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PubMed1989

Resolution and binding site determination of D,L-thyronine by high-performance liquid chromatography using immobilized albumin as chiral stationary phase. Determination of the optical purity of thyroxine in tablets.

Human and bovine serum albumin bound to silica or aminopropyl silica were used as chiral stationary phases (CSPs). D,L-Thyronine, D,L-tryptophan, N-benzoyl-D,L-phenylalanine, D,L-warfarin and D,L-benzoin could be resolved on these CSPs using a mobile phase of 0.05 M phosphate buffer, pH 7.0. The capacity factor of D-thyronine was higher than that of L-thyronine. The resolution of D,L-thyronine was completely lost by the presence of bilirubin in the mobile phase, but only little affected by caprylate. By contrast, the resolution of D,L-tryptophan was not affected by bilirubin, but lost by the presence of caprylate. These results are consistent with binding of D-thyronine to the bilirubin binding site and L-tryptophan to the caprylate binding site in albumin, respectively, and suggests that such "displacement chromatography" can be used for the determination of binding sites. The optical purity of D-thyroxine in tablets was determined indirectly after de-iodination by catalytic hydrogenation.

Amino Acid Oxidoreductases↗
PubMedDate not supplied

The importance of employing homologous serum free of thyronines in radioimmunoassays to assess circulating thyroid hormones in rainbow trout.

Although abundant, available information regarding the values of circulating thyronines in the rainbow trout is misleading and confusing. The present study demonstrates the importance of maintaining species serum-homology when measuring thyronines with RIA to avoid spurious results. The utilization of homologous (trout) serum free of thyronines in the standard curve allowed the standardization of accurate and specific radioimmunoassays to quantitate circulating T3 and T4 levels in 10 microliters of rainbow trout serum. Detection limit was 50 pg for both thyronines. Inter- and intra-assay coefficients of variation were minor to 10%. Mean values for T3 and T4 +/- SEM in the trout population studied (n = 34) were 23.6 +/- 1.2 and 12.0 +/- 2.3 ng/ml respectively. A positive and significant correlation (p < 0.005) between body weight and T3 was observed, confirming the active participation of this thyronine in growth processes.

Animals↗
PubMed2005

Conformational changes of 3,5,3'-triiodo L-thyronine induced by interactions with phospholipid: physiological speculations.

The conformational changes of 3,5,3'-triiodo L-thyronine induced by interaction with phospholipids were analyzed by Raman spectroscopy. The spectra were interpreted in terms of two conformers of this hormone in equilibrium in the lipid medium, depending on the orientation of the 3'-iodine with respect to the ring alpha. Theoretical geometry optimizations on both conformers in vacuo and in different solvents, together with the respective calculated energies support the experimental results. The presence of only one iodine atom in the phenolic ring allows assumption of a higher flexibility of 3,5,3'-triiodo L-thyronine and a better accommodation into the lipid medium compared to 3,5,3',5'-tetraiodo L-thyronine. The possible physiological implications of structural differences that appear in membrane models between 3,5,3'-triiodo L-thyronine and 3,5,3',5'-tetraiodo L-thyronine are discussed.

Animals↗
PubMed1998

Glutamine synthetase expression and activity are regulated by 3,5,3'-triodo-L-thyronine and hydrocortisone in rat oligodendrocyte cultures.

