摘要
目的研究抗氧化剂对丙戊酸(VPA)肝毒性的保护作用及其相关机制。方法采用健康21日龄Wistar大鼠作为研究对象,以VPA及苯巴比妥(PB)灌胃制作动物模型,同时给予VitE及辅酶Q10(CoQ10)作为干预措施,通过化学比色法、高效液相色谱、油红染色、电镜等手段,观察肝线粒体呼吸酶系、脂质过氧化状况、肝脏凝血因子合成功能的改变和肝细胞脂肪变的情况等。结果1.VPA及VPA+PB使幼鼠肝线粒体细胞色素aa3含量分别下降58.80%和61.80%,与对照组比较,差异非常显著(P<0.01)。VitE+CoQ10对细胞色素aa3含量有明显保护作用。检测肝线粒体呼吸链关键酶活性表明,灌以VPA或VPA+PB动物的肝线粒体细胞色素氧化酶(CCO)及琥珀酸脱氢酶(SDH)活力均显著低于对照组(P均<0.01),而VitE+CoQ10对两者活力均有明显保护作用;2.VPA+PB使实验鼠凝血因子PT、TT、APTT、Fbg含量显著改变。VitE+CoQ10表现出对肝脏凝血因子合成功能的保护作用;3.VPA组及VPA+PB组幼鼠肝线粒体谷胱甘肽(GSH)含量均显著低于同日龄对照组(P均<0.01),而线粒体丙二醛(MDA)含量均显著增高(P<0.05);4.肝脏组织形态学观察显示,VPA组及VPA+PB组幼鼠均出现门管区为主的肝细胞脂肪变性,脂肪细胞数分别高出对照组9.2倍和15.7倍,差异非常显著(P<0.01)。VitE+CoQ10干预后脂肪变性肝细胞数目显著减少(P<0.01)。结论VitE和CoQ10具有较好的防治VPA肝毒副作用的能力。
Objective To study the protection and mechanism of co-administration of vitamin E with coenzyme Q10（CoQ10） to valproate -associated hepatotoxicity in infantal rats. Methods The rat models were established by oral administration of valproic acid（VPA） in ablactation （21 days） Wistar rats, at doses of 500 mg/（kg·d） during 30 days,other groups received the same amount of VPA with phemobarbitone（PB） and co-administration with vitamin E and CoQ10. The changes of liver cell morphology and the blood coagulation test, as well as the contents of succinic dehydrogensse （SDH）, cytochrome oxidase （CCO）, cytochrome, the levels of glutothione（GSH） and malondial dehyde（MDA） in rat liver mitochondria were detected by chromatometry, HPLC, Oil-Red-O staining and electron microscope, respectively. Results 1. Average content of cytochrome aa3 in liver mitochondria of infantal rats were reduced by 58.80 % and 61.80 % because of administration of VPA and VPA added with PB. The protection against the loss of cytochrome aa3 by coadministration of VitE and CoQ10 was obvious. As for activities of SDH and CCO, which affected by VPA and VPA added with PB iri rats, were significantly lowered compared with control group（P〈0.01 ）. However activities of SDH and CCO were effectively protected by coadrninistration with VitE and CoQ10;2. In all rats received with VPA and PB, there were significant abnormalities in function of blood coagulation and serum fibrinogen were shown. Furthermore, liver coagulation function was effectively protected with VitE and CoQ10 from VPA added with PB; 3. Compared with control group, levels of glotathione-SH（GSH） in liver mitochondria were significantly decreased in infantal rats treated with VPA or added with PB（ P〈0.01 ）, whereas the levels of malondialdehyde（MDA） were significantly increased in infantal rats（P〈0.05 ）. The levels of GSH and MDA in mitochondria were still normal in rats which treated with VitE and CoQ10 ; 4. Significant lipid vacuoles primarily occurred in periportal areas of liver lobule in infantal rats received with VPA or and VPA added with PB on frozen sections stained with Oil-Red-O,and the numbers of bepatocyte contained lipid droplets in infant rats was 9.2 times higher than that in control rats, 15.7 times higher in VPA added with PB group,and there was significant difference statistically between them, respectively（P〈0.01 ）. It were indicated that lipid droplets in liver cells induced by VPA could partly prevented with coadministration of VitE＋CoQ10,and the lipid droplets also was confirmed by electron microscopic examination. Conclusion Antioxidant are effective in treating VPA-associated hepatotoxicity.
出处
《实用儿科临床杂志》
CAS
CSCD
北大核心
2006年第6期364-366,共3页
Journal of Applied Clinical Pediatrics
关键词
丙戊酸
维生素E
辅酶Q10
肝损伤
幼鼠
valproic acid
vitamin E
coenzyme Q10
liver injury
infantal rat
作者简介
傅大干，男，主治医师，博士学位，研究方向为神经系统疾病。
