Regulation of the Conversion of Thyroxine to Triiodothyronine in the Perfused Rat Liver

Abstract

A B S T R A C T This study was undertaken to de-termine 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'-deiodination to T3, which was not saturated at a T4 concentration of 60 ,ug/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 ,g/dl, T3 production retumed to normal. Again, no change in the rate of conversion of T4 to T3 was observed.Presented in part at the Annual Meeting of The American Society for Clinical Investigation, Washington, D. C., 6 May 1979(1979 1614These 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.

pH-dependency of iodothyronine metabolism in isolated perfused rat liver

“…Determination of the intracellular pH (Table 1), representing mainly the pH of the cytosolic compartment (Soboll et al, 1980), allows the conclusion that the pH optimum in vitro of 6.5-6.9 of the L-thyroxine 5'-deiodinase of the endoplasmatic reticulum (Auf dem Brinke et al, 1979;Fekkes et al, 1979), which is a cytosolic orientated membrane-integrated enzyme (Kohrle & Hesch, 1979), corresponds well with the optimum of T3 production of liver perfused with medium of pH 7.2, which results in an intracellular pH of about 6.5. In contrast, hepatic content and net uptake of T4 and T3 are not dependent on pH (compare Tables 3 and 4) and agree well with previously published data from experiments using different perfusion systems (Flock & Owen, 1965;Hillier, 1972;Hesch et al, 1975;Jennings et al, 1979;Pardridge & Mietus, 1980;Carter et al, 1979). One major discrepancy between our model and some of those reports is the low disappearance and/or degradation of T3.…”

“…Significant output of T3 was detectable after 30 min (P <0.05) and remained linear for up to 120 min. This pattern was comparable with data reported by Flock & Owen (1965), Hesch et al (1975) and Jennings et al (1979). Interestingly, however, T3 output by the perfused rat liver was dependent on the pH of perfusion (Figs.…”

“…This demonstrates that the fast and slow components of T4 net uptake are not caused by binding of T4 to the fluorocarbon medium applied in the perfusion system itself. A similar finding was reported for media containing erythrocytes or albumin (Flock & Owen, 1965;Jennings et al, 1979).…”

“…& Owen, 1965;Hillier, 1972). After introduction of specific radioimmunoassays, hepatic T3 production from T4 was found by Hesch et al (1975) and by Jennings et al (1979;Jennings, 1981), but not by van der Heide (1980). From these experiments the enzymic character of 5'-deiodination of T4 in perfused rat liver became evident.…”

Thyroid hormone status in protein energy malnutrition in Indian children

“…Studies from Bangladesh (7) and Turkey (8) also reported that the mean total T 3 and T 4 levels were significantly lower in PEM cases as compared to controls. Animal studies have shown that during starvation, T 4 uptake by liver (9) and the activity of enzyme 5-deiodinase (10) are decreased.…”