Inhibition of Iodothyronine 5′-Deiodinase by Iopanoic Acid Does Not Block Nuclear T3 Accumulation During Rat Fetal Development

Abstract

ABSTRACT. We studied the effect of iopanoic acid (IOP), an iodinated contrast medium, on iodothyronine 5'4eio-dinase (5'D) and nuclear T3 content (nT3) in fetal tissues. In 18-and 20 day-old fetuses from control dams, nT3 was higher in interscapular brown adipose tissue (IBAT, 69 + 5 and 281 f 8 fmollmg of DNA) than in brain (16 f 2 and 42 f 3 fmollmg of DNA) or liver (5.6 2 1 and 27 f 2 fmol/mg of DNA). IOP administration (10 mg, twice daily) to pregnant rats on days 18 and 19 postconception significantly blocked 5'D activity in fetal IBAT and brain at day 20. Liver 5'D was not affected. The rise in nT3 was not modified by IOP treatment in IBAT, but it was enhanced in brain and liver of IOP-treated fetuses on day 20. In contrast, in adult rats, IOP treatment reduced IBAT nTa. Prolongation of IOP treatment until day 21 decreased fetal body weight on day 22 and inhibited IBAT 5'D. No change was produced in mitochondrial oxidative capacity, the subunit I1 of cytochrome oxidase, or uncoupling protein mRNA expression in IBAT from IOP-treated fetuses. Thus, the finding that IOP does not decrease the nT3 of fetal IBAT explains the lack of effect of IOP on uncoupling protein expression in fetuses, in contrast with the known decrease in adults. Present results also show that IOP increases nT3 in brain and liver, indicating a general incapacity of IOP to decrease nT3 in fetal tissues. It is concluded that the effects of IOP during fetal life differ from those in adults. (Pediatr Rcs 35: [91][92][93][94][95]1994 Supported by grant PB89-0227 from the Spanish Ministry of Education and Science and from the CIRIT (Generalitat de Catalunya, Spain). Alex Tuca is supported by a fellowship from the Generalitat de Catalunya (Spain).A large proportion of the T3 produced in humans and in rats is generated by 5'-deiodination (5'D) of T4 in peripheral tissues (1). Two types of enzymatic system catalyzing 5'D have been described. Type I and type I1 5'-deiodinases (5'D-I and 5'D-11) differ in catalytic residues, reaction kinetics, substrate and inhibitor specificities, tissue distribution and ontogenic profiles (2-9). 5'D-I is most abundant in liver and kidney, but is detectable in other tissues (4,s). 5'D-I1 is present mainly in the brain, pituitary and BAT (5, 6). Interestingly, tissues expressing 5'D-I and 5'D-I1 differ in their dependence on T3 or T4 in plasma for intracellular T3. IOP, a cholecystographic contrast agent, is an inhibitor of 5'D (lo), and has been used to demonstrate the importance of local T4-to-T3 conversion in tissues expressing 5'D-11, such as pituitary (1 1), brain (12) and BAT (1 3).BAT is the main site for nonshivering adaptative thermogenesis, and it has a high mitochondrial oxidative capacity and a unique mitochondrial UCP that causes dissipation of the energy of metabolic oxidation as heat (14). BAT must be fully differentiated at birth, as its thermogenic activity is especially important during the neonatal period (15). The onset of UCP gene transcription, which may be considered as the key point of brow...