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Nrf2-regulated phase-II detoxification enzymes and phase-III transporters are induced by thyroid hormone in rat liver

Authors

  • Pamela Cornejo,

    1. Faculty of Medicine, Diego Portales University, Santiago, Chile
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  • Romina Vargas,

    1. Molecular and Clinical Pharmacology Program, Faculty of Medicine, Institute of Biomedical Sciences, University of Chile, Santiago, Chile
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  • Luis A. Videla

    Corresponding author
    1. Molecular and Clinical Pharmacology Program, Faculty of Medicine, Institute of Biomedical Sciences, University of Chile, Santiago, Chile
    • Address for correspondence to: Prof. Luis A. Videla, Programa de Farmacología Molecular y Clínica, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universitdad de Chile. Tel.: 56-2-9786256; Fax: 56-2-7372783; E-mail: lvidela@med.uchile.cl.

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Abstract

Thyroid hormone (T3)-induced calorigenesis triggers the hepatic production of reactive oxygen species (ROS) and redox-sensitive nuclear transcription factor erythroid 2-related factor 2 (Nrf2) activation. The aim of this study was to test the hypothesis that in vivo T3 administration upregulates the expression of phase II and III detoxification proteins that is controlled by Nrf2. Male Sprague-Dawley rats were given a single intraperitoneal dose of 0.1 mg T3/kg or T3 vehicle (controls). After treatment, rectal temperature of the animals, liver Nrf2 DNA binding (EMSA), protein levels of epoxide hydrolase 1 (Eh1), NADPH-quinone oxidoreductase 1 (NQO1), glutathione-S-transferases Ya (GST Ya) and Yp (GST Yp), and multidrug resistance-associated proteins 2 (MRP-2) and 4 (MRP-4) (Western blot), and MRP-3 (RT-PCR) were determined at different times. T3 significantly rose the rectal temperature of the animals in the time period studied, concomitantly with increases (P < 0.05) of liver Nrf2 DNA binding at 1 and 2 h after treatment, which was normalized at 4–12 h. Within 1–2 h after T3 treatment, liver phase II enzymes Eh1, NQO1, GST Ya, and GST Yp were enhanced (P < 0.05) as did phase III transporters MRP-2 and MRP-3, whereas MRP-4 remained unchanged. In conclusion, enhancement of liver Nrf2 DNA binding elicited by in vivo T3 administration is associated with upregulation of the expression of detoxification and drug transport proteins. These changes, in addition to antioxidant protein induction previously observed, may represent cytoprotective mechanisms underlying T3 preconditioning against liver injury mediated by ROS and chemical toxicity. © 2013 BioFactors 39(5):514–521, 2013

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