Dictamnine-induced hepatotoxicity in mice: the role of metabolic activation of furan.

Cortex Dictamni is extensively used as an herbal medicine worldwide, but is believed to induce hepatotoxicity and even causes mortality in many Asian and European countries. As the most abundant furoquinoline alkaloid ingredient of Cortex Dictamni, dictamnine (DIC) can be metabolically activated by CYP3A to an epoxide metabolite, which possesses the potential to induce hepatotoxicity by covalent binding with proteins. As yet, the hepatotoxicity of DIC and the role played by metabolic activation remain unknown. Here, we found that DIC caused acute liver injury in a time- and dose-dependent manner in mice. The hepatic and urinary DIC epoxide intermediates were observed in DIC-treated mice. Ketoconazole, a CYP3A inhibitor, significantly reduced the hepatotoxicity of DIC and inhibited the formation of reactive metabolites of DIC. Moreover, treatment with 2,3-dihydro-DIC, a DIC analog synthesized by selective reduction of the furan moiety, produced no hepatotoxicity in mice, and no reactive metabolite was formed, suggesting a structural necessity of furan moiety in DIC hepatotoxicity. A time course of gradual hepatic glutathione consumption was observed in DIC-treated mice, while depletion of hepatic glutathione by L-buthionine-S,R-sulfoximine enhanced the hepatotoxicity of DIC. Collectively, this study demonstrates that DIC induces acute hepatocellular injury in mice, and that metabolic activation of furan plays a crucial role in DIC-induced hepatotoxicity.