Experimental study on susceptibility of high risk factors related with hepatotoxicity of valproic acid / 中国药理学通报

ABSTRACT

Aim To explore the differences of pathogenesis for the hepatotoxicity induced by chronic treatment of valproic acid(VPA) in different ages,and in combination administration with inducers of liver enzyme.Methods Animal models were established by oral administration chronically with VPA at doses of 200 or 500 mg?kg~(-1) per day in 30 days for 50 Wistar rats(infant and adult rats) with inducers of liver enzyme Phenobarbital(PB) or not.Mitochondria were obtained by differential centrifugation.Levels of liver enzymes,coagulation factors,plasma ammonia,VPA and PB serum levels,and L-carnitine in sera,as well as the changes of respiratory enzymes and lipid peroxidation in hepatic mitochondria were measured.Mitochondrial membrane potential(MMP) and mRNA expression of CYP450 reductase in liver were determined by flow cytometer and in situ hybridization,and morphological changes of hepatocytes were observed under microscope with Oil-Red-O staining.Results ① In all rats treated with higher dose of VPA added with PB or not,there were no significant elevations of liver enzymes(ALT and AST).However significant abnormalities of function of blood coagulation and serum fibrinogen were shown, and the levels of plasma ammonia and L-carnitine were also changed significantly,and the changes were notable in infant rats or in those rats added with PB. ② Average contents of cytochrome aa3 in liver mitochondria of infant rats were reduced by 58.80% and 61.80% because of administration of high dose VPA and high dose VPA added with PB,but were reduced by 37.55% and 46.53% in adults.As for activities of SDH,which affected by high dose VPA in infants,were significant decreased by 44.8% and 57.9%,respectively,but still in normal range in adult groups.Activities of CCO in liver mitochondria were significantly lowered by high dose VPA or added with PB compared with controls(P