title: Nrf2-regulated phase-II detoxification enzymes and phase-III transporters are induced by thyroid hormone in rat liver.
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.
authors.affiliation: Faculty of Medicine, Diego Portales University, Santiago, Chile.
authors.forename: Pamela
authors.initials: P
authors.lastname: Cornejo
authors.forename: Romina
authors.initials: R
authors.lastname: Vargas
authors.forename: Luis A
authors.initials: LA
authors.lastname: Videla
mesh_terms: D000818:Animals; D004247:DNA / Q000235:genetics / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D004790:Enzyme Induction; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D008297:Male; D050217:Metabolic Detoxication, Phase II; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D014284:Triiodothyronine / Q000502:physiology*
chemical_list: D004247:DNA; D005982:Glutathione Transferase; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D016660:NAD(P)H Dehydrogenase (Quinone); D051267:NF-E2-Related Factor 2; D014284:Triiodothyronine; C495637:Nfe2l2 protein, rat; C114462:multidrug resistance-associated protein 3; C507703:NQO1 protein, rat
keywords: liver Nrf2; phase-II detoxification enzymes; phase-III transporters; thyroid hormone