Investigation of Tetrahydroxystilbene Glucoside, the Idiosyncratic Hepatotoxic Component of <i>Polygonum multiflorum</i> Thunb., and Its Toxicity Attenuation by <i>Ganoderma lucidum</i>

Abstract

Background: A previous study has also shown that the hepatotoxic of Polygonum multiflorum is idiosyncratical hepatotoxic, but the idiosyncratic hepatotoxic component, and its toxicity attenuation method was not well understood. Methods: We used serum biochemical indicator, histopathology and metabolomics methods to investigate the liver injury induced by Polygonum multiflorum, its different fractions and tetrahydroxystilbene glucoside (TSG) in an LPS-induced immune stress rat model. We determined their structures and dynamically assessed the component changes during transformation using high-performance liquid chromatography coupled with diode-array detection and electrospray ionization tandem mass spectrometry (HPLC-DAD-MSn). We examined the intracellular and extracellular distribution and activities of I²-D-glucosidase and lignin peroxidase, determined the functions of lignin peroxidase by inhibitors and agonists. In vitro, the cellular toxicity of TSG was detected after biotransformation. Findings: We discovered that TSG was the main idiosyncratic hepatotoxic component and its hepatotoxicity showed a dose-dependent effect. A suitable biotransformation system of TSG was established with Ganoderma lucidum, then p-hydroxybenzaldehyde and 2,3,5-trihydroxybenzaldehyde can be found as transformation products of TSG in the system. The transformation mechanism involves two extracellular enzymes, I²-D-glucosidase and lignin peroxidase. The former can remove glycosylation of TSG firstly and then the latter also can break the double bond of remaining glycosides. The cellular toxicity of TSG was attenuated. Interpretation: TSG was the idiosyncratic hepatotoxic component of Polygonum multiflorum Thunb., and its toxicity after biotransformation by Ganoderma lucidum was attenuated. The finding has potential application value and provides a novel method for the toxicity attenuation in the food and drug field. Funding Statement: This work was supported by the National Science foundation of China (no. 81503238, 81503041), the Science Research Projects of Chinese Pharmacopoeia (no. Z18), the Science Research Projects of the Hunan Provincial Department of Education (no. 17C1213), and the Key Projects of the Changsha Municipal Science and Technology Bureau (no. K1406030-31). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: Animal care and treatments were conducted according to established guidelines and protocols approved by Animal Care and Use Committee of the University of Hunan University of Chinese Medicine (Changsha, China).