Differences in primary cellular factors influencing the metabolism and distribution of 3,5,3′-L-triiodothyronine and L-thyroxine

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167

A B S T R A C T Further studies have been performed to define the kinetic characteristics of nuclear triiodothyronine (T3) binding sites in rat liver (J. Clin. Endocrinol. Metab. 1972. 35: 330). Sequential determination of labeled T3 associated with nuclei and cytoplasm over a 4-h period allowed analysis of the relationship of T3 in nuclear and cytoplasmic compartments. A rapid interchange of hormone between nuclei and cytoplasm was demonstrated, and in vitro incubation experiments with nuclei yielded no evidence favoring metabolic transformation of T3 by the nuclei. In vivo displacement experiments were performed by subcellular fractionation of liver i h after injection of ["JI]T3 with increasing quantities of unlabeled T3. The nuclear binding capacity for T3 could be defined (0.52 ng/mg DNA). Analysis of these experiments also allowed an estimation of the association constant of nuclear sites for T3 (4.7 X 10"M'). The affinity of these sites for T3 was estimated to be 20-40 fold greater than for thyroxine (T4). Chromatographic analysis of the nuclear radioactivity after injection of labeled T4 indicated that the binding of T4 by the nucleus could not be attributed to in vivo conversion of T4 to T3 but reflected intrinsic cross-reactivity of the two iodothyronines at the nuclear binding sites.

Section: Resultsmentioning

confidence: 70%

Limited Binding Capacity Sites for l-Triiodothyronine in Rat Liver Nuclei

Oppenheimer¹,

Schwartz²,

Koerner³

et al. 1974

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167

“…However, quantitative assessment of MCR of rTs has not been reported in this (or any other) previous study. Calculation of MCR has been conducted in this study by an integral noncompartmental approach which is considered more appropriate for measurement of MCR of rapidly disappearing iodothyronines than the conventional single-compartmental technique (14)(15)(16). Some assessment of the validity of measurements of MCR-rT3 is also provided by the data on MCR of other, extensively studied, iodothyronines, Ti and T3; these data were obtained by methods similar to those used for MCR of rT3.…”

Section: Discussionmentioning

confidence: 99%

An assessment of daily production and significance of thyroidal secretion of 3, 3', 5'-triiodothyronine (reverse T3) in man.

Chopra¹

1976

303

111

A B S T R A C T While 3,3',5'-triiodothyronine (reverse TS, rTs) has been detected both in human serum and in thyroglobulin, no quantitative assessment of its metabolic clearance rate (MCR), production rate (PR), or secretion by the thyroid is yet available. This study examines this information in euthyroid subjects and evaluates it in light of similar information about two other iodothyronines in the thyroid: 3,5,3'-triiodothyronine (Ta) and thyroxine (T4). Thus, it was noted that rTs is cleared from human serum at a much faster rate than are Ts and T4; the mean (±-SE) MCR of rT3 was 76.7±5.4 liters/day in 10 subjects, whereas MCR-T3 and MCR-T4 in 8 of them were 26.0±2.2 liters/day and 1.02±0.06 liters/day, respectively. Therefore, even though the mean serum concentration of rT3, 48+2.8 ng/ 100 ml, was much lower than that (128±6.7 ng/100 ml) of T3, the mean PR-rTs (36.5+2.8 ,ug/day) and the mean PR-T3 (33.5±3.7 Ag/day) were similar; in comparison, the mean serum concentration and PR of T4 were 8.6± 0.5 ,ug/100 ml and 87.0±3.9 Mg/day, respectively. These data and those on the relative proportion of rT3, T3, and Ts in 10 thyroid glands were used to assess the significance of the contribution of thyroidal secretion to PRrTs and PR-Ta. It was estimated that whereas thyroidal secretion may account for about 23.8% of serum T3 (or PR-Ta), it may account for only about 2.5% of serum rTa (or PR-rTs). Since peripheral metabolism of T4 is the only known source of rT3 and Ta other than the thyroidal secretion, it could be calculated that as much as 73.0 Ag or 84% of daily PR-T4 may normally be metabolized by monodeiodination either to T3 or to rT3.MCR and PR of various iodothyronines were also examined in five cases with hepatic cirrhosis, where, as documented previously, serum rT3 may be elevated while Received for publication 2 September 1975 and in revised form 20 February 1976. serum Ta is diminished. The mean MCR-rT3 in these cases (41.0 liters/day) was clearly (P < 0.005) less than that (76.7 liters/day) in normal subjects. This was the case at a time when the mean MCR-Ta (26.7 liters/day) and the mean MCR-T4 (1.19 liters/day) did not differ from those (vide supra) in normal subjects. Distinct from changes in MCRs, the mean PR-rT3 (33.0 Ag/day) was similar to, and the mean PR-T3 (10.1 ug/day) and the mean PR-T4 (66.4 Mg/day) were much less than, the corresponding value in normal subjects. Furthermore, while the ratio of PR-rT3 and PR-T4 (rT3/T4) in individual patients was either supranormal or normal, the ratio of PR-Ta and PR-T4 (T3/T&) was clearly subnormal. The various data suggest that: (a) just as in the case of T3, the thyroid gland is a relatively minor source of rT3; peripheral metabolism of T4 is apparently its major source; (b) the bulk of T4 metabolized daily is monodeiodinated to T3 or to rT3; (c) monodeiodination may be an obligatory step in metabolism of T4; (d) monodeiodination of T4 to rTa is maintained normal or is increased in hepatic cirrhosis at a time when monodeiodination of T4 to Ta is decr...

