Iodothyronine Metabolism in Rat Liver Homogenates

Michael M. Kaplan; Robert D. Utiger

doi:10.1172/JCI108957

To investigate mechanisms of extrathyroidal thyroid hormone metabolism, conversion of thyroxine (T₄) to 3,5,3′-triiodothyronine (T₃) and degradation of 3,3′,5′-triiodothyronine (rT₃) were studied in rat liver homogenates. Both reactions were enzymatic. For conversion of T₄ to T₃, the K_m of T₄ was 7.7 μM, and the V_max was 0.13 pmol T₃/min per mg protein. For rT₃ degradation, the K_m of rT₃ was 7.5 nM, and the V_max was 0.36 pmol rT₃/min per mg protein. Production of rT₃ or degradation of T₄ or T₃ was not detected under the conditions employed. rT₃ was a potent competitive inhibitor of T₄ to T₃ conversion with a K_i of 4.5 nM; 3,3′-diiodothyronine was a less potent inhibitor of this reaction. T₄ was a competitive inhibitor of rT₃ degradation with a K_i of 10.2 μM. Agents which inhibited both reactions included propylthiouracil, which appeared to be an allosteric inhibitor, 2,4-dinitrophenol, and iopanoic acid. Sodium diatrizoate had a weak inhibitory effect. No inhibition was found with α-methylparatyrosine, Fe⁺², Fe⁺³, reduced glutathione, β-hydroxybutyrate, or oleic acid.

Fasting resulted in inhibition of T₄ to T₃ conversion and of rT₃ degradation by rat liver homogenates which was reversible after refeeding. Serum T₄, T₃, and thyrotropin concentrations fell during fasting, with no decrease in serum protein binding as assessed by a T₃-charcoal uptake. There was no consistent change in serum rT₃ concentrations. Dexamethasone had no effect in vitro. In vivo dexamethasone administration resulted in elevated serum rT₃ concentrations after 1 day, and after 5 days, in inhibition of T₄ to T₃ conversion and rT₃ degradation without altering serum T₄, T₃, or thyrotropin concentrations. Endotoxin treatment had no effect of iodothyronine metabolism in liver homogenates. In kidney homogenates the reaction rates and response to propylthiouracil in vitro were similar to those in liver. No significant T₄ to T₃ conversion or rT₃ production or degradation could be detected in other tissues.

These data suggest that one iodothyronine 5′-deiodinase is responsible for both T₄ to T₃ conversion and rT₃ degradation in liver and, perhaps, in kidney. Alterations in serum T₃ and rT₃ concentrations induced by drugs and disease states may result from decreases in both T₃ production and rT₃ degradation consequent to inhibition of a single reaction in the pathways of iodothyronine metabolism.