Hepatotoxicity or hepatoprotection of emodin? Two sides of the same coin by 1H-NMR metabolomics profiling

Highlights: • Emodin's bidirectional role in mice liver was revealed by metabolomics profiling. • Emodin ameliorated CCl₄-induced energy metabolism dysfunction in mice livers. • Emodin inhibited NF-κB signaling pathway to relieve CCl₄-induced inflammation. • GSH, xanthine metabolism was involved in overdosed emodin-induced hepatotoxicity. Emodin is the major anthraquinone component of many important traditional Chinese herbs, such as Rheum palmatum L. and Polygonum multiflorum Thunb. They have been popular health products but recently aroused concerns about their hepatotoxicity, which are believed to be arising from the contained anthraquinones, such as emodin. However, emodin exerts potent hepatoprotective ability, such as anti-fibrotic, anti-oxidative, and anti-inflammatory effects. In this study, ¹H NMR based metabolomics approach, complemented with histopathological observation, biochemical measurements, western blotting analysis and real-time quantitative PCR (RT-qPCR), was applied to interpret the paradox of emodin (30 mg/kg, 10 mg/kg BW) using both healthy mice (male, ICR) and chronic CCl₄-injured mice (0.1 mL/kg, 0.35% CCl₄, 3 times a week for a month). Emodin exerted a weight loss property associated with its lipid-lowing effects, which helped alleviate CCl₄-induced steatosis. Emodin effectively ameliorated CCl₄-induced oxidative stress and energy metabolism dysfunction in mice liver via regulating glucose, lipid and amino acid metabolism, and inhibited excessive inflammatory response. In healthy mice, emodin only exhibited hepatoxicity on high-dosage by disturbing hepatic anti-oxidant homeostasis, especially GSH and xanthine metabolism. This integrated metabolomics approach identified the bidirectional potential of emodin, which are important for its rational use.