Pathogenesy Of Acute Liver Injury Induced By Ethanol And Protective Effects Of Silymarin In Rats

Background The mechanisms by which ethanol causes liver injury have not completely been clear yet. Ethanol-induced oxidative stress and peroxidation of membrane lipids appeares to play a major role in acute ethanol liver injury. The CYP2E1 is the form of cytochrome P450 enzymes, which is inducde by ethanol. CYP2E1 not only can metabolize many drugs, but also can catalyze the metabolism of ethanol. In this process, more reactive toxic products were produced. The oxidative stress and peroxidation of membrane lipids caused by CYP 2E1 can lead to liver damage in the short term, which is an important mechanism in liver injury induced by ethanol. Silymarin which is a safe, stable and effective liver protective drugs has a strong antioxidant effect, but the study about the effects and the mechanisms of Silymarin on liver injury induced by acute ethanol administration are very little and not yet clear.Therefore, to establish the model of acute ethanol liver injury, clarify the pathogenesy of acute ethanol liver injury and explore the hepatoprotective mechanism of drugs on acute ethanol liver injury are very important.Objective To establish the model of acute ethanol liver injury and investigate the effects and the mechanism of Silymarin on rat liver injury induced by acute ethanol administration.Methods 32 male SD rats were randomly divided into 4 groups with 8 rats in each group:the normal control group, the model control group, the Silymarin in low does and high does group. The normal control group received normal saline by gavage, and the others were prepared with ethanol (5g/Kg) administration by gavage. In the Silymarin groups, Silymarin was gavaged at a dose of 100mg/ Kg or 200mg/ Kg in an hour after with ethanol administration. After the last dosing,the rats were fasted for 6 hours.Then the rats were anesthetized and taken the blood from the abdominal aorta before put to death.The activities of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), the levels of serum total cholesterol (TC), triglyceride (TG), the activity of superoxide dismutase (SOD) and the level of malondialdehyde (MDA) in liver tissue homogenates were analyzed by biochemical method. Histopathological change was observed with hematoxylin and eosin (HE) staining. The expression of TNF-αand IL-1βin the liver tissues were tested by immunohistochemistry. The expression of CYP2E1 mRNA in rat liver were measured by reverse transcription-polymerase chain reaction (RT-PCR).Results Compared with normal control group, the model control group developed significantly steatosis, obvious swelling, infiltration of inflammatory cells and punctiform necrosis in hepatic lobules and the levels of ALT,AST and MDA were increased in model control group(respectively, P<0.05 and P<0.01 ).Similarly, the expression level of TNF-α,IL-1βand CYP2E1 mRNA in rat liver was significantly increased in model control group(P<0.01) compared with normal control group. Besides, in comparison with model control group, Silymarin can ameliorate ethanol-induced hepatic fat degeneration, infiltration of inflammatory cells and punctiform necrosis,and significantly reduce the degree of pathological changes in liver tissue. The levels of ALT and MDA in Silymarin treatment groups were markedly lower than in model group(respectively, P<0.01 and P<0.05), and the SOD activities in Silymarin treatment groups were higher than in model group (P<0.05 ) . The serum level of AST in the group receiving the high dose of Silymarin was also lower than in model control group(P<0.05). Moreover, the expression levels of TNF-α,IL-1βand CYP2E1 mRNA in rat liver in groups with silymarin treatment were significantly lower than in model control group(respectively, P<0.01 and P<0.05).Conclusions Silymarin can protect against the liver injury induced by acute ethanol administration, and the mechanisms may be related to anti-oxidative stress, ahti-inflammmatory, as well as inhibiting the expression of TNF-α, IL-1β, other cytokines, inflammtatory mediators and CYP2E1 mRNA in rat liver.