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Biomedical subjects

E C Jorgensen

Publications and source records attributed to E C Jorgensen.

At least 19 recordsLinked to original sources
PubMed1986

Comparative effects of 3,5-dimethyl-3'-isopropyl-L-thyronine (DIMIT) and 3,5-diiodo-3'-isopropylthyroacetic acid (IpTA2) on body weight gain and lipid metabolism in genetically obese Zucker rats.

3,5-Dimethyl-3'-isopropyl-L-thyronine (DIMIT) and 3,5-diiodo-3'-isopropylthyroacetic acid (IpTA2), two thyroid hormone analogs, have been tested in genetically obese Zucker rats and their lean littermates, in comparison with thyroxine (T4) and triiodothyronine (T3) for their thyromimetic activities on body weight gain and lipid levels in serum and liver. The compounds were administered for 9 weeks by orogastric tube to 6- to 8-week-old animals. While body weight gain remained practically unchanged in the lean rats, it decreased significantly in the obese individuals, especially with IpTA2. The serum lipid concentrations were also decreased in the obese rats in comparison with their lean littermates, especially with DIMIT. The connection observed between the structure of DIMIT and IpTA2 on one hand and their effects on the other is in good agreement with previous studies. Our results confirm that the iodine substituents are not necessary for thyromimetic activity and demonstrate that the isopropyl substituent in 3' plays an important role in the serum lipid-lowering effect of the thyroid hormone analogs tested.

Animals↗
PubMed1984

Comparative effects of thyroid hormone analogs on the activities of brain and liver mitochondria and nuclei in thyroidectomized rats.

Several thyroid hormone analogs have been tested for thyromimetic activity on rat brain and liver subcellular organelles. The compounds were administered immediately after thyroidectomy to 90 g male S-D rats for 10 days, by daily s.c. injection. In cerebral cortex and liver we measured the activities of mitochondrial succinate cytochrome c reductase and alpha-GPD, and nuclear RNA polymerase I. Brain mitochondrial enzymes were unchanged in thyroidectomized (Tx) and in Tx-treated rats, whereas the activities of these enzymes in liver mitochondria were partially restored by the treatments. RNA polymerase I activity in brain and liver dropped significantly 10 days after thyroidectomy and daily injection of thyroid hormones or analogs maintained the nuclear activity at a normal level. Correlation between the structure of thyroid hormone analogs and their subcellular effects is in good agreement with previous binding and in vivo studies. Enzyme activities stimulated by T3 were lowered by replacing the T3 side-chain by an acetic acid group or by substituting the bridged oxygen atom by atom by CO. In contrast, the activity was enhanced by substituting iodine with a 3' isopropyl group. Although less active than iodine, the 3,5-dimethyl substituents may be introduced without a complete loss of nuclear activity.

Animals↗
PubMed1982

[Metabolic effects of 3,5-dimethyl-3'-isopropyl-L-thyronine (DIMIT) in constant infusion by osmotic minipump to hypothyroid rat (author's transl)].

Our experiments show that the T3 nonhalogenated analog 3,5-dimethyl-3'-isopropyl-L-thyronine (DIMIT) exhibits the general activities of thyroid hormones. DIMIT delivered to hypothyroid Rat by constant infusion or sc injections increases bodyweight gain, BMR before or after epinephrine and phosphorylative oxidation of liver mitochondria.

Animals↗
PubMed1982

Computer graphics in drug design: molecular modeling of thyroid hormone-prealbumin interactions.

Computer graphics modeling of the thyroxine-prealbumin complex provides a detailed picture of the interactions between thyroxine and prealbumin. A wide variety of thyroid hormone analogue-prealbumin complexes were modeled by calculating the molecular surfaces of the analogues and the prealbumin hormone-binding site. Analogues with high binding affinity were observed to fill more of the hormone-binding site than low-affinity analogues. These surface models described many aspects of the hormone-protein interaction which were not obvious using simple wire models and led us to develop a model which accounts for thyroid hormone-prealbumin structure-activity relationships and ultimately to predict and measure the relative binding affinities of four previously untested thyroid hormone analogues to prealbumin.

Chemical Phenomena↗
PubMed1982

Maturational effect of triiodothyronine and its analog 3,5-dimethyl-3'-isopropyl-L-thyronine on sucrase activity in the small intestine of the developing rat.

In this study we compared the effect of 3,5-dimethyl-3'-isopropyl-L-thyronine (DIMIT) with that of triiodothyronine (T3) on sucrase activity in the small intestine of the fetal and suckling rat. DIMIT (5 micrograms/100 g BW) was injected into pregnant Sprague--Dawley rats on days 17-20 of gestation and DIMIT (10 and 50 micrograms/100 g BW) and T3 (10 and 50 micrograms/100 g BW) were given subcutaneously to two groups of sucklings on days 4-7 and 11-14. Fetal animals were sacrificed on day 21 of gestation; sucklings on days 8 and 15. Sucrase activity in the proximal, middle, and distal small intestine was assayed. DIMIT and T3 suppressed serum thyroid-stimulating hormone (TSH) in the fetus and suckling. Sucrase activity was increased in all small intestinal segments in the fetal and older suckling groups. In the younger sucklings the effect was seen only in the middle and distal segments. In both fetal and suckling groups the sucrase response was dose related. Thus, DIMIT has a thyromimetic effect on development of sucrase activity. The lack of sucrase reactivity in the proximal segment of the younger (8-day-old) sucklings to the administration of either DIMIT or T3 is interesting but unexplained.

Animals↗
PubMed1980

Transplacental stimulation of lung development in the fetal rabbit by 3,5-dimethyl-3'-isopropyl-L-thyronine.

