顺式藁苯内酯在大鼠体内外的代谢及其代谢物的药理活性研究

Pharmacological Activities of Z-ligustilide and Metabolites in Rats

目的研究顺式藁苯内酯(Z-ligustilide,Z-LIG)在大鼠体内外的代谢并同步比较Z-LIG及其主要代谢物体外的药理活性。方法采用Z-LIG在大鼠体内代谢和在大鼠体外肝微粒体中孵育的实验方法,借助高效液相色谱、高分辨质谱、紫外和核磁共振谱对孵育产物进行提取、分离和鉴定,并同步比较Z-LIG及其主要代谢产物对H2O2诱导PC12细胞毒性的保护效应。结果获得Z-LIG在大鼠体内及体外肝微粒体中代谢产物的高效液相色谱图,体外实验分离纯化、鉴定的川芎内酯Ⅰ(senkyunolideⅠ,SYL)系Z-LIG的主要代谢产物;Z-LIG与SYL对H2O2所致的PC12细胞损伤均有显著保护作用。结论SYL是Z-LIG的主要代谢产物,初步研究提示二者对细胞氧化损伤有相似的保护作用。

Objective To study the metabolism of Z-ligustilide（Z-LIG）in vivo and in vitro in rats and the pharmacological activities of Z-LIG and metabolites in vitro. Methods The biotransformation of Z-LIG in rats in vivo was tested. Z-LIG was also incubated with rat liver mierosomes in vitro. The incubated product was extracted, separated and identified with high performance liquid chromatography （HPLC）, high resolution mass spectrometry, nuclear magnetic resonance spectrum and UV. The effects of Z-LIG and its main metabolites on hydrogen peroxide （H2O2）-induced injuries were examined in cultured PC12 cells. Results The HPLC analysis of the metabolites of Z-LIG was obtained. Senkyunolide Ⅰ （SYL） isolated from in vitro incubation was identified as the main metabolite of Z-LIG. Both Z-LIG and SYL showed significant and concentration-dependent protection against H2O2-induced injuries in PC12 cells. Conclusion SYL is the main metabolite of Z-LIG in rats. Z-LIG and SYL exert similar protective effects against oxidative damage in cultured PC12 cells.