Metabolomic profiling of emodin-induced cytotoxicity in human liver cells and mechanistic study

Abstract

Emodin is one of the most representative natural anthraquinone polyphenols and the liver is one of the major target organs for drug-induced toxicology. The hepatocyte is frequently affected due to its role in emodin metabolism and accumulation. Although the hepatotoxicity of emodin has been reported, its toxicological mechanism is still unclear. The purpose of the present study was to evaluate the cytotoxicity of emodin in cultured human normal liver cells (L-02), to investigate the toxicity-related metabolic pathways and to predict the possible toxicity mechanism. Cell viability was analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cytotoxicity tests demonstrated a concentration-dependent toxic effect of emodin on L-02 cells. Cells were treated for 48 h with low, medium and high doses of emodin, respectively, and then subjected to metabolomics analysis using ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS). Intracellular metabolomics analysis revealed that emodin significantly disturbed cellular glutathione and fatty acid metabolism. In addition, an emodin-cysteine adduct was identified in cell culture medium, and its level increased with increasing concentrations of emodin. The possible relationship among metabolic disorders, adduct formation and emodin hepatotoxicity was also discussed. This study provides new insight into the cytotoxicity of emodin on metabolic pathways in human liver cells.

Mesoporous silica nanoparticles SBA-15 loaded with emodin upregulate the antioxidative defense of Euproctis chrysorrhoea (L.) larvae

“…radicals (Huang et al, 1992;Srinivas et al, 2007;Qu et al, 2013;Liu et al, 2015;Zhao et al, 2017). However, the effects and molecular mechanisms of EO action on insect antioxidative defense are still unexplored.…”

“…Only SBA-15|EO-treated larvae exhibited higher GR activity (Figure 4), which could indicate the involvement of this system in the prevention of the establishment of toxic conditions due to the accumulation of hydroxyperoxide or other ROS. It was shown that EO has the potential to disturb GSH metabolism in normal (human) liver cells (Liu et al, 2015), as judged by the decreased levels of both GSH and GSSG, and the increased level of its metabolite, glutamate (Liu et al, 2015).…”

“…EO significantly increased ROS levels and oxidative stress in human T cells (Qu et al, 2013). The EO-induced disturbance of metabolic pathways in liver cells, including disruption of glutathione metabolism, has been considered as a mechanism of indirect toxicity of EO (Liu et al, 2015).…”

“…By interacting with enzymes, transporters, channels, and receptors, EO has access to multiple cellular targets and can interfere with many pathways, which is a common feature of many plant phenolics (Mueller et al, 1998;Srinivas et al, 2007 and references therein;Teng et al, 2012;Dong et al, 2016). As a quinone, EO has a marked oxidative impact on the cellular redox status and on the generation of reactive oxygen species (ROS) (Rahimipour et al, 2001;Srinivas et al, 2007;Mecklenburg et al, 2009;Martín-Cordero et al, 2012;Qu et al, 2013;Liu et al, 2015;Lennicke et al, 2016). EO can be reduced to its semiquinone, which in the presence of molecular oxygen generates the superoxide anion (O 2 al., 2009;Lennicke et al, 2016).…”

“…It is distributed in the leaves, fruits, flowers, bark, and roots, mostly in the form of different glycosides (sugar derivatives), but is also found in a free form as aglycone (Izhaki, 2002 and references therein). EO possesses numerous biological properties, including bactericidal, fungicidal, immunosuppressive, hepatoprotective, and anticancer activities (Srinivas et al, 2007;Martín-Cordero et al, 2012;Qu et al, 2013;Liu et al, 2015;Dong et al, 2016). EO is important in mediating plant-plant (Knight et al, 2007), plant-animal (Trial and Dimond, 1979;Sacerdote and King, 2014), plant-microorganism (Lee et al, 2013), and plant-abiotic environmental interactions (Izhaki, 2002).…”