Detection of Emodin Derived Glutathione Adduct in Normal Rats Administered with Large Dosage of Polygoni Multiflori Radix

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 PMRinduced 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.

Proteomics Unravels Emodin Causes Liver Oxidative Damage Elicited by Mitochondrial Dysfunction

“…Analysis of serum samples from rats in the control and emodin groups indicated that emodin induced liver injury (Yang et al, 2018). Previous studies have also found that emodin induced liver injury in vivo and in vitro to some extent (Li et al, 2012;Zhang et al, 2010;Liu et al, 2015b;Ma et al, 2015;Jiang et al, 2017), similar to our observation.…”

“…In the down-regulated proteins, 11 proteins related to redox regulatory were found (Table S6), which increased susceptibility to oxidative stress and contributed to the disruption of redox homeostasis and ultimately damaged biomolecules (Liu et al, 2009). Previous studies have found that emodin could induce oxidative stress by producing ROS and consuming antioxidants such as GSH and SOD (Ma et al, 2015;Jiang et al, 2017;Jiang et al, 2018). However, in this study, emodin could inhibit Prdx, Gpx, thioredoxin system and glutaredoxin system, which is a new discovery.…”

“…As one of their mutual active ingredients, emodin is considered to be responsible for the toxic effect on livers (Yang et al, 2019). Previous studies have shown that emodin can elevate ROS levels accompanied by consumption of SOD and GSH (Ma et al, 2015;Jiang et al, 2017;Jiang et al, 2018) and lead to oxidative stress (Cui et al, 2014). Further studies have found that emodin can alter mitochondrial membrane potential (Cui et al, 2014), down-regulate GAPDH expression and MDH activities (Yang et al, 2018), and inhibit protein expressions and activities of mitochondrial respiratory chain (Lin et al, 2019), which implied that emodin has a potential damaging effect on liver mitochondrial function.…”

Advances in the Study of the Potential Hepatotoxic Components and Mechanism of Polygonum multiflorum

“…In addition, the reactive metabolite overproduction depletes GSH, which could result in hepatotoxicity [ 102 – 104 ]. Research also found that emodin could conjugate with GSH, forming emodin-GSH and depleting GSH in PM-induced liver injury rats [ 40 – 42 ]. An increasing number of studies have shown that mitochondrial damage may be a factor and pathway that predisposes individuals to PM-induced liver injury.…”

The Modulatory Role of CYP3A4 in Dictamnine-Induced Hepatotoxicity

“…It is widely accepted that cytochrome P450 (CYPs)-mediated metabolic activation is responsible for the hepatotoxicity of some natural products ( Njuguna et al, 2012 ; Ruan et al, 2014 ; Lin et al, 2016 ) via the formation of reactive electrophilic intermediates that react with nucleophilic sites of macromolecules, such as protein ( Xia et al, 2016 ), glutathione ( Jiang L.L. et al, 2017 ), and nucleic acid ( Yu et al, 2014 ).…”