Cysteine-Based Protein Covalent Binding and Hepatotoxicity Induced by Emodin

Abstract

Emodin (EMD) is a major ingredient of Polygonum multiflorum Thunb. (PMT), which has shown adverse liver reactions. Despite multiple pharmacological activities, EMD is reported to show various toxicities. Our early study demonstrated the reactivity of EMD to glutathione. This study aimed to determine the covalent interaction of hepatic protein with EMD and the correlation of the protein modification with hepatotoxicity induced by EMD. EMD-derived protein adduction was detected in an incubation mixture containing mouse liver homogenates and EMD. Such protein adduction was also observed in hepatic protein obtained from mice exposed to EMD. The protein covalent binding occurred in time-and dose-dependent manners. Pretreatment of L-buthionine-sulfoximine significantly potentiated EMD-induced adduction and hepatotoxicity caused by EMD and lipopolysaccharide co-treatment. As expected, EMD-derived protein modification was observed in mouse primary hepatocytes treated with EMD. The increase in EMD exposure concentration intensified EMD-derived protein adduction and increased EMD-induced cell death. The susceptibility of hepatocytes to EMD cytotoxicity and the intensity of EMD-induced protein adduction were attenuated by the co-treatment of hepatocytes with N-acetyl cysteine. A good association of protein modification with hepatotoxicity induced by EMD was illustrated, which facilitates the understanding of the mechanism of hepatotoxicity induced by EMD.

Emodin disrupts the Notch1/Nrf2/GPX4 antioxidant system and promotes renal cell ferroptosis

“…Drugs containing rhubarb ingredients such as R. palmatum have been widely used in clinical practice, including the treatment of gastric and kidney diseases or the promotion of blood circulation (Shrimali et al, 2013). With the deepening of pharmacological research, several studies have reported that emodin causes nephrotoxicity, hepatotoxicity, and reproductive toxicity, especially at high doses and with long‐term use (Dong et al, 2016; Ni et al, 2022; Wang, Ding, et al, 2022), and ultimately causes impaired tissue and organ function. We observed statistically significant pathological lesions in the emodin‐exposed kidneys in our preliminary experiment.…”

A Network-Pharmacology-Combined Integrated Pharmacokinetic Strategy to Investigate the Mechanism of Potential Liver Injury due to Polygonum multiflorum

“…According to the half-life (T 1/2 ), the clearance rate (CLz/F), and the average residence time (MRT), the overall component could still be detected at 24 h after administration, elimination was slow, and it easily persisted in the body, suggesting that this may be related to the potential liver injury due to PM. Literature reports have shown that TSG, EM, and EG may be the material basis of PM-induced specific liver injury, and they have synergistic effects [ 37 , 38 , 39 , 40 ]. In our integrated pharmacokinetic study, the weights of TSG, EM, and EG were 30.19%, 49.43%, and 13.77%, respectively, and the sum of the three was 93.39%, accounting for a relatively large proportion, which provided a reference for the above theory at the level of substance content in vivo.…”

Chemical nature of metabolic activation of natural products in traditional Chinese medicines possibly associated with toxicities

“…The electrophilicity of emodin enables it to react with cysteine residues in murine liver proteins. Aberrant hepatic protein adduction by emodin leads to hepatotoxicity [42] . Furthermore, 5-hydroxyemodin, generated by emodin metabolic activation of CYP1A1, is found to induce oxidative stress in cells [43] .…”