“…Within a restricted range, hormonal tissue effects appear to be grossly proportional to the exchangeable hormonal tissue pool (32). Since only 5% of total body T3 in the rat is bound to plasma protein, and the rest is contained within the cells (26), the total exchangeable body pool of Ta can be regarded as a first approximation of the tissue pool. Thus, the following equation can be written:…”

Section: Discussionmentioning

confidence: 99%

“…The fractional removal rate of T4 (X4), was determined from the residual T4 in the carcass. The fractional removal rate of T8 (X3), was measured in a separate series of paired animals as previously described (26). It was possible to calculate K, the fractional rate of nonradioactive T4 to Ts conversion, and the conversion ratio (CR), the percentage of nonradioactive T4 ultimately converted to T3, by appropriate substitution of carcass '5I-T8/ 'I-T4, X4, and Xs, and t = 48 hr into the following equation 1 -e(-4)t In some animals, fecal and urinary radioactivity were also measured.…”

Section: Introductionmentioning

confidence: 99%

“…It was possible to calculate K, the fractional rate of nonradioactive T4 to Ts conversion, and the conversion ratio (CR), the percentage of nonradioactive T4 ultimately converted to T3, by appropriate substitution of carcass '5I-T8/ 'I-T4, X4, and Xs, and t = 48 hr into the following equation 1 -e(-4)t In some animals, fecal and urinary radioactivity were also measured. The fraction of total radioactivity disposed of via the deiodinative pathways, Fu, and the fraction of total radioactivity disposed via the fecal route, Ff, were calculated as previously described (26). The fractional fecal excretion rate (X1) and the fractional deiodinative removal rate (Xu) were calculated respectively from the product of X and Ff and X and Fu.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Propylthiouracil inhibits the conversion of l-thyroxine to l-triiodothyronine

Oppenheimer¹,

Schwartz²,

Surks³

1972

Self Cite

266

A B S T R A C T 6-n-propylthiouracil (PTU) administered to male Sprague-Dawley rats maintained on 2 and 5 Ag L-thyroxine (T4)/100 g body weight resulted in a marked reduction in the rate of conversion of L-thyroxine to L-triiodothyronine (Ts). These effects could not be ascribed to induced hypothyroidism since the group maintained on 5 *g T4/day had normal levels of liver mitochondrial alpha glycerophosphate dehydrogenase. In confirmation of previous studies, PTU also reduced the fractional rate of deiodination of T&. These observations provide a possible explanation of the many published observations indicating that PTU antagonizes the tissue effects of T4 but not of T3. The data suggest that monodeiodination of To but not of T8 is essential before hormonal effects can be manifested at the cellular level.