CYP3A Activation and Glutathione Depletion Aggravate Emodin-Induced Liver Injury

Abstract

1,3,8-Trihydroxy-6-methylanthraquinone (emodin), a widely existing natural product in herbal medicines, has been reported to be hepatotoxic, but the exact underlying mechanism is still not fully understood. The objective of the present study was to evaluate the role of CYP3A and glutathione (GSH) in emodin-induced liver injury. Primary human hepatocytes were exposed to emodin with and without addition of CYP3A inducer/inhibitor and GSH synthesis inhibitor. It was found that emodin-mediated cytotoxicity increased when CYP3A was activated and GSH was depleted. Hepatotoxicity induced by emodin in rats by activation/inhibition of CYP3A and depletion of GSH was further investigated. Administration of emodin in combination with l-buthionine sulfoximine (BSO) or dexamethasone (DEX) resulted in aggravated liver injury, whereas pretreatment with ketoconazole (KTZ) suppressed the side effects caused by emodin. In addition, plasma exposure of emodin and its glucuronide metabolite were measured by ultraperformance liquid chromatography triple quadrupole mass spectrometry. Emodin and its glucuronide were lower in BSO-, DEX-, and KTZ- co-treated rats compared with those administered with emodin alone. In conclusion, these mentioned results suggested that CYP3A induction and GSH depletion might be involved in hepatotoxicity induced by emodin. This study may help to understand the risk factors and the mechanism of hepatotoxicity of emodin in humans.

Proteomics Unravels Emodin Causes Liver Oxidative Damage Elicited by Mitochondrial Dysfunction

“…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.…”

Herb-Induced Liver Injury: Phylogenetic Relationship, Structure-Toxicity Relationship, and Herb-Ingredient Network Analysis

“…It has been proved that emodin induces liver injury by inhibiting proton transport, inhibiting bile acids transporters, and activating a mitochondrial apoptosis pathway [78,79]. Additionally, GSH depletion and CYP3A induction may be also related to the hepatotoxicity of emodin [80]. Recently, based on quantitative proteomics, L02 cells were adopted to investigate the potential mechanism of emodin-induced hepatocyte apoptosis.…”

Is Emodin with Anticancer Effects Completely Innocent? Two Sides of the Coin

“…The US National Toxicology Program has reported that exposure to emodin resulted in enhanced cases of renal tubule pigmentation in male and female mice and increased cases of nephropathy in female mice. Administration of emodin ensued in a remarkable reduction in cell viability and inhibition of the proliferation of HK-2 cells [ 207 , 208 ]. Emodin has been recorded to cause reproductive toxicity.…”