N,N-dimethylformamide (DMF) is a colorless industrial solvent that is frequently used for chemical reactions. Epidemiologic studies and clinical case reports have consistently indicated that the main toxic effect after exposure to DMF is hepatotoxicity. Previous studies have suggested that oxidative stress is the pivotal molecular event of DMF-mediated hepatotoxicity; however, its underlying mechanism remains unclear. In this study, we found that DMF (0-150 mM) exposure induced an increase in reactive oxygen species (ROS) levels and inhibited the transcriptional activity of nuclear factor erythroid-2-related factor-2 (NRF2) in a dose-dependent manner. Subsequently, our research revealed that the elevated ROS levels and the decline in NRF2-mediated anti-oxidative response in HL-7702 and HuH6 cells might be due to the DMF-induced accumulation of retinoid X receptor α (RXRα) protein. Further investigation demonstrated that phosphorylation of the RXRα protein, which is mediated by the activation of extracellular signal-regulated kinase (ERK), leads to the inhibition of RXRα protein degradation and in turn the accumulation of RXRα after DMF exposure. These findings provide information that improves our understanding of the role of RXRα in DMF-induced hepatotoxicity.
Keywords: DMF; ERK; NRF2/ARE; ROS; RXRα; oxidative stress.
© 2019 John Wiley & Sons, Ltd.