A B S T R A C T We have studied 5'-deiodination of thyroxine (T4) and 3,3',5'-triiodothyronine (rT3) in rat pituitary tissue in vitro, with respect to substrate specificity, reaction kinetics, effects of 6-n-propyl-2-thiouracil (PTU), and the time course of effects of thyroid hormone depletion and repletion. Removal of one phenolic iodine or both tyrosyl iodines from the T4 molecule resulted in compounds that were not deiodinated, but alterations in the alanine side chain had little effect.5'-Deiodination of 2 nM rT3 by pituitary microsomes from euthyroid rats was inhibited >90% by 1 mM PTU, but was inhibited <10% by 100 nM T4. The apparent Michaelis constant (K.n) and maximum velocity (Vll~ax) for rT3 at 20 mM dithiothreitol (DTT) were 33 nM and 84 pmol/mg protein per h. This reaction followed ping-pong type reaction kinetics when concentrations of DTT sitive rT3 5'-deiodination (K, = 1.3 nM). T4 5'-deiodination by hypothyroid microsomes was not affected by PTU, was competitively inhibited by rT3 (Ki, 1.7 nM), and exhibited sequential type reaction kinetics with DTT as cosubstrate. When T4 5'-deiodination was measured in euthyroid and hypothyroid microsomes, respectively, the apparent Km and Vma. for T4 at 20 mM DTT, were 0.9 nM and 0.55 pmol/mg protein per h (euthyroid), and 0.8 nM and 6.9 pmol/mg protein per h (hypothyroid).The T4 5'-deiodination rate and the PTU-insensitive, but not total, rT3 5'-deiodination rate (i.e. measured in the presence and the absence of 1 mM PTU, respectively) in pituitary homogenates were significantly elevated 24 h after thyroidectomy. PTU-insensitive activity continued to increase until at .30 d after thyroidectomy it was 11 times the PTU-insensitive activity in controls. At the latter time, PTU-sensitive rT3 5'-deiodinase activity appeared to be decreased. The increase in PTU-insensitive T4 and rT3 5'-deiodination observed 48
In rats subjected to thyroidectomy there was a two- to fourfold increase in cerebral cortex iodothyronine 5'-deiodinase activity within 24 hours. This increase was prevented by thyroxine replacement. The increased cortical 5'-deiodinase in chronically hypothyroid rats was normalized within 4 hours by a single intravenous injection of triiodothyronine. These results indicate that the adult central nervous system can give a very rapid biochemical response to thyroid hormone.
Plasma 3,5,3'-triiodothyronine (T3) and 3,3',5'-triiodothyronine concentrations were measured in fetal sheep prior to death in utero and after thyroidectomy. In six fetal sheep who subsequently died in utero, plasma rT3 concentrations were elevated in all for 2 to 13 days prior to death. There were no consistent changes in plasma T4 concentrations. In two thyroidectomized fetal sheep, plasma T4 and rT3 concentrations fell to low levels. Plasma T3 concentrations remained low and there was no increase in plasma T3 in the last week prior to parturition like that which occurs in normal fetal sheep. Parturition was preceded by the normal increase in fetal plasma cortisol concentrations and occurred at the normal time. These data indicate that plasma rT3 concentrations are increased as a result of illness in fetal sheep and that such measurements may be useful as an indicator of fetal distress. The normal increase in plasma T3 late in gestation is not necessary for the late gestational cortisol surge or for normal parturition.
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