Anti-HBV activity of (R)-gentiandiol, a metabolite of Swertiamarin, in transgenic mice: Insights from non-targeted serum metabolomics

Swertiamarin, a predominant component in many traditional Chinese swertia herbs, shows significant anti-HBV activity clinically. (R)-gentiandiol and (S)-gentiandiol are the metabolites of swertiamarin in vivo. In this study, HBsAg, HBeAg and HBV-DNA were determined in liver tissue of HBV-transgenic C57BL/6NCrl mice to analyze anti-HBV activities of swertiamarin, (R)-gentiandiol and (S)-gentiandiol. It was found that HBsAg, HBeAg and HBV-DNA levels were significantly reduced in a dose-dependent manner when (R)-gentiandiol was administered at 1.5, 3 and 6 mg/kg. However, (S)-gentiandiol showed no anti-HBV activity at all. In addition, we also performed untargeted metabolomics to discover biomarkers and metabolic pathways of swertiamarin and (R)-gentiandiol in HBV-transgenic C57BL/6NCrl mice. A total of 15 candidate biomarkers were obtained. Meanwhile, the metabolic disorders including 8 metabolic pathways, such as taurine and hypotaurine metabolism were explored. Taurine and hypotaurine metabolism was the primary pathway for (R)-gentiandiol to regulate HBV-transgenic C57BL/6NCrl mice. It is the first time to clarify real active anti-HBV metabolites of swertiamarin, which can offer more insights into anti-HBV activities of swertia herbs, and bring novel ideas for new drug development in anti-HBV herbs.