Glutamine synthetase plays a central role in the detoxification of brain ammonia. Previously, we demonstrated that in vitro glutamine synthetase is expressed by all macroglial cell types and is developmentally regulated in oligodendrocyte lineage. Furthermore, glutamine synthetase is increased in secondary cultures of oligodendrocytes following a 72 h treatment with 30 nM 3,5,3'-triodo-L-thyronine [Baas, D., Bourbeau, D., Sarliève, L. L., Ittel, M. E., Dussault, J. H. and Puymirat, J., Oligodendrocyte maturation and progenitor cell proliferation are independently regulated by thyroid hormone. Glia, 1997, 19, 324-332]. Hydrocortisone also increases glutamine synthetase activity after 72 h [Fressinaud, C., Weinrauder, H., Delaunoy, J. P., Tholey, G., Labourdette, G. and Sarliève, L. L., Glutamine synthetase expression in rat oligodendrocytes in culture: regulation by hormones and growth factors. J. Cell. Physiol., 1991, 149, 459-468]; however, it is still unknown whether these increases in glutamine synthetase expression in oligodendrocytes after 3,5,3'-triodo-L-thyronine and hydrocortisone application are dose- and time-dependent. To further investigate this issue, we measured glutamine synthetase levels by Northern analysis, immunostaining and determination of glutamine synthetase activity after 3,5,3'-triodo-L-thyronine or hydrocortisone stimulation. We find that in rat oligodendrocyte secondary cultures, 3,5,3'-triodo-L-thyronine and hydrocortisone cause a dose- and time-dependent increase in glutamine synthetase mRNA, protein and activity. However, these hormones do not exert an additive or synergistic effect. Because purines, pyrimidines, and certain amino acids necessary for the synthesis of myelin components, are, in part, provided by the glutamine synthetase pathway, 3,5,3'-triodo-L-thyronine effect on myelination development and maturation could be mediated in part, through the glutamine synthetase gene regulation.

Animals↗
PubMed1988

Chemically blocked analog assays for free thyronines. II. Use of equilibrium dialysis to optimize the displacement by chemical blockers of T4 analog and T3 analog from albumin while avoiding displacement of T4 and T3 from thyroxin-binding globulin.

Chemical blockers used to displace thyronine analog from albumin in analog kits for assay of free thyroxin (FT4) or free triiodothyronine (FT3) may also displace thyroxin (T4) or triiodothyronine (T3) from thyroxin-binding globulin (TBG), resulting in an apparent TBG dependence of results of free hormone estimates. We used equilibrium dialysis and antibody binding to assess the displacement of thyronine analogs and thyronines from albumin and TBG by use of chemical blockers. We chose a combination of two chemical blockers, which eliminated thyronine analog-albumin binding but minimized thyronine displacement from TBG for use in FT4 and FT3 assays. These blocked-analog free-hormone assays yielded accurate clinical results in euthyroid patients, hypo- and hyperthyroid patients, and in pregnant women. FT4 results were not entirely normalized in all nonthyroidally ill patients, indicating that decreased analog-albumin binding is not the only factor resulting in low FT4 results. In current Diagnostic Products Corp. (DPC) FT4 and FT3 blocked-analog kits, the blocker concentrations are the same as we used in these assays.

Dialysis↗
PubMed1978

Molecular conformation of a halogen-free thyroxine analog: 4-Methoxy-3,5,3-trimethyl-L-thyronine N-acetyl ethyl ester.

The molecular conformation of the halogen-free thyroxine analog 4-methoxy-3,5,3'-trimethyl-L-thyronine -n-acetyl ethyl ester has been determined by x-ray diffraction techniques. The unsubstituted parent compound, trimethylthyronine, has significant biological activity in rat thymocyte tests when compared with the thyroid hormone 3,5,3'-triiodo-L-thyronine (T3). Although no activity data are available for the analog studied, it is presumed to be inactive because of the 4-methoxy blocking group. The observed conformation of this structure is similar to that found for the natural hormone T(3). The 3'-methyl group is distal, the overall conformation is cisoid, and the diphenyl ether conformation is twist-skewed. The results of this diffraction study show that methyl substituents are capable of maintaining the thyronine conformation required for hormonal activity; they suggest that iodine enhances hormone-protein binding because of the electronic effects it produces either by alteration of molecular charge distributions or by direct charge-transfer interactions with the serum or nuclear binding proteins.

Models, Molecular↗
PubMed1984

A radioimmunoassay of 3,5-dimethyl-3'-isopropyl-L-thyronine.

