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

Recent studies have shown that approximately 75% of the nuclear 3,5,3'-triiodothyronine (T(3)) present in adult rat cerebral cortex (Cx) derives from 5'-deiodination of thyroxine (T(4)) within this tissue. The activity of iodothyronine 5'-deiodinase (I 5'D), the enzyme catalyzing T(4) to T(3) 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 T(4) to T(3) conversion in Cx were measured in the same pups. Serum T(4) concentrations varied from /= 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 T(4). Serum T(3) 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 approximately 250 ng T(4)/100 g body weight to 2-wk-old, 20-mg-MMI pups (one-sixth the normal T(4) production rate) led to both a 1.8-ng/g cortical tissue increment in cortical T(3) and a significant increase in AT at 24 h, compared with a 0.38-ng/g cortical tissue T(3) increment and no change in AT in euthyroid controls. The larger increment in T(3) of the 20-mg-MMI pups was due in great part to increased fractional T(4) to T(3) conversion. Although the latter resulted in greater serum T(3) concentrations, three-fourths of the newly formed T(3) 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 T(3) in the Cx of the neonatal rat is produced locally. Serum T(4) appears to serve both as a precursor for T(3) 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 T(3) concentrations despite marked reductions in serum T(4). This mechanism seems to be particularly effective around 2 wk of age when many thyroid-hormone-dependent maturational changes occur in the rat Cx.