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

Thyroid hormone (T 3 )‐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 T 3 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 T 3 /kg or T 3 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. T 3 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 T 3 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 T 3 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 T 3 preconditioning against liver injury mediated by ROS and chemical toxicity. © 2013 BioFactors 39(5):514–521, 2013