A simple, sensitive, and specific RIA has been developed to measure 3,5-dimethyl-3'-isopropyl-L-thyronine (DIMIT) in unextracted serum. The RIA employs a DIMIT-binding antibody obtained from a rabbit immunized with DIMIT-human serum albumin conjugate and [125I]T3 as the radioligand. 8-Anilino-1-naphthalene sulfonic acid and barbital buffer (0.075 M; pH 8.6) were used to minimize serum binding of DIMIT and [125I]T3. The detection threshold of the RIA was 0.03 microgram/dl. Recovery of nonradioactive DIMIT added to serum averaged 104%. 3,5,3'-Triiodothyroacetic acid cross-reacted maximally (78%) in the RIA, followed by T3 (56%), 3,5-diethyl-3'-isopropyl thyronine (43%), 3,3'-diiodothyronine (T2; 12%), tetraiodothyroacetic acid (6.7%), 3'-monoiodothyronine (T1; 0.54%), 3.5-T2 (0.34%), 3-T1 (0.26%), and T4 (0.25%); rT3, 3',5'-T2, thyronine, iodotyrosines, and KI cross-reacted 0.1% or less. The coefficient of variation averaged 7.4% within an assay and 9.0% between assays. After ip administration of DIMIT to the rat, the mean serum DIMIT concentration rose in a dose-related fashion from less than 0.12 microgram/dl in the controls to 44 micrograms/dl in those receiving 200 micrograms/100 g BW daily for 3 days; serum T4 and TSH levels declined significantly in animals receiving 3.2 micrograms DIMIT/(100 g BW X day) or more. After a single ip injection of DIMIT to the rat, serum DIMIT levels increased from a control value of 0.04 to 9.8 micrograms/dl at 2 h and then decreased progressively, with a half-life approximating 7.2 h. Serum TSH was suppressed for up to 24 h, while serum T4 and T3 were suppressed for up to 48 h after the injection. Concentrations of DIMIT 15 h after a dose of 10 micrograms, ip, to approximately 150-g rats were (nanograms per g; mean +/- SE) 19 +/- 2.3 in serum, 30 +/- 3.5 in liver, 23 +/- 2.4 in kidney, 19 +/- 4.7 in heart, 16 +/- 3.4 in skeletal muscle, and 20 +/- 3.0 in brain. DIMIT administration to pregnant rats [3 micrograms/(100 g BW X day) for 3 days, im] resulted in mean +/- SE DIMIT concentrations (micrograms per dl) of 0.51 +/- 0.14 in maternal serum, 0.57 +/- 0.04 in fetal serum, and 0.46 +/- 0.07 in amniotic fluid. A DIMIT dose of 10 micrograms/(100 g BW X day) for 3 days in maternal rats resulted in mean DIMIT concentrations (micrograms per dl) of 1.8 +/- 0.06 in maternal serum, 1.4 +/- 0.10 in fetal serum, and 1.3 +/- 0.17 in amniotic fluid.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1998

Effect of 3,5-diiodo-L-thyronine on thyroid stimulating hormone and growth hormone serum levels in hypothyroid rats.

We have investigated the biological effects of physiological doses of 3,5-diiodo-L-thyronine (3,5-T2) and 3,3'-diiodo-L-thyronine (3,3'-T2) (at doses from 2.5 to 10 microg/100 g BW) on serum TSH and GH levels in rats made hypothyroid by propylthiouracil and iopanoic acid administration. In such animals deiodinase activities were inhibited and thyroid hormones serum levels strongly reduced. The effects of T2s were compared with those elicited by 3,5,3'-triiodo-L-thyronine (T3) (2.5 microg/100 g BW).The serum TSH level was much greater in hypothyroid rats than in euthyroid ones. T3 administration suppressed TSH by 88% compared to control (i.e, the level in hypothyroid rats); it thus reached a value not significantly different from that seen in the euthyroid rats. 3,5-T2 produced a similar effect, suppressing the TSH level by about 75% compared to control; it thus reached values not significantly different from those of the euthyroid and T3-treated rats. By contrast, 3,3'-T2 had no effect on TSH, whatever the dose. The serum GH level was much lower in hypothyroid rats than in euthyroid ones. T3 administration increased the GH level by about 5-fold, restoring it to the value seen in euthyroid rats. 3,5-T2-treated hypothyroid rats, at all the doses used (from 2.5 to 10 microg/100 g BW), showed increased serum GH levels: at a dose of 10 microg/100 g BW the level reached a value about 5-fold higher than that in hypothyroid rats. This value was not significantly different from those of euthyroid and T3-treated rats. 3,3'-T2 did not affect GH levels whatever the dose. Thus, 3,5-T2 (but not 3,3'-T2) seems to mimic the effects of T3 on serum TSH and GH levels in rats.

Animals↗
PubMed1994

Analysis of the binding of 3,3',5-triiodo-L-thyronine and its analogues to mutant human beta 1 thyroid hormone receptors: a model of the hormone binding site.

