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Induction of NAD(P)H:quinone oxidoreductase: interplay between Ah receptor and Nrf2.
Wang-L; He-X; Szklarz-G; Ma-Q
Toxicologist 2012 Mar; 126(Suppl 1):458
NAD(P)H:quinone oxidoreductase (NQO1) catalyzes the obligatory two electron reduction of quinones and quinoide compounds bypassing redox cycling and production of reactive oxygen radicals and protecting cells from toxicity. Induction of NQO1 is considered as a model for analyzing transcriptional regulation of many cytoprotective enzymes and proteins. The aryl hydrocarbon receptor (AhR) mediates the induction of NQO1 by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and benzo[a]pyrene (Bap); whereas, the antioxidant-activated receptor/transcription factor Nrf2 is critical for induction by antioxidants such as tert-butylhydroquinone (tBHQ). Induction of the genes by AhR agonists or antioxidants requires "dioxin response element" (DRE) or "antioxidant response element" (ARE), respectively. We previously reported a cross-interaction between AhR and Nrf2 signal transduction is required for induction of NQO1 by TCDD (Ma et al, Biochem J 377, 205- 213, 2004). In this study, we analyzed the interaction between AhR and Nrf2 at the promoter of NQO1. Chromatin immunoprecipitation analyses revealed that treatment with TCDD recruits both AhR and Nrf2 to the promoter region where a DRE and an ARE locate; the finding is in agreement with the result from genetic studies in which induction by TCDD or Bap was shown to require both AhR and Nrf2. TCDD-induced binding of AhR and Nrf2 to DNA is time-dependent. Consistent with the activation of Nrf2, TCDD treatment inhibits Keap1-dependent ubiquitination and proteasomal degradation of Nrf2 resulting in the stabilization and nuclear accumulation of Nrf2. Co-immunoprecipitation experiments revealed that AhR directly interacts with Nrf2 in the presence of TCDD. Our findings demonstrate that AhR interacts with Nrf2 to control induction of NQO1 by AhR ligands.
Oxidation-reduction-reactions; Quinones; Cytotoxicity; Aryls; Hydrocarbons; Dioxins; Benzopyrenes; Antioxidants
106-51-4; 1746-01-6; 50-32-8
The Toxicologist. Society of Toxicology 51st Annual Meeting and ToxExpo, March 11-15, 2012, San Francisco, California