Thyrotropin-Mediated Induction of Thyroidal Iodothyronine Monodeiodinases in the Dog*

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Abstract
To investigate the effect of TSH administration on thyroidal iodothyronine-deiodinating activity, in vitro conversion of T4 to T3, T3 to 3,3′-diiodothyronine (T2), and rT3 to T2 by canine thyroid, liver, and kidney homogenate was examined, comparing tissues from TSH-treated dogs (3 IU bovine TSH daily for 3 days) with tissues from sex- and weight-matched saline-treated controls. The in vitro conversion activities were studied in the presence of 4 mM dithiothreitol at pH 6.5 for outer ring (T4 to T3 and rT3 to T2) and at pH 7.8 for inner ring (T3 to T2) deiodination. Iodothyronine-monodeiodinating activity in dog thyroid is heat labile (inactivated at 56 C × 5 min) and pH dependent, inhibited by propylthiouracil (0.2 mM) and ipodate (0.2 mM), unaffected by methimazole (up to 4 mM), ascorbate (up to 0.1 M), or KI (up to 4 mM), and is localized in the microsomal fraction. TSH markedly stimulated thyroidal inner and outer ring iodothyronine-monodeiodinating activities. Baseline rates of T4 to T3, T3 to T2, and rT3 to T2 conversion in dog thyroid were 0.9 ± 0.2, 1.4 ± 0.2 and 23.7 ± 4.6 ng T3 (or T2)/mg tissueμg substrate/30 min at 37 C, respectively. A significant increase in each conversion activity was found after TSH treatment (T4 to T3, T3 to T32, and rT3 to T2 conversions were 2.8 ± 0.4, P < 0.005; 2.9 ± 0.3, P < 0.005; and 49.5 ± 6.4, P < 0.01, respectively). The TSH caused no significant increase in iodothyronine-monodeiodinating activity in liver or kidney. Kinetic studies using thyroid homogenate showed that TSH-mediated stimulation of inner and outer ring monodeiodinating activities was associated with increases in the maximum velocity (Vmax) (the Vmax was 12.3, 25.3, and 113 pmol for T4, T3, and rT3, respectively, in the controls and was 53.4, 112, and 272 pmol, respectively, in TSH-treated animals) but no demonstrable change in apparent Km (4.0, 3.6, and 0.4 μM for T4, T3, and rT3, respectively). Thyroidal iodothyronine monodeiodination did not increase until 24–48 h after the first dose of TSH. It is concluded that TSH induces a significant increase in both inner and outer ring iodothyronine-monodeiodinating activities in the the thyroid but not in the liver or kidney; the increases in Vmax of the deiodinations (without change in Km values) and the delay in onset of the increase suggest that TSH increases the synthesis of the deiodinase(s) in the thyroid.