Induction of murine NAD(P)H:quinone oxidoreductase by 2,3,7,8-tetrachlorodibenzo-p-dioxin requires the CNC basic leucine zipper transcription factor NRF2. Cross-interaction between AHR and NRF2 signal transduction.
Ma-Q; Kinneer-K; Bi-Y; Chan-JY; Kan-YW
Drug Metab Rev 2004 Sep; 36(Suppl 1):146
2,3,7,8-tetrachlorodibenzo-p-dixoin induces phase II drug-metabolizing enzyme NAD(P)H:quinone oxidoreductase (EC 188.8.131.52, NQO1, DT-diaphorase) in a wide range of mammalian tissues and cells. We analyzed the molecular pathway mediating NQO1 induction by TCDD in mouse hepatoma cells. Inhibition of protein synthesis with cycloheximide (CHX) completely blocks induction of NQO1 by TCDD as well as the basal expression and induction by phenolic antioxidant 2-t-butylbenzene-1,4-diol (tBHQ), implicating a labile factor in NQO1 mRNA expression. The inhibition is both time and concentration-dependent, requires inhibition of protein synthesis, and occurs at a transcriptional level. Inhibition of NQO1 transcription by CHX correlates with a rapid reduction of CNC bZip transcription factor Nrf2 through the 26S proteasome pathway. Moreover, blocking Nrf2 degradation with proteasome inhibitor MG132 increases the amount of Nrf2 and superinduces NQO1 in the presence of TCDD or tBHQ. Finally, genetic experiments using AhR, Arnt, or Nrf2-deficient cells reveal that, while induction of NQO1 by TCDD depends on the presence of AhR and Arnt, the basal and inducible expression of NQO1 by either TCDD or tBHQ requires functional Nrf2. The findings demonstrate a novel role of Nrf2 in the induction of NQO1 by TCDD and provide new insights into the mechanism by which Nrf2 regulates the induction of phase II enzymes by both phenolic antioxidants and AhR ligands.
Mammalian-cells; Laboratory-animals; Animals; Animal-studies; Enzymes; Phenols; Phenolic-compounds; Antioxidants; Genetic-factors
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, USA
106-51-4; 1746-01-6; 66-81-9
Abstract; Conference/Symposia Proceedings
Drug Metabolism Reviews