Oxidative stress regulates type 3 deiodinase and type 2 deiodinase in cultured rat astrocytes

Endocrinology. 2008 Jul;149(7):3713-21. doi: 10.1210/en.2007-1462. Epub 2008 Apr 17.


Type 2 deiodinase (D2) and type 3 deiodinase (D3) locally achieve the determination of the concentration of T3, which binds to the thyroid hormone receptor with high affinity. D2 converts T4 into T3, and D3 degrades T4 and T3. Neurons take up T3 released by astrocytes, the main cerebral site for the D2 expression. Because oxidative stress is believed to be involved in several neurological disorders, we explored the effects of oxidative stress on D3 and D2 in primary culture of rat astrocytes. H2O2 (250 microm) increased D3 activity with maximal effects around 8 h. Stimulation of D3 activity by H2O2 was synergistic with T4, phorbol ester, and also cAMP. H2O2 (250 microm) did not affect basal D2 activity but inhibited the stimulation of D2 activity by cAMP and factors implicating cAMP-independent pathways in astrocytes, TSH, and phorbol ester. N-Acetyl cysteine and selenium repletion, which respectively increase intracellular glutathione and glutathione peroxidase, inhibited D2 and D3 regulation by H2O2, whereas L-buthionine sulfoximine, which decreases intracellular glutathione, mimicked H2O2 effects. Oxidative stress up-regulated D3 and inhibited cAMP-stimulated D2 by transcriptional mechanisms. A decrease in cAMP by oxidative stress could contribute to the inhibition of cAMP-stimulated D2. Using specific inhibitors of signaling pathways, we show that the ERK pathway was required in D2 and D3 regulation by oxidative stress and that the p38 MAPK pathway was implicated in H2O2-induced D3. We suggest that the expected decrease in T3 might modulate the cellular injury of oxidative stress in some pathological brain conditions.

MeSH terms

  • Animals
  • Astrocytes / cytology
  • Astrocytes / drug effects*
  • Astrocytes / metabolism
  • Buthionine Sulfoximine / pharmacology
  • Cells, Cultured
  • Cyclic AMP / metabolism
  • Enzyme Activation / drug effects
  • Gene Expression Regulation, Enzymologic / drug effects
  • Glutathione / metabolism
  • Glutathione Peroxidase / metabolism
  • Hydrogen Peroxide / pharmacology*
  • Iodide Peroxidase / genetics
  • Iodide Peroxidase / metabolism*
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Oxidants / pharmacology
  • Oxidative Stress*
  • Phorbol Esters / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Reverse Transcriptase Polymerase Chain Reaction
  • Selenium / metabolism
  • Thyroxine / metabolism
  • Triiodothyronine / metabolism


  • Isoenzymes
  • Oxidants
  • Phorbol Esters
  • RNA, Messenger
  • Triiodothyronine
  • Buthionine Sulfoximine
  • Hydrogen Peroxide
  • Cyclic AMP
  • Iodide Peroxidase
  • Glutathione Peroxidase
  • Glutathione
  • Selenium
  • Thyroxine