Activation of Nrf2 as a Chemopreventive Strategy Against 4-ABP-induced Bladder Cancer

摘要

Developed an LC-MS/MS method capable of measuring 2 adducts in 10~(8) nucleosides using only 1.25 (mu)g of DNA per analysis. Nrf2 protects human bladder carcinoma RT-4 cells against 4-ABP in vitro. Gender affects adduct levels: dG-C8-4-ABP levels were higher in bladder tissue of male mice than female mice and higher in liver tissue of female mice than male mice. Nrf2 acts outside the bladder to potentiate 4-ABP-induced DNA damage in the bladder: higher levels of dG-C8-4-ABP were detected in bladder tissue of wild type male mice than Nrf2 knockout male mice. Liver glucuronidation of 4-ABP may play a role in increasing the bioavailability of 4-ABP to the bladder of wild type mice: (1) Western blots of liver homogenates show that Nrf2 up-regulates two UTG isozymes. (2) Liver UGT activity was elevated in Nrf2~(+/+) mice compared to Nrf2~(-/-) mice. (3) 4-ABP-N-glucuronide levels were higher in Nrf2~(+/+) mice compared to Nrf2~(-/-) mice. SF and CPDT activate Nrf2 and the Nrf2 signaling pathway in human bladder cells and mouse bladder tissue. SF and CPDT inhibit 4-ABP DNA adduct formation in human bladder cells and mouse bladder tissue. Both SF and CPDT require Nrf2 to significantly mitigate 4-ABP DNA adduct formation.