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A B S T R A C T 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 suggest that there may be a PTU-insensitive pathway of T4 to T3 conversion in some tissues. To address this question, we [1251]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 Received for publication 3 August 1981 and in revised form 19 January 1982. 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 "locally generated" T3 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. INTRODUCTION3,5,3'-Triiodothyronine (T3)' appears to be the major active thyroid hormone at the cellular level (1). Studies in man and in rat indicate that more than two-thirds of extrathyroidal triiodothyronine (T3) is produced via 5'-deiodination of thyroxine (T4), a reaction which occurs in many tissues (2). In some (liver, kidney, and heart), the bulk of intracellular T3 exchanges rapidly with plasma (3, 4). However, in the pituitary, the T3 produced from T4 does not immediately equilibrate with the plasma T3 (2). Furthermore, this locally produced T3 makes a contribution of 50% or more to the intracellular T3 in this tissue (2,5). T4 to T3 conversion, at rates sufficiently rapid to make a significant contribution to total intracellular T3, has been recently identified in the rat central nervous system (6-8). Similarly this locally generated T3 does not readily exchange with serum T3. Furthermore, whereas hypothyroidism increases the T4 5'-deiodination in the pituitary (9) and brain (10), this condition decreases the activity of this process in the liver (9). The reason for this difference between various organs is not apparent and could reflect intrinsic differences in the pathways of T3 generation. ['25IJT3 in excess of that derived from plasma is that generated locally in the tissue (T3 [T4J).In the present experiments, [1251I]T4, -100 jsCi/100 g body wt (4,200 uCi/Mg sp act), and ['31I]T3, -10 uCi/100 g body wt (2,800 gCi/Pg sp act), were injected int...

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