Schisantherin A alleviates hepatotoxicity induced by diosbulbin B in mice via suppressing metabolic activation of diosbulbin B.

Diosbulbin B (DLB) is the most abundant diterpene lactone in herbal medicine Dioscorea bulbifera L. (DB). DLB is able to cause severe liver injury. The early studies showed that CYP3A4-mediated metabolic activation of DLB to form the corresponding cis-enedial metabolite was associated with DLB-induced hepatotoxicity. Schisantherin A (SchA), the primary lignan ingredient isolated from herbal medicine Schisandra fructus (SF), can inhibit CYP3A4 activity. The objective of the study is to examine the protective effect of SchA against DLB-induced hepatotoxicity and the underlying mechanism. Biochemical and histopathological examination demonstrated that SchA exhibited dose-dependent protection against DLB-induced hepatotoxicity. In vitro experiments showed that SchA reduced the generation of DLB-derived pyrrole-glutathione (GSH) conjugates, indicating the metabolic activation of DLB in vitro was inhibited by SchA. Toxicokinetic studies displayed that the maximal concentration (Cmax) and area under the concentration-time curve (AUC) of DLB in mouse blood and liver were significantly increased after pretreatment with SchA, leading to augmenting the accumulation of DLB in vivo. Additionally, SchA ameliorated hepatic GSH depletion induced by DLB, increased urinary excretion of DLB, and reduced excretion of DLB-GSH conjugates in urine, suggesting that the metabolic activation of DLB in vivo was inhibited by SchA. In summary, our studies manifested the protection of SchA against hepatotoxicity of DLB was correlated with inhibiting metabolic activation of DLB. Thus, our study may provide the prospects for developing SchA as a detoxification candidate for DLB intoxication and may explain the protective mechanism of SF against liver injury induced by DB.