Hepatoprotective effect of withanolide-rich fraction in acetaminophen-intoxicated rat: decisive role of TNF-, IL-1, COX-II and iNOS

Context: Overdose of acetaminophen (APAP) is common in humans and is often associated with hepatic damage. Withania somnifera (L.) Dunal (Solanaceae) shows multiple pharmacological activities including antioxidant and anti-inflammatory potential.Objective: To evaluate the possible mechanism of hepatoprotective activity of withanolide-rich fraction (WRF) isolated from a methanolic extract of Withania somnifera roots.Materials and methods: Hepatotoxicity was induced by oral administration of APAP (750mg/kg, p.o.) for 14d. The control group received the vehicle. APAP-treated animals were given either silymarin (25mg/kg) or graded doses of WRF (50, 100 and 200mg/kg) 2h prior to APAP administration. Animals were killed on 15th day and blood and liver tissue samples were collected for the further analysis.Results: In WRF-treated group, there was significant and dose-dependent (p<0.01 and p<0.001) decrease in serum bilirubin, ALP, AST and ALT levels with significant and dose-dependent (p<0.01 and p<0.001) increase in hepatic SOD, GSH and total antioxidant capacity. The level of MDA and NO decreased significantly (p<0.01) by WRF treatment. Up-regulated mRNA expression of TNF-, IL-1, COX-II and iNOS was significantly down-regulated (p<0.001) by WRF. Histological alternations induced by APAP in liver were restored to near normality by WRF pretreatment.Conclusion: WRF may exert its hepatoprotective action by alleviating inflammatory and oxido-nitrosative stress via inhibition of TNF-, IL-1, COX-II and iNOS.