Experimental Study On Protective Effects Of Tiopronin On CsA-induced Hepatotoxicity

Objective: The aim of this experiment was to explore the mechanism of CsA-induced hepatotoxicity and the protective effects of Tiopronin. Methods: Forty SD rats were divided into tbur groups: Nomal group, CsA group, Tio group(CsA+Tiopronin), Ver group(CsA+Verapamil), CsA, Tiopronin, Verpamil was administered once a da by gavage at a dose of 25mg/kg, 250mg/kg, 10mg/kg respectively. At the first day, the first week, the second week, the concentration of serum alanine amainotransferase(ALT), total protein(TP), albumin(ALB), total bile acid(TBA), total bilirubin(TBIL), directive bilirubin(DBIL), superoide dismutase(SOD), malomdialdyhyde(MDA) were monitored. The contents of liver MDA, glutathione(GSH) and the activity of cytochrome P45 03A4(P4503A4) were determined. Llepatic morphological changes were observed by light and electron microcopies. Result: Serum ALT, TBA, TBIL increased shaiply in CsA group ,and the cholestasis was the most notable represent. TP, ALB decreased with the lafter more obviously, instincting the protein synthesis compromised and utilizatin increased, CsA induced serum MIDA increased, SOD decreased and liver homogenates IvLDA increased, GSH decreased, indicating the formation of oxgen free radicals, lipid peroxidatiom and GSLI depletion. The activity of P4503A4 was inhibited. Tiopronin could decrease ALT, TBA,TBIL, (P<0.01) which were increased by CsA. Tiopronin could improve SODQ?O.Ol) and depress MDA(P=0.05 1), antagonizing lipid peroxidation. Verpamil could suppress the rise of TBA (P<0.05), with no influence on ALT. Light microscope examination showed that CsA induced vacuolar degeneration, focal and massive necrosis, accompanied by the soakage of inflammatory cells. With the use of Tiopronin, the degree and area of necrosis were shrinked. Electron microcope examination explored that CsA made the mitochondril swelling, vacuoliization, endoplasmic reticulum dilatation and degranulation. The membrane of nuclei and mitochondrial blurred or vanished. Given Tiopronin , mitochondrial, endoplasmic reticulum and their membrane were resumed. Conclusion: CsA nduced hepatotoxicity was obvious and its mechanism was complex. Tiopronin could alleviate CsA-induced hepatic injury to a certain.