To understand the nature of the thyroid hormone binding site, we characterized the binding of 3,3',5-triiodo-L-thyronine (T3) and its analogues to eight naturally occurring mutated human beta 1 thyroid hormone receptors (h-TR beta 1). The mutant receptors were derived from patients with the syndrome of generalized thyroid hormone resistance, and each has a point mutation in the hormone binding domain (KT, R338W; TP, L450H; IR, D322H; NN, G347E; AH, P453H; OK, M442V; RL, F459C; and ED, A317T). Compared to the wild-type h-TR beta 1, binding of T3 was reduced by as much as 97% for the mutants. The order of binding affinity of wild-type h-TR beta 1 to the analogues is T3 > D-T3 > L-thyroxine > 3,5-diiodo-L-thyronine > 3,3',5'-triiodo-L-thyronine. The mutant receptors showed essentially the same order of reduced affinities for the analogues, but the amounts of the reductions varied in each case. These results suggest specific local interactions (interplay) of analogues with the mutated residues in the receptors. On the basis of these data and a putative structure of the hormone binding domains as an eight-stranded alpha/beta barrel, we propose the location of the hormone in the binding site of h-TR beta 1. Ionic bonds anchor the hormone's alanine side chain to loop 4 of the 8-fold alpha/beta barrel. The phenyl ring lies across the amino-terminal face of the domain with the phenoxy ring pointing downward into the barrel interacting with beta-strand 8 on the opposite side.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding Sites↗
PubMed2004

Effect of thyroid hormone binding proteins on insulin receptor binding of B1-thyronine-insulin analogues.

Certain thyronine-insulin analogues, which form non-covalent complexes with plasma proteins, have been shown to act preferentially in the liver. We hypothesized that this property may be dependent on the ability of the analogue to bind to the insulin receptor without prior dissociation from the binding protein. NaB1-L-thyroxyl-insulin, NaB1-3,3',5'-triiodothyronine-insulin, NaB1-D-thyroxyl-insulin and NaB1-L-thyroxyl-aminolauroyl-insulin were compared with insulin for their capacity to inhibit the binding of [125I]TyrA14-insulin to rat liver plasma membrane in albumin-free buffer. Effective doses at 50% maximum inhibition of binding (ED50) were calculated with and without addition of the thyroid hormone binding proteins transthyretin, thyroxine binding globulin and human serum albumin. The binding of thyronine-insulin analogues to insulin receptors was inhibited in a dose-dependent manner by the addition of thyroid hormone binding proteins at concentrations in the physiological range. Complexes of thyronine-insulin analogues with thyroid hormone binding proteins exhibit impaired insulin receptor binding affinities compared with those of the analogues in their free form. Hepatoselectivity in vivo may not depend on binding of the intact complexes to hepatocytes. These results have implications for the physiological role of hormone binding proteins and the in vivo properties of other insulin analogues which bind to plasma proteins.

Animals↗
PubMed1985

Fasting induces the generation of serum thyronine-binding globulin in Zucker rats.

Five-month-old lean and obese Zucker rats were fasted for up to 7 days (lean rats) or 28 days (obese rats), and serum total and free T4 and T3 concentrations, percent free T4 and T3 by equilibrium dialysis, and the binding of [125I] T4 to serum proteins by gel electrophoresis were measured. In the lean rats, a 4- or 7-day fast resulted in significant decreases in serum total and free T4 and T3 concentrations. There was a decrease in the percent free T3 after 7 days of starvation. In contrast, a 4- or 7-day fast did not alter any of these variables in the obese rats. However, after 14 or more days of starvation, serum total T4 and T3 concentrations increased, and the percent free T4 and T3 decreased, resulting in no change in the serum free T4 or T3 concentrations in the obese rats. The percent of [125I]T4 bound to serum thyronine-binding globulin increased and the percent bound to thyronine-binding prealbumin decreased with the duration of the fast in both the lean and obese rats. The increase in serum thyronine-binding globulin binding of T4 can explain the increase in serum total T4 and T3 concentrations, the decrease in percent free T4 and T3, and the normal free hormone concentration in the long term fasted obese rats. The findings in the lean rats appear to be due to a combination of the known central hypothyroidism that occurs during 4-7 days of fasting and the fasting-induced changes in T4 binding in serum. Changes in T4 and T3 binding in serum during fasting in the rat must be considered when the effects of fasting on serum concentrations of the thyroid hormones, thyroid hormone kinetics, and the peripheral action of the thyroid hormones are evaluated.

