Journal of ethnopharmacology · 2025
The protective effect of Schisandra lignans on the hepatotoxicity induced by the metabolic activation of dictamnine.
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Lin Dongju, Li Guangyao, Deng Haoran, Wang Shuo
Аннотация
ETHNOPHARMACOLOGICAL RELEVANCE: Dictamnine (DIC) is the predominant pharmacological and hepatotoxic component of Cortex Dictamni (CD). CYP3A-mediated metabolic activation plays an important role in DIC-induced hepatotoxicity. Schisandra lignans (SCLs) are the major hepatoprotective ingredients of Schisandra chinensis (SC). CD and SC are frequently used as herb pairs in traditional Chinese medical formulas particularly for the treatment of eczema and urticarial. Our preliminary studies have shown that SC can protect against CD-induced liver injury. However, the underlying protective mechanism of SC against CD-induced liver injury has remained unknown.
AIM OF THE STUDY: This study aims to investigate the effects of SCLs on the hepatotoxicity and metabolic activation of DIC and elucidate the underlying hepatoprotective mechanism from the perspective of the inhibition of CYP3A-mediated metabolic activation.
MATERIAL AND METHODS: The protective effect of SCLs against DIC-induced hepatotoxicity was evaluated by biochemical analysis and liver histological observation. The effect of SCLs on the in vitro metabolic activation of DIC was assessed by detecting the level of DIC-N-acetylcysteine (NAC) conjugates in mouse liver microsomal incubations. The effect of SCLs on the metabolic activation in vivo of DIC was examined by monitoring the toxicokinetic behaviors of DIC, DIC-induced hepatic GSH depletion, the cumulative urine excretion of DIC, the levels of DIC-NAC conjugates in urine and liver of mice, and the formation of DIC-derived cysteine-protein adducts.
RESULTS: Our findings indicated that SCLs protected against DIC-induced hepatotoxicity in a dose-dependent manner. SCLs exhibited dose-dependent inhibitory effect on the formation of DIC-NAC conjugates in liver microsomal incubations, indicating SCLs inhibited the metabolic activation of DIC in vitro. SCLs increased Cmax and AUCs of DIC in the blood and liver of mice, leading to the enhancive accumulation of DIC in the circulation. Pretreatment with SCLs relieved hepatic GSH depletion induced by DIC, promoted the urinary excretion of DIC, inhibited the formation of reactive metabolite of DIC in urine and liver of mice, and reduced the production of DIC-derived cysteine-protein adducts, suggesting that SCLs influenced absorption, distribution, metabolism, and excretion (ADME) of DIC by suppressing the metabolic activation of DIC in vivo.
CONCLUSIONS: The study demonstrated the protective effect of SCLs against hepatotoxicity induced by DIC was related to the inhibition of CYP3A-mediated metabolic activation of DIC. Therefore, the study demonstrated that SCLs may serve as the candidate drugs for the intoxication of DIC. Moreover, our findings may interpret the protective mechanism of SC against CD-induced liver injury.
AIM OF THE STUDY: This study aims to investigate the effects of SCLs on the hepatotoxicity and metabolic activation of DIC and elucidate the underlying hepatoprotective mechanism from the perspective of the inhibition of CYP3A-mediated metabolic activation.
MATERIAL AND METHODS: The protective effect of SCLs against DIC-induced hepatotoxicity was evaluated by biochemical analysis and liver histological observation. The effect of SCLs on the in vitro metabolic activation of DIC was assessed by detecting the level of DIC-N-acetylcysteine (NAC) conjugates in mouse liver microsomal incubations. The effect of SCLs on the metabolic activation in vivo of DIC was examined by monitoring the toxicokinetic behaviors of DIC, DIC-induced hepatic GSH depletion, the cumulative urine excretion of DIC, the levels of DIC-NAC conjugates in urine and liver of mice, and the formation of DIC-derived cysteine-protein adducts.
RESULTS: Our findings indicated that SCLs protected against DIC-induced hepatotoxicity in a dose-dependent manner. SCLs exhibited dose-dependent inhibitory effect on the formation of DIC-NAC conjugates in liver microsomal incubations, indicating SCLs inhibited the metabolic activation of DIC in vitro. SCLs increased Cmax and AUCs of DIC in the blood and liver of mice, leading to the enhancive accumulation of DIC in the circulation. Pretreatment with SCLs relieved hepatic GSH depletion induced by DIC, promoted the urinary excretion of DIC, inhibited the formation of reactive metabolite of DIC in urine and liver of mice, and reduced the production of DIC-derived cysteine-protein adducts, suggesting that SCLs influenced absorption, distribution, metabolism, and excretion (ADME) of DIC by suppressing the metabolic activation of DIC in vivo.
CONCLUSIONS: The study demonstrated the protective effect of SCLs against hepatotoxicity induced by DIC was related to the inhibition of CYP3A-mediated metabolic activation of DIC. Therefore, the study demonstrated that SCLs may serve as the candidate drugs for the intoxication of DIC. Moreover, our findings may interpret the protective mechanism of SC against CD-induced liver injury.