The antioxidant-activated transcription factor Nrf2 controls both the ARE- and DRE-dependent induction of NAD(P)H:quinone oxidoreductase: cross-interaction between Nrf2 and AHR signal transduction.
Ma-Q; Kinneer-K; Bi-Y
Drug Metab Rev 2003 Jan; 35(Suppl 1):106
NAD(P)H:quinone oxidoreductase (NQOR. DT -diaphorase) is inducible by phenolic antioxidants via ARE-mediated gene transcription, and by 2,3,7,8-tetrachlorodibenzo-p-dioxin through DRE-dependent signal transduction. In this study, we examined the interaction between ARE- and DRE-dependent pathways. Treatment with cycloheximide blocks the basal, tBHQ-inducible, and TCDD-inducible expression of NQOR in hepalclc7 cells. The inhibition is time and concentration-dependent, requires inhibition of protein synthesis. and occurs at the level of NQOR gene transcription. Examining Nrf2 protein stability reveals that Nrf2 is a labile protein; inhibition of the 26S proteasome mediated protein degradation by MG 132 enhances the induction of NQOR by both tBHQ and TCDD. Lastly, analyses of the induction in Nrf2 -/- embryonic fibroblast cells derived from Nrf2 knockout mice demonstrate that Nrf2 is required for basal, tBHQ-inducible. and TCDD-inducible expression of NQOR. These findings reveal that Nrf2 serves as a mater regulator of mouse NQOR gene expression and implicate cross-interaction between ARE- and DRE-dependent pathways in the induction of phase II enzymes.
Mathematical-models; Models; Analytical-processes; Analytical-models; Analytical-chemistry; Laboratory-animals; Genes; Genetics
Receptor Biology Laboratory, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, 1095 Willowdale Rd, Morgantown, WV 26505
Abstract; Conference/Symposia Proceedings
Drug Metabolism Reviews