Evidence for two tissue-specific pathways for in vivo thyroxine 5'-deiodination in the rat

Abstract

Propylthiouracil (PTU) is a well known inhibitor of thyroxine (T4) to triiodothyronine (T3) conversion as evidenced by its effect in several in vitro systems and by the decrease in serum T3 caused by this drug in either rats or man receiving T4 replacement. However, the failure of PTU to decrease the intrapituitary T3 concentration and to completely blunt the serum T3 concentration in T4-replaced athyreotic rats suggests that there may be a PTU-insensitive pathway of T4 to T3 conversion in some tissues. To address this question, we have studied the in vivo effect of PTU treatment on the generation of [125I]T3 from [125I]T4 in the serum and cerebral cortex (Cx), cerebellum (Cm), liver (L), and anterior pituitary (P) of euthyroid rats. Whereas PTU decreased the concentration of [125I]T3 in the serum, L homogenates, and L nuclei after [125I]T4, it did not affect the concentration of [125I]T3 in homogenates or nuclei of Cx, Cm, or P. Iopanoic acid pretreatment significantly reduced the [125I]T3 concentration in serum, homogenates, and cell nuclei of all these organs. Neither agent affected the metabolism or tissue distribution of simultaneously injected [131I]T3. The presence of PTU in these tissues was evaluated by in vitro assessment of iodothyronine 5'-deiodinating activity using both [125I]T3 and [125I]T4 as substrates. In agreement with the in vivo findings, generation of [125I]T3 from T4 in vitro was not affected by PTU in Cx, Cm, P but it was inhibited by 76% in L. However, rT3 5'-deiodination, known to be sensitive to PTU in these tissues, was inhibited in all four indicating that the PTU given in vivo was present in significant amounts. These results demonstrate that in rat Cx, Cm, and P unlike liver, PTU does not inhibit T4 to T3 conversion in vivo despite the presence of the drug in the tissues in amounts that significantly inhibit reverse T3 5'-deiodination. These results show that in vivo 5'-deiodination of T4 proceeds via a PTU-insensitive pathway in the central nervous system and pituitary, while this pathway is not quantitatively important in the L. This mechanism accounts for the ocally generatedT3 in central nervous system and pituitary and could also provide the approximately one-third of extrathyroidally produced T3 not blocked by PTU administration in athyreotic T4-replaced rat.