This study was undertaken to determine what factors control the conversion of thyroxine (T4) to triiodothyronine (T3) in rat liver under conditions approximating those found in vivo. Conversion of T4 to T3 was studied in the isolated perfused rat liver, a preparation in which the cellular and structural integrity is maintained and that can perform most of the physiologic functions of the liver. The perfused liver readily extracted T4 from perfusion medium and converted it to T3. Production of T3 by the perfused liver was a function of the size of the liver, the uptake of T4 by the liver, and the presence of T4-5'-deiodinase activity. Production of T3 was increased by increasing the uptake of T4 by liver, which could be accomplished by increasing the liver size, by increasing the perfusate T4 concentration, or by decreasing the perfusate albumin concentration. These changes occurred without altering the conversion of T4 to T3. The liver had a large capacity for extracting T4 and for T4-5'-deiodinaton to T3, which was not saturated at a T4 concentration of 60 μg/dl. Production of T3 was decreased by inhibiting hepatic T4-5'-deiodinase with propylthiouracil, which decreased T3 production by decreasing the conversion of T4 to T3. Propylthiouracil did not alter hepatic T4 uptake. Fasting resulted in a progressive decrease in hepatic T4 uptake to 42% of control levels by the 3rd d of fasting; this was accompanied by a proportionate decrease in T3 production. The rate of conversion of T4 to T3 did not change during fasting. When T4 uptake in 2-d-fasted rat livers was raised to levels found in fed rats by increasing the perfusate T4 concentration from 10 to 30 μg/dl, T3 production returned to normal. Again, no change in the rate of conversion of T4 to T3 was observed. These results indicate that the decreased hepatic T3 production during fasting primarily results from decreased hepatic uptake of T4, rather than from changes in T4-5'-deiodinase activity. Thus, these studies have delineated a new mechanism that functions independently of enzyme quantity or activity whereby production of T3 from T4 is regulated.
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