Comparison of genetic and pharmacologic activation of Nrf2 signaling

Genetic versus chemoprotective activation of Nrf2 signaling: overlapping yet distinct hepatic gene expression profiles between Keap1 knockout and triterpenoid treated mice Loss of Nrf2 signaling increases susceptibility to acute toxicity, inflammation, and carcinogenesis in mice due to the inability to mount adaptive responses. By contrast, disruption of Keap1 (a cytoplasmic modifier of Nrf2 turnover) protects against these stresses in mice; although dominant negative mutations in Keap1 have been identified recently in some human cancers. Global characterization of Nrf2 activation is important to exploit this pathway for chemoprevention in healthy, yet at-risk individuals and also to elucidate the consequences of hijacking the pathway in Keap1-mutant human cancers. This analysis also enables a global characterization of the pharmacodynamic action of CDDO-Im at a low dose that is relevant to chemoprevention. Liver-targeted conditional Keap1-null (CKO) mice provide a model of genetic activation of Nrf2 signaling. By coupling global gene expression analysis of CKO mice with analysis of pharmacologic activation using the synthetic oleanane triterpenoid CDDO-Im, we are able to gain insight into pathways affected by Nrf2 activation. CDDO-Im is an extremely potent activator of Nrf2 signaling. CKO mice were used to identify genes modulated by genetic activation of Nrf2 signaling. The CKO response was compared to hepatic global gene expression changes in wild-type mice treated with CDDO-Im at a maximal Nrf2 activating dose. n=3/group, male 9 week old mice were used. Mice were treated with a single dose of vehicle (10% Cremophor-EL, 10% DMSO, and PBS) or 30 umol CDDO-Im/kg body weight by gavage and sacrificed 6 h later.