Pharmacogenomic comparison between D3T- and CDDO-Im in mouse liver tissue

The Keap1/Nrf2 signaling pathway is a tractable target for the pharmacological prevention of tumorigenesis. 3H-1,2-dithiole-3-thione (D3T) and 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im) are representative members of two classes of Nrf2-activating chemopreventive agents. Natural dithiolethiones have been widely used in clinical trials for cancer chemoprevention. Synthetic triterpenoids, however, have been shown to be significantly more potent Nrf2 activators and are under clinical evaluation for the treatment of chronic kidney disease. This study seeks to characterize the structure-activity relationship between D3T and CDDO-Im in mouse liver tissue. To this end we treated Wt and Nrf2-null mice with 300 umol/kg bw D3T and 3, 10, and 30 umol/kg bw CDDO-Im every other day for 5 days and evaulated global gene expression changes as a product of both treamtent and genotype using Affymetrix microarray. Hepatic global gene expression changes in the liver tissue of Wt and Nrf2-null mice treated with vehicle (10% Cremophor-EL, 10% DMSO, and PBS), 300 umol/kg bw D3T, or 3, 10, 30 umol/kg bw CDDO-Im. 12 week old male mice were treated by gavage every other day for 5 days, resulting in 3 total administrations of treatment. Animals were euthanized 24 hours following the 3rd treatment. n=4/treatment/genotype, male 12 week old mice were used.