Animals↗
PubMed1997

3,5-Diiodo-L-thyronine (T2) has selective thyromimetic effects in vivo and in vitro.

Recent data have suggested that the iodothyronine, 3,5-diiodo-l-thyronine (T2), has selective thyromimetic activity. In vivo, T2 has been shown to suppress TSH levels at doses that do not produce significant peripheral manifestations of thyroid hormone activity. Furthermore, T2 has been shown to produce smaller increments in peripheral indices of thyroid status than does T3, when doses resulting in equivalent suppression of circulating TSH are compared. We have assessed the selective thyromimetic activity of T2 in vivo and in vitro, and performed in vitro studies to assess the potential molecular basis for these selective properties. T2 was 100-fold less potent than T3 in stimulating GH mRNA levels in GH3 cells. In contrast, the iodothyronines were almost equivalent in their ability to downregulate TRbeta2 mRNA levels in this cell line. Both 3,3'-diiodo-L-thyronine and thyronine exhibited no significant thyromimetic effects on either process. In vivo, doses of T2 and T3 that were equivalent in their induction of hepatic malic enzyme (ME) mRNA did not produce equivalent suppression of circulating TSH, with T2 being only 27% as effective as T3. T2 was up to 500-fold less potent than T3 in displacing [125I]-T3 from in vitro translated specific nuclear receptors (TRs) and GH3 cell nuclear extracts. Electrophoretic mobility shift assays, assessing the ability of T2 to produce dissociation of TRbeta1 homodimers from inverted palindrome T3 response elements, indicated that T2 was also 1000-fold less potent than T3 in this respect. These data confirm that T2 has significant thyromimetic activity, and that this activity is selective both in vivo and in vitro. However, there are no data to support a selective central effect, T2 being relatively more potent in stimulating hepatic ME mRNA than in suppression of TSH in vivo. The basis for this differential thyromimetic activity is not selective affinity of the different TR isoforms for T2, or divergent properties of T2 in competitive binding and functional assays in vitro.

Animals↗
PubMed1993

Saturable, stereospecific transport of 3,5,3'-triiodo-L-thyronine and L-thyroxine into GH4C1 pituitary cells.

The mechanism of uptake of the thyroid hormones, 3,5,3'-triiodo-L-thyronine (L-T3) and L-thyroxine (L-T4), was studied in rat pituitary GH4C1 cells. The major portion (approximately 65%) of L-T3 transport was stereospecific and saturable. Transport of L-T3 was 8-10 times more rapid than transport of D-T3. [125I]L-T3 transport was saturable at microM concentrations; a Lineweaver-Burk plot was linear with Km = 0.4 microM and Vmax = 4 pmol/min/10(6) cells. Unlabeled analogs competed with [125I]L-T3 uptake in the order L-T3 > or = L-T4 >> 3,3',5'-triiodo-L-thyronine (reverse-T3), D-T3, D-T4, and L-thyronine. L-T3 and L-T4 also both effectively inhibited [125I]L-T4 transport. Uptake of [125I]L-T3 was inhibited 40-55% by large neutral amino acids and 77% by 80 microM beta-2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid, an inhibitor selective for the L system of amino acid uptake. Conversely, L-T3 inhibited the transport of [3H]leucine by pituitary cells (IC50 = 2 microM), but D-T3 and 3,5,3'-triiodothyroacetic acid (Triac) did not. L-Leucine was transported much more efficiently (Vmax = 0.65 mumol/min/10(6) cells) than L-T3 by GH4C1 cells. The results show that L-T3 and L-T4 share the same stereospecific transport pathway in pituitary cells, that the transport mechanism is saturable at supraphysiological thyroid hormone concentrations, and that the L system is partially responsible for L-T3 transport.

Animals↗
PubMed1984

3'-Acetyl-3,5-diiodo-L-thyronine: a novel highly active thyromimetic with low receptor affinity.

