Abstract
Polygoni Multiflori Radix (PMR) has been commonly used as a tonic in China for centuries. PMR-associated hepatotoxicity has been drawing increasingly more attention in recent years in parallel with its wide utilization. Anthraquinones (AQs) are recognized as the main hepatotoxic components in PMR. However, the exact underlying mechanism of AQs poisoning is still not fully understood. Herein, we proposed a hypothesis that metabolic activation of AQs such as emodin was involved in PMR-induced liver injury, AQs followed to generate the electrophilic reactive metabolites and subsequently formed covalent adduct with cellular nucleophiles in the liver to exert hepatotoxicity. In the present study, the link of cytotoxicity of PMR in primary human hepatocytes and the depletion of glutathione (GSH) was investigated by MTT assay and UHPLC-QqQ-MS/MS analysis. The results showed that PMR depleted GSH and therefore induced cytotoxicity. Then, emodin-GSH adduct was identified in bile of liver injured rats after intragastric administration of PMR or emodin with the aid of UHPLC-QTOF-MS/MS method. Our findings not only provided confirmative evidence that the mechanism of hepatotoxicity induced by AQs in PMR involved key metabolic steps, but also revealed that emodin-GSH adduct had potential to be further developed as a sensitive and traceable biomarker for the assessment of PMR-induced liver injury.
Highlights
Polygoni Multiflori Radix (PMR), derived from the dried root of Polygonum multiflorum Thunb. (Family Polygonaceae), has been commonly used as a Chinese herbal medicine in clinical practice for health promotion and disease treatment for thousands of years, with the Chinese name “Heshouwu” (Lin et al, 2015a)
As the cytotoxicity was observed with the treatment of PMR, we further investigated the relationship between GSH depletion and the cytotoxicity in primary human hepatocytes, with the aid of UHPLC-QqQ-MS/MS method
A recent research demonstrated that combined treatment with lipopolysaccharide and PMR resulted in acute idiosyncratic liver injury in rats, and revealed that 2,3,5,4 -tetrahydroxy cis-stilbene2-O-β-glucoside was closely associated with the idiosyncratic hepatotoxicity of PMR (Li et al, 2017)
Summary
Polygoni Multiflori Radix (PMR), derived from the dried root of Polygonum multiflorum Thunb. (Family Polygonaceae), has been commonly used as a Chinese herbal medicine in clinical practice for health promotion and disease treatment for thousands of years, with the Chinese name “Heshouwu” (Lin et al, 2015a). (Family Polygonaceae), has been commonly used as a Chinese herbal medicine in clinical practice for health promotion and disease treatment for thousands of years, with the Chinese name “Heshouwu” (Lin et al, 2015a). It is traditionally valued for hair-blacking, liver and kidneytonifying and anti-aging effects (Lin et al, 2015c). PMR-induced liver injury in clinic has been constantly reported in recent years (Yu et al, 2011). The earliest case of liver injury induced by PMR was recorded in 1996 in China (But et al, 1996). A broad spectrum of chemicals such as stilbenes, anthraquinones (AQs), flavonoids, and phospholipids
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