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

被引:169
作者
Goldring, CEP
Kitteringham, NR
Elsby, R
Randle, LE
Clement, YN
Williams, DP
McMahon, M
Hayes, JD
Itoh, K
Yamamoto, M
Park, BK
机构
[1] Univ Liverpool, Dept Pharmacol & Therapeut, Liverpool L69 3GE, Merseyside, England
[2] Univ W Indies, Fac Med Sci, Pharmacol Unit, St Augustine, Trinidad Tobago
[3] Univ Dundee, Biomed Res Ctr, Dundee, Scotland
[4] Univ Tsukuba, Ctr Tsukuba Adv Res Alliance, Tsukuba, Ibaraki 305, Japan
关键词
D O I
10.1002/hep.20183
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
The transcription factor NF-E2-related factor 2 (Nrf2) plays an essential role in the mammalian response to chemical and oxidative stress through induction of hepatic phase II detoxification enzymes and regulation of glutathione (GSH). Enhanced liver damage in Nrf2-deficient mice treated with acetaminophen suggests a critical role for Nrf2; however, direct evidence for Nrf2 activation following acetaminophen exposure was previously lacking. We show that acetaminophen can initiate nuclear translocation of Nrf2 in vivo, with maximum levels reached after 1 hour, in a dose dependent manner, at doses below those causing overt liver damage. Furthermore, Nrf2 was shown to be functionally active, as assessed by the induction of epoxide hydrolase, heme oxygenase-1, and glutamate cysteine ligase gene expression. Increased nuclear Nrf2 was found to be associated with depletion of hepatic GSH. Activation of Nrf2 is considered to involve dissociation from a cytoplasmic inhibitor, Kelch-like ECH-associated protein 1 (Keap1), through a redox-sensitive mechanism involving either GSH depletion or direct chemical interaction through Michael addition. To investigate acetaminophen-induced Nrf2 activation we compared the actions of 2 other GSH depleters, diethyl maleate (DEM) and buthionine sulphoximine (BSO), only 1 of which (DEM) can function as a Michael acceptor. For each compound, greater than 60% depletion of GSH was achieved; however, in the case of BSO, this depletion did not cause nuclear translocation of Nrf2. In conclusion, GSH depletion alone is insufficient for Nrf2 activation: a more direct interaction is required, possibly involving chemical modification of Nrf2 or Keap1, which is facilitated by the prior loss of GSH.
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页码:1267 / 1276
页数:10
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