丙戊酸钠对大鼠肝细胞毒性作用的形态学观察

Morphological observation of the valproate hepatotoxicity in rat's primary cultured hepatocyte

目的:为丙戊酸钠(VPA)肝毒性是否与剂量与合并用药有关提供形态学依据。方法:利用肝细胞原代培养技术,分别在光镜及电镜下观察不同浓度VPA及VPA与苯巴比妥钠(PB)或卡马西平(CBZ)合用对肝细胞一般形态及超微结构的影响。结果:光镜下观察细胞形态、核膜、核仁,细胞的折光性,各用药组与对照组相比均无明显改变。电镜对超微结构的观察:对照组肝细胞的细胞核完整,胞浆内线粒体丰富,呈椭圆形,可见内质网。与对照组相比,当VPA浓度为50mg/L时,可见肝细胞部分线粒体略肿胀,呈球形,嵴减少;当VPA浓度为100mg/L时,可见肝细胞线粒体肿胀略为明显,嵴减少,部分肝细胞内有少量脂滴;当VPA浓度为200mg/L时,可见肝细胞部分线粒体呈空泡状,肝细胞内脂滴增多。单独应用VPA组与合并用药组相比,合并用药组可见到内质网扩张较为明显,线粒体损伤程度和脂肪变性程度与单独应用VPA组没有明显加重。结论:VPA损害线粒体结构,并可以引起细胞脂肪变性,且存在剂量依赖关系。在治疗范围内,VPA与PB或CBZ合用没有加重肝细胞的损伤。

Objective： To provide the morphological evidence to find out whether VPA hepatotoxicity is related to dose and ploytherapy or not. Methods ： Rat primary hepatocytes were cultured. The changes of hepatocyte morphology were observed by the phase contrast microscope and eletron microscope. Results; 1 Optics microscopic observation., there was no difference in the cell shape, the nucleus membrane, the nucleus and the cell refraction among groups. 2 Electron microscopic observation of hepatocyte., when the concentration of VPA was 50mg/L, part of the mitochondrials were swelling, with reduction of cristae; when the concentration was 100mg/L, these changs were more significant, part of the hepatocytes had a few lipid vacuoles ; when the concentration was 200mg/L, some mitochondrials were vacuolar. VPA-plus-PB or VPA-plus-CBZ didn＇t aggravate those changes. Conclusion.. VPA can injure the configuration of mitochondrials, and induce lipid denaturalization , which is dose-related. VPA-plus- PB or VPA-plus-CBZ didn＇t aggravate the hepatocyty injury in therapeutic range.