Metabolic activation, hepatic protein covalent binding, and cytotoxicity of arctigenin

Arctigenin (ATG) is an important component isolated from the fruit of the medicinal plant Arctium lappa L., with anti-inflammatory, antiviral and anti-tumor properties. Although ATG has been reported to induce hepatotoxicity in beagle dogs and SD rats, and the underlying mechanisms remained unclear. The aim of this study was to investigate the metabolic activation of ATG and to define the potential correlation between the metabolic activation of ATG and its hepatotoxicity. A quinone methide intermediate was identified in vitro and in vivo , and CYP3A dominated the metabolic activation. ATG was found to show significant cytotoxicity at 50 μM in cultured mouse primary hepatocytes. The ATG-derived quinone methide metabolite assaulted cysteine residue of hepatic protein to form protein covalent binding. The observed protein modification was most likely associated with the cytotoxicity of ATG observed.