Comparison of Iodothyronine 5′-Deiodinase and Other Thyroid-Hormone-dependent Enzyme Activities in the Cerebral Cortex of Hypothyroid Neonatal Rat

Abstract

Recent studies have shown that ∼75% of the nuclear 3,5,3′-triiodothyronine (T₃) present in adult rat cerebral cortex (Cx) derives from 5′-deiodination of thyroxine (T₄) within this tissue. The activity of iodothyronine 5′-deiodinase (I 5′D), the enzyme catalyzing T₄ to T₃ conversion, increases rapidly after thyroidectomy, suggesting that this could be a compensatory response to hypothyroxinemia. To evaluate this possibility during the period of central nervous system maturation, we studied several thyroid hormone-responsive enzymes (aspartic transaminase [AT], succinic dehydrogenase [S.D.], and Na/K ATPase) in the Cx of 2-, 3-, and 4-wk-old rats. The rats were made congenitally hypothyroid by placing 1, 2, 5, and 20 mg methimazole (MMI) in 100 ml of the mothers' drinking water from day 16 of gestation throughout the nursing period and to the litters after weaning. In addition, serum thyroid hormones, I 5′D, and, in some experiments, in vivo T₄ to T₃ conversion in Cx were measured in the same pups. Serum T₄ concentrations varied from 3 was less affected by MMI than was T₄. At 2 wk, decreases in AT, S.D., and ATPase were present in the 20-mg-MMI group but not in the 5-mg-MMI pups despite low serum T₄ (3 in the 5-mg-MMI rats. Cortical I 5′D activity was 10-fold the control value in 5- and 20-mg-MMI animals at 2 wk but increased only three- to fivefold at 3 and 4 wk. I 5′D correlated inversely with serum T₄ (r ≥ 0.96) at all ages, but the less marked elevation of this enzyme in 3- and 4-wk-old pups was not accompanied by an increase in serum T₄. Serum T₃ increased or remained the same between 2 and 3 wk. These results suggested that the 10-fold increase in I 5′D at 2 wk protected the 5-mg-MMI group from tissue hypothyroidism, but that the three- to fivefold increase at 3 and 4 wk could not. Injection of ∼250 ng T₄/100 g body weight to 2-wk-old, 20-mg-MMI pups (one-sixth the normal T₄ production rate) led to both a 1.8-ng/g cortical tissue increment in cortical T₃ and a significant increase in AT at 24 h, compared with a 0.38-ng/g cortical tissue T₃ increment and no change in AT in euthyroid controls. The larger increment in T₃ of the 20-mg-MMI pups was due in great part to increased fractional T₄ to T₃ conversion. Although the latter resulted in greater serum T₃ concentrations, three-fourths of the newly formed T₃ in the cortex was generated in situ, and it was blocked by iopanoic acid as was the increase in AT. We conclude that 70-80% of the T₃ in the Cx of the neonatal rat is produced locally. Serum T₄ appears to serve both as a precursor for T₃ and as a critical signal for increases in cortical I 5′D. The increased I 5′D can result in normal or near-normal cerebrocortical T₃ concentrations despite marked reductions in serum T₄. This mechanism seems to be particularly effective around 2 wk of age when many thyroid-hormone-dependent maturational changes occur in the rat Cx.