Thyroid Hormone Metabolism and the Source of Plasma Triiodothyronine in 2-Week-Old Rats: Effects of Thyroid Status*

Abstract

Earlier studies have shown larger increments in serum triiodothyronine [T3] in 2 wk old congenitally hypothyroid rats than in euthyroid controls after injections of small doses of thyroxine T4. Since hepatic and renal 5''-deiodination of T4 to T3 in vitro (5''D-I) is reduced during the neonatal period and in hypothyroidism, those results sugest that there may be major changes in the distribution and metabolism of T3 or that an alternative enzymatic pathway is the predominant source of extrathyroidally produced T3 in these rats. The alternative pathway 5'' deiodination [5''D]-II, is a relatively minor source of serum T3 in adult euthyroid rats, but the contribution of this pathway to the extrathyroid T3 pool during the neonatal period and in hypothyroxinemia is not known. [125I]T4 and [131I]T3 kinetics and fractional T4 to T3 conversion were studied in 2-wk-old euthyroid and hypothyroid rats and the source of circulating T3 explored by manipulating 5''D-I activity with propylthiouracil and that of 5''D-II with thyroid hormone. The plasma clearance rate of T4 was increased in hypothyroid rats, a difference entirely accounted for by the faster fractional rate of irreversible removal in the hypothyroid pups. Plasma clearance rate of T3 was reduced in hypothyroid rats owing to the reduced volume of distribution of T3. Fractional T4 to T3 conversion was 2- to 3-fold higher in euthyroid or hypothyroid neonates than in adult rats. In euthyroid rats the serum concentration of T4 was 36 .+-. 1 (standard errror of the mean) ng/ml and that of T3 0.61 .+-. 0.03 ng/ml, and the production rates were 432 and 159 ng day-1 30 g-1 body wt [BW] for T4 and T3, respectively. About 80% of the T3 in euthyroid neonates was produced extrathyroidally. Hepatic and renal 5''D-I are the main sources of serum T3 in 2 wk old rats. Liver and kidney 5''D-I activities were 40 and 65% of the corresponding adult values in euthyroid neonates, and in hypothyroid pups were further reduced to 15 and 17%. 5''D-II, previously reported to be high central nervous tissue and pituitary, was 7- to 10-fold higher in brown adipose tissue (BAT) of hypothyroid pups than in that of euthyroid ones. Doses of propylthiouracil that inhibited liver and kidney 5''D-I .gtoreq. 90% decreased fractional conversion of [125I]T4 to [125I]T3 only by 25% in euthyroid and not at all in hypothyroid neonatal rats. A single dose of 1.8 .mu.g T4/100 g BW, given 25 h before the tracers to hypothyroid pups, reduced [125I]T3 generation by 30%. This dose of T4 decreased 5''D-II by 63% in interscapular BAT, but did not affect liver or kidney 5''D-I. A 5''D-II pathway is the predominant mechanism for extrathyroid T3 production in the euthyroid neonatal and the only pathway demonstrable in the hypothyroid neonate. In these situations 5''D-II is not only responsible for local T3 production in brain and pituitary, as in the adult rat, but also for most of circulating T3. The significant amounts of 5''D-II in BAT, and the responses of 5''D-II to hypothyroidism and adrenergic stimulation in this tissue, suggest that BAT may be an important site of T3 production in the neonate.