Activation of hepatic Nrf2 in vivo by acetaminophen in CD-1 mice

摘要: The transcription factor NF-E2-related 2 (Nrf2) plays an essential role in the mammalian response to chemical and oxidative stress through induction of hepatic phase II detoxification enzymes regulation glutathione (GSH). Enhanced liver damage Nrf2-deficient mice treated with acetaminophen suggests a critical for Nrf2; however, direct evidence Nrf2 activation following exposure was previously lacking. We show that can initiate nuclear translocation vivo, maximum levels reached after 1 hour, dose dependent manner, at doses below those causing overt damage. Furthermore, shown be functionally active, as assessed by epoxide hydrolase, heme oxygenase-1, glutamate cysteine ligase gene expression. Increased found associated depletion GSH. Activation is considered involve dissociation from cytoplasmic inhibitor, Kelch-like ECH-associated protein (Keap1), redox-sensitive mechanism involving either GSH or interaction Michael addition. To investigate acetaminophen-induced we compared actions other depleters, diethyl maleate (DEM) buthionine sulphoximine (BSO), only which function acceptor. For each compound, greater than 60% achieved; case BSO, this did not cause Nrf2. In conclusion, alone insufficient activation: more required, possibly modification Keap1, facilitated prior loss (HEPATOLOGY 2004;39:1267–1276.)