Thyroid Hormone Regulates Rat Placental Type III lodothyronine Deiodinase Activity by Inducing Kinetic Changes Different from Those in the Same Isozyme in Rat Brain.

Abstract

Abstract. The kinetics of type III iodothyronine deiodinase (5-D) in rat placenta and brain and the role of phospholipids in enzyme activity were determined. Pregnant Sprague-Dawley rats were given either vehicle (control group) or T4 (15 jug/100 g bw/day; hyperthyroid group) from the 14th to the 21st day of gestation. Mitochondrial-microsomal fractions of the placenta and brain were used as the source of T4 5-D. Placental T4 5-D activity in the hyperthyroid group was increased when determined at 13 nM T4, but it was not significantly different from the control value when assayed at 1.3 ,uM T4. In contrast, T4 5-D in the brain was significantly increased in the hyperthyroid group regardless of the substrate concentration. Hyperthyroid rats showed decreased Km for placental 5-D and increased Vmax for brain 5-D. CM-Sephadex chromatography of solubilized placental microsomes was performed to determine whether phospholipids cause a reduction in the Km of placental 5-D in hyperthyroid rats. T3 5-D activity was undetectable unless protein-containing fractions were combined with phospholipidcontaining fractions in the reaction mixture. Kinetic studies revealed that phospholipids had no effects on either Km or Vmax of placental T3 5-D. These data indicate that 5-D activity in the rat placenta is increased in hyperthyroidism with different kinetic changes from those in the brain, and that phospholipids have no effects on the kinetic parameters of placental 5-D whereas they are essential for the enzyme activity.

Decreased translation of Dio3 mRNA is associated with drug-induced hepatotoxicity

“…Previously, changes in D3 activity have been found to correlate strongly with changes in expression of Dio3 mRNA [49]; however, we found no evidence for the change in protein production being regulated at a transcriptional level. Moreover, one of the PredTox compounds (FP007SE) showed a transcriptional increase in Dio3 mRNA within the liver following high-dose treatment (Figure 6A).…”

“…In the rat, D3 activity is reduced in cases of hypothyroidism [28,49], although the extent of the change varies between tissues [20]. The observed reductions in T 3 and T 4 , along with the transcriptional down-regulation of Dio1 mRNA (Supplementary Figure S4 at http://www.biochemj.org/bj/453/bj4530071add.htm), which is known to be down-regulated in cases of hypothyroidism, indicated that the livers of the treated rats were in a hypothyroid state [17,50].…”

Thyroid Hormone Receptor α and Regulation of Type 3 Deiodinase

“…Previous studies have shown that D3 mRNA levels increase in brain and placenta during hyperthyroidism and decrease during hypothyroidism (15)(16)(17). However, the mechanism of this regulation remains unknown.…”

Local impact of thyroid hormone inactivation

“…TH regulates D3 expression at transcriptional level in several other systems (St Germain et al 1994, Van der Geyten et al 1999b). In the rat, D3 activity is increased in hyperthyroidism and decreased in hypothyroidism (Mori et al 1995, Escobar-Morreale et al 1997. TH and retinoic acid also upregulate D3 activity and mRNA in cultured glial cells (Esfandiari et al 1994).…”