Ameliorative effect of Schisandrol B against Diosbulbin B-induced hepatotoxicity via inhibiting CYP3A4-mediated bioactivation

Abstract

Diosbulbin B (DBB), the major component isolated from herbal medicine Dioscorea bulbifera L. (DBL), can trigger severe hepatotoxicity. The previous studies demonstrated that DBB-induced hepatotoxicity is closely relevant to the bioactivation mediated by CYP3A4 and subsequent generation of adducts with cellular proteins. Schisandrol B (SchB), the primary lignan ingredient in herbal medicine Schisandra chinensis (SC), is able to inhibit CYP3A activity. The objective of this study is to investigate the protective effect of SchB against hepatotoxicity induced by DBB and to explore the underlying mechanism. Biochemical and histopathological analysis demonstrated that SchB exerted dose-dependent protective effect against DBB-induced hepatotoxicity. In vitro metabolism assay showed that the formation of pyrrole-glutathione (GSH) conjugates of DBB was inhibited by SchB in a concentration dependent manner, suggesting SchB inhibited the bioactivation of DBB in vitro. Pharmacokinetic studies demonstrated that SchB enhanced C_max and AUCs of DBB in mouse blood and liver, resulting in accelerating the accumulation of DBB in the circulation. In addition, pretreatment with SchB alleviated DBB-induced hepatic GSH depletion, obviously facilitated the excretion of DBB in urine, and reduced the urinary excretion of DBB-GSH conjugates, indicating that SchB affected absorption, distribution, metabolism, and excretion (ADME) of DBB by inhibiting the bioactivation of DBB in vivo. In conclusion, our findings demonstrated the amelioration of SchB against DBB-induced hepatotoxicity was correlated with the inhibition of CYP3A4-mediated bioactivation of DBB. Thus, the findings indicated that SchB may serve as a potential candidate drug for the treatment of DBB intoxication.