A novel mechanism involved in the enhancement of glutathione synthesis in liver by silymarin and its pharmacological significance

Silymarin has been used for the treatment of liver injury. We investigated the alterations in sulfur amino acid metabolism induced by silymarin and its pharmacological significance. Male mice were treated with silymarin (100 or 200 mg/kg, po) every 12h for a total of 3 doses. Silymarin elevated hepatic methionine level by 24% at the lower dose and by 34% at the higher dose when measured at 6h after the last dosing, but decreased methionine adenosyltransferase expression in a dose-dependent manner. S-adenosylmethionine or homocysteine concentration was not changed, whereas cystathionine, cysteine and glutathione (GSH) were increased significantly. Cystathionine β-synthase was induced, but cysteine dioxygenase was down-regulated in liver. Total oxygen radical scavenging capacity of liver was increased and hepatic lipid peroxidation was diminished significantly. In mice pretreated with silymarin the hepatotoxicity induced by acetaminophen (APAP; 500 mg/kg, ip) was reduced as measured by elevation of serum enzyme activities and histopathological examination. Plasma APAP level was not changed, while APAP-GSH, APAP-cysteine and APAP-mercapturate were elevated significantly. However, expression of CYP2E1, CYP1A or CYP3A was not increased by silymarin. These results indicate that the increment of APAP-GSH conjugates should be attributed to the increase in conjugation of N-acetyl-p-benzoquinoneimine with GSH. In conclusion, the results show that silymarin enhances hepatic GSH generation by elevating cysteine availability via an increment in cysteine synthesis and an inhibition of its catabolism to taurine, which subsequently contributes to the antioxidant defense of liver. It is also suggested that silymarin may protect the liver from reactive electrophilic substances by increasing detoxification via conjugation with GSH.

Keywords: Silymarin, glutathione, antioxidant, acetaminophen, cytochrome P450