The 4'-phenolic hydroxyl group of thyroid hormones plays an important role in receptor binding, and it has been suggested that the interaction of this hydroxyl group with the receptor involves hydrogen bonding via donation of the acidic hydrogen in a trans disposition to the 3'-substituent of the hormones. In order to test this hypothesis we have synthesised, and measured the hepatic receptor affinity and thyromimetic activity of 3'-acetyl-3,5-diiodo-L-thyronine (3'-Ac-T2), a compound in which the formation of such a receptor-phenol hydrogen bond is precluded by the presence of a strong intramolecular hydrogen bond between the 3'-acetyl- and 4'-hydroxyl groups. In confirmation of the hypothesis, 3'-Ac-T2 has a low affinity (0.5% of that of 3,5,3'-triiodo-L-thyronine, T3) for the T3-receptor in isolated rat hepatic nuclei. By contrast the thyromimetic activity (assessed by its ability to induce rat hepatic glycerol-3-phosphate dehydrogenase and increase the qO2 of liver slices) was roughly equal to that of T3. This apparent discrepancy was resolved when it was found that the capacity of 3'-Ac-T2 to occupy hepatic receptors after in vivo administration, was about 100 times greater than predicted from its in vitro affinity. The reason for this difference between in vivo and in vitro nuclear binding is unknown at the present time.

Animals↗
PubMed1993

Inhibition of low density lipoprotein oxidation by thyronines and probucol.

Oxidation of low density lipoproteins (LDL) results in increased macrophage uptake of LDL which may contribute to the formation of macrophage-derived foam cells in the early atherosclerotic lesion. In this study we show that thyroxine (T4), its optical antipodes, certain desiodo analogs and probucol inhibited cupric sulfate-catalyzed oxidation of human LDL in a concentration-dependent manner as assessed by measuring the electrophoretic mobility, thiobarbituric acid reactive substances (TBARS) and LDL degradation in mouse macrophages. In Cu(2+)-catalyzed LDL oxidation at 24 hr, the TBARS level was 80 nmol/mg LDL protein/24-hr incubation. The concentrations (microM) of each agent producing 50% inhibition in the formation of oxidized LDL (IC50) for TBARS, electrophoretic mobility and macrophage degradation, respectively, were 1.13, 1.27 and 1.30 for reversed triiodothyronine; 1.33, 1.80 and 1.27 for triiodothyronine; 1.33, 1.37 and 1.37 for racemic thyroxine, DL-T4; 1.10, 1.40 and 1.50 for L-T4; 1.13, 1.33 and 1.23 for D-T4; and 1.47, 1.63 and 1.37 for probucol. No differences in inhibitory potency were observed when rT3, T3, the optical antipodes of T4 and the hydrophobic antioxidant drug probucol were compared. In air-induced LDL oxidation, TBARS was 16.1 nmol/mg LDL protein/6-hr incubation. The IC50 concentrations (microM) for TBARS and diene conjugation, respectively, were 0.187 and 0.336 for D-T4; 0.205 and 0.243 for L-T4 and 1.30 and 3.02 for probucol. With air-induced LDL oxidation conditions, the L-T4 concentrations included the physiological range, and thyroid-binding globulin did not modify the inhibitory effect of the endogenous enantiomer, L-T4. Putative uptake of this stereoisomer into LDL inhibited oxidation of these lipoproteins. Since concentrations of these thyronines which blocked air-induced LDL oxidation were in the physiological range, we conclude that thyronines, like the pharmacological agent probucol, limit the oxidative modification of LDL and thus may serve as natural inhibitors of atherogenesis.

Air↗
PubMed1988

Thyroid hormone analogues. Synthesis of 3'-substituted 3,5-diiodo-L-thyronines and quantitative structure-activity studies of in vitro and in vivo thyromimetic activities in rat liver and heart.

