showed that the accumulation of ferulic acid in the heart was significantly increased by borneol, and the relaxation rate of rat thoracic aorta was enhanced obviously. In summary, the borneol in Suxiaojiuxin pills can expand cell space and increase intestinal permeability by acting on TrpM8, thus promoting the intestinal absorption, tissue distribution and target organ enrichment of drugs.
作者
王洁
闫孟琳
张曼
姜民
白钢
WANG Jie;YAN Meng-lin;ZHANG Man;JIANG Min;BAI Gang(State Key Laboratory of Medicinal Chemical Biology,College of Pharmacy,Nankai University,Tianjin 300071,China)
出处
《药学学报》
CAS
CSCD
北大核心
2022年第3期700-706,共7页
Acta Pharmaceutica Sinica
基金
国家自然科学基金资助项目(81673637)。
关键词
冰片
瞬时离子通道蛋白M8
外翻肠囊
组织分布
引经报使
borneol
transient receptor potential cation channel
subfamily M
member 8
everted intestinal sac
tissue distribution
guiding action
