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

Propylthiouracil (PTU) is a well known inhibitor of thyroxine (T(4)) to triiodothyronine (T(3)) conversion as evidenced by its effect in several in vitro systems and by the decrease in serum T(3) caused by this drug in either rats or man receiving T(4) replacement. However, the failure of PTU to decrease the intrapituitary T(3) concentration and to completely blunt the serum T(3) concentration in T(4)-replaced athyreotic rats suggest that there may be a PTU-insensitive pathway of T(4) to T(3) conversion in some tissues. To address this question, we have studied the in vivo effect of PTU treatment on the generation of [(125)I]T(3) from [(125)I]T(4) in the serum and cerebral cortex (Cx), cerebellum (Cm), liver (L), and anterior pituitary (P) of euthyroid rats. Whereas PTU decreased the concentration of [(125)I]T(3) in the serum, L homogenates, and L nuclei after [(125)I]T(4), it did not affect the concentration of [(125)I]T(3) in homogenates or nuclei of Cx, Cm, or P. Iopanoic acid pretreatment significantly reduced the [(125)I]T(3) concentration in serum, homogenates, and cell nuclei of all these organs. Neither agent affected the metabolism or tissue distribution of simultaneously injected [(131)I]T(3). The presence of PTU in these tissues was evaluated by in vitro assessment of iodothyronine 5'-deiodinating activity using both [(125)I]rT(3) and [(125)I]T(4) as substrates. In agreement with the in vivo findings, generation of [(125)I]T(3) from T(4) in vitro was not affected by PTU in Cx, Cm, P but it was inhibited by 76% in L. However, rT(3) 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 T(4) to T(3) conversion in vivo despite the presence of the drug in the tissues in amounts that significantly inhibit reverse T(3) 5'-deiodination. These results show that in vivo 5'-deiodination of T(4) 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 "locally generated" T(3) in central nervous system and pituitary and could also provide the approximately one-third of extrathyroidally produced T(3) not blocked by PTU administration in athyreotic T(4)-replaced rat.