Nrf2 exerts an unfavorable role in chemical hepatotoxicity in mice by maintaining CYP2E1 protein stability.
TL;DR
Results indicate that Nrf2 facilitates chemical bioactivation by maintaining the stability of CYP2E1, which is partially mediated by ROS and heme signaling.
Abstract
Nuclear factor erythroid 2-related factor 2 (Nrf2) is generally recognized for its protective role against chemical toxicity. However, in some cases the function of Nrf2 is not as expected. Using wild-type (WT) and Nrf2-knockout (Nrf2-KO) mice, we investigated the role of Nrf2 in hepatic injury induced by the typical hepatotoxicants, thioacetamide (TAA) and diethylnitrosamine (DEN). Both acute and chronic liver injury models were established. In the present study, Nrf2 deficiency was found to alleviate hepatic injury induced by TAA and DEN. Bioactivation of both TAA (reflected by its urinary oxidized metabolites and hepatic acetyllysine levels) and DEN (indicated by urinary acetaldehyde and hepatic O6-EtG levels) was significantly decreased in Nrf2-KO mice. Nrf2 deficiency resulted in a decrease in protein levels as well as an accelerated protein degradation of CYP2E1, which is considered the major enzyme catalyzing bioactivation of these chemicals. The decrease in CYP2E1 protein levels was accompanied by a significant increase in ROS and heme levels in response to chemical challenge in Nrf2-KO primary hepatocytes. These effects were reversed by the ROS scavenger N-acetylcysteine and the heme inhibitor 4,6-dioxoheptanoic acid. Collectively, these results indicate that Nrf2 facilitates chemical bioactivation by maintaining the stability of CYP2E1. This effect is partially mediated by ROS and heme signaling. Nrf2 acts as a promoter in chemical-induced hepatic injury, especially CYP2E1-dependent toxicants (TAA and DEN).