Silymarin prevents acetaminophen-induced hepatotoxicity via up-regulation of the glutathione conjugation capacity in mice

Abstract Our previous study showed that silymarin, a mixture of flavonolignans extracted from seeds of milk thistle, modulated hepatic transsulfuration reactions, leading to an increase in glutathione (GSH) synthesis. To investigate its pharmacological significance, we determined the effect of silymarin on acetaminophen (APAP)-induced liver injury. Silymarin administration to mice prevented the induction of APAP-hepatotoxicity as measured by changes in plasma enzyme activities, hepatic lipid peroxidation and formation of nitrotyrosine protein-adducts. Depletion of hepatic GSH was inhibited significantly. Plasma APAP, APAP-glucuronide or APAP-sulfate level was not changed, but APAP-GSH, APAP-cysteine and APAP- N -acetylcysteine levels were elevated. Silymarin treatment did not induce proteins or activities of Cyp2e1, Cyp1a2, and Cyp3a11, the major cytochrome P450 subtypes responsible for the metabolic activation of APAP to a reactive metabolite, N -acetyl- p -benzoquinoneimine. The results suggest that the hepatoprotective effect of silymarin is associated with an increase in the metabolic disposition of N -acetyl- p -benzoquinoneimine via up-regulation of the GSH conjugation capacity.