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

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.