Twenty-nine novel 3'-substituted derivatives of the thyroid hormone 3,3',5-triiodo-L-thyronine (T3) have been synthesized by using established methods and by a new route involving manipulation of a 3'-formyl intermediate. In vitro hormone receptor binding (to intact nuclei) and in vivo thyromimetic activity (induction of mitochondrial 3-phosphoglycerate oxidoreductase, GPDH) were measured in rat liver and heart for these new analogues and for the 18 previously reported 3'-substituted 3,5-diiodo-L-thyronines. Analysis of the binding data using theoretical conformational and quantitative structure-affinity methods implies that the 3'-substituent recognition site on the thyroid hormone receptor is hydrophobic and limited in depth to the length of the natural iodo substituent, but has sufficient width to accommodate a phenyl or cyclohexyl group. Receptor binding is reduced by approximately 10-fold in 3'-acyl derivatives which form strong intramolecular acceptor hydrogen bonds with the adjacent 4'-hydroxyl. The compounds studied showed no differences in their relative affinities for heart and liver nuclei, suggesting that receptors in these tissues are similar. However, the relationships between thyromimetic activity (induction of GPDH) and nuclear binding showed some tissue differences. A high correlation between activity and binding is observed for full agonists in the heart, but an equally significant correlation for the liver data is only seen when 3'-substituent bulk (molar refractivity) is included in the analysis. These results suggest the possibility that differential tissue penetration or access to receptors may occur in vivo.

Animals↗
PubMed1989

The effect of thyroxine, 3, 5-dimethyl-3'isopropyl-L-thyronine and iodized oil on fetal brain development in the iodine-deficient sheep.

Studies have been carried out to investigate the role of maternal and fetal thyroid function in the effects of iodine deficiency on fetal brain development in sheep. Iodine deficiency was established with an especially prepared low-iodine diet of maize and pea pollard. The iodine-deficient sheep were mated and the end of the second trimester of pregnancy (100 days gestation) were divided into groups which received either a sc injection of T4 or 3,5-dimethyl-3-isopropyl-L-thyromine or an injection of iodized oil. AT 140 days gestation (10 days prior to parturition) comparison of the fetuses delivered by hysterotomy revealed that the retarded fetal brain development observed in iodine deficiency was greatly improved by T4 and by iodized oil. However, T4 and iodized oil failed to correct the reduction in the number and the increase in the length of synaptic appositions which were observed in the fetal cerebral cortex after iodine deficiency. In addition, the histological appearance of the fetal thyroid gland and the levels of plasma thyroid hormones were restored to normal. The administration of 3,5-dimethyl-3'-isopropyl-L-thyronine had no effect on the retarded fetal brain and body development of the iodine-deficient fetuses. The lack of response may be due to the ability of 3,5-dimethyl-3'-isopropyl-L-thyronine to cross the ovine placenta as no reduction in the abnormally elevated fetal plasma TSH observed in spite of a fall in maternal plasma TSH and apparent restoration of maternal thyroid function.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Characterization of 3,5,3'-triiodo-L-thyronine transport into hepatocytes isolated from juvenile rainbow trout (Oncorhynchus mykiss), and comparison with L-thyroxine transport.

Uptake of 3,5,3'-triiodo-L-thyronine (T3) by isolated trout hepatocytes was characterized after 40 sec incubation of cells in a balanced salts medium containing [125]T3, and compared to L-thyroxine (T4) uptake (Riley and Eales, Gen. Comp. Endocrinol. 90, 31-42, 1993). T3 uptake resembled T4 uptake in several ways. There was a small (< 10%) diffusion component. The balance of the uptake was temperature- and energy-dependent and involved a protein carrier, but did not depend on the presence of Na+ in the medium or Na+ transport. Tyrosine and phenylalanine were ineffective competitors. Inhibition by colchicine and chloroquine indicated an endocytotic process. T3 uptake differed from T4 uptake in having a higher pH optimum (6-8) than T4 (5-6), and in having a much lower Kt (0.074 microM) than T4 (0.52 microM). T3 uptake was far more strongly inhibited than T4 uptake by TRIPROP (8% of control uptake), reverse T3 (9%), and 3,3'-diiodo-L-thyronine (9%). T4 inhibited T3 transport (Ki = 0.18 microM), but kinetic analyses indicated that the mutual inhibitions were noncompetitive, suggesting separate T3 and T4 binding sites. In conclusion, T3 uptake into isolated trout hepatocytes resembles that for T4 uptake in being an energy-dependent, carrier-mediated endocytotic process, but differs from T4 uptake in having a lower Kt, a higher pH optimum, and a greater sensitivity to inhibition by related iodothyronines. T3 and T4 uptakes may involve separate carrier systems, providing scope for individual control of T3 and T4 uptake by trout hepatocytes.

Animals↗