The effect of thyroid hormone on maturation of fetal rabbit lung was studied with maternal treatment using 3,5-dimethyl-3'-isopropyl-L-thyronine (DIMIT), a synthetic analogue of triiodothyronine. To investigate the in vivo kinetics and distribution of DIMIT, we prepared [3H]DIMIT and injected both pregnant rats (18-21 d gestation) and rabbits (25 d gestation). In the rat, maximal concentrations of radioactivity in maternal plasma, fetal plasma, and amniotic fluid occurred within 10 min, 1-2 h, and 4-6 h, respectively, after intramuscular injection. After 7 h the concentration of radioactivity in fetal plasma was 163 and 71% of the maternal level in rats and rabbits, respectively, indicating that DIMIT readily crosses the placenta. We treated pregnant rabbits for 1-2 d with DIMIT in doses of 0.5-3 mg/kg per d and examined the fetuses at 26 and 27 d gestation. Treatment did not affect fetal growth or viability. In fetal liver, DIMIT increased the activity of NADPH cytochromeac reductase by 64% and decreased the glycogen content by 73% compared to controls. The rate of choline incorporation by lung minces increased in dose-dependent manner to a maximum of +104% at 3 mg/kg DIMIT; this does stimulated by 38% the activity of lung phosphatidic acid phosphatase (PAPase), a corticosteroid-responsive enzyme, but there was no increase in tissue PAPase activity at most lower doses of DIMIT that enhanced choline incorporation. Treated lungs had 38% less glycogen tha controls, but there was no effect on tissue levels of DNA, protein, or phospholipid. DIMIT treatment increased the amount of total phospholipid (+163%). saturated phosphatidylcholine (+330%), and PAPase activity (+134%) in lung lavage fluid. The DIMIT effects on both choline incorporation by lung minces and phospholipid content of lavage fluid were substantially greater than what had occurred with an optimal dose of betamethasone. DIMIT also increased corticosteroid binding capacity in fetal plasma and produced a dose-dependent increase (maximal threefold) in total and free corticoids of both maternal and fetal plasma. It is estimated that elevated endogenous corticoids probably account for less than one-third of the increases in phospholipid synthesis and secretion observed at the higher doses of DIMIT. These data indicate that administration of DIMIT to pregnant rabbits accelertes maturation of the surfactant system in fetal lung. The magnitude of the effects on phospholipid synthesis and secretion, along with the minimal effect of PAPase activity in fetal lung tissue, suggest that thyroid hormones affect different biochemical processes from those influenced by glucocorticoids.

Adrenal Cortex Hormones↗
PubMed1980

Suppression of thyrotropin by 3,5-dimethyl-3'-isopropyl-L-thyronine in euthyroid and hypothyroid rats.

The effect of 3,5-dimethyl-3'-isopropyl-L-thyronine (DIMIT) a nonhalogenated thyroid hormone analog, on plasma and pituitary TSH levels was studied in euthyroid and 5-day-thyroidectomized (T-5d) rats. The minimal dose of DIMIT which suppressed basal plasma TSH for a 24-h period was 5.3 micrograms/100 g BW in the euthyroid rats and 5.2 micrograms/100 g BW in the T-5d group. The equipotent doses of T3 were 1.0 and 1.5 micrograms/100 g BW, respectively. Thus, the apparent DIMIT to T3 molar ratio ranged from 6.6 in the hypothyroid to 10 in the euthyroid group. The suppression of TRH-induced TSH release in the euthyroid rats required a high dose of DIMIT (9.2 micrograms/100 g BW), resulting in a DIMIT to T3 molar ratio of 17. Time-course studies comparing the effects of equipotent doses of DIMIT and T3 on TSH release rates in euthyroid and T-5d rats have shown a maximal suppression by 3--24 h after the administration of both T3 and DIMIT. However, the recovery from the effect was slower after T3. TSH synthesis in the T-5d group was similarly suppressed by DIMIT and T3. DIMIT has significant thyromimetic activity in euthyroid and hypothyroid rats, as evidenced by the suppresion of TSH synthesis and release.

Animals↗
PubMed1980

Uptake of L-triiodothyronine into human cultured lymphocytes.

The cellular uptake of [125I]L-triiodothyronine and its analogues was investigated in IM-9 human cultured lymphocytes. Uptake of L-triiodothyronine was one half maximal within 15 min of incubation and maximal within 45 min. The efflux of the hormone followed first order kinetics having a one half time of 15 min. Treating the cells with either the mitochondrial inhibitors antimycin-A and potassium cyanide, or lowering the incubation temperature to 12 degrees C, markedly reduced uptake. The uptake of [125I]L-triiodothyronine was saturable having an affinity constant (Kd) of 110 nM. When thyroid hormone analogues were studied D-triiodothyronine and triiodothyroacetic acid (analogues known to bind avidly to nuclear receptors) competed only weakly with [125I]L-triiodothyronine for uptake. These findings indicated the importance of the intact L-alanine side chain of the thyroid hormone molecule for its uptake into lymphocytes. Other studies, with cultured rat hepatocytes, demonstrated a similar saturable uptake system for [125I]L-triiodothyronine. These studies suggest, therefore, that the uptake of thyroid hormones and their analogues into cells may be an important step in the biological actions of these hormones.

Animals↗
PubMed1979

A model for thyroid hormone--receptor interactions.

Theoretical electronic structure calculations on the thyroid hormones and analogues, as well as model hormone--receptor interactions, have been carried out. These studies (a) support the concept that the 4'-OH group is a H-bond donor to the in vivo nuclear receptor and suggest that at the receptor this OH group is trans to the 3' (distal) substituent; (b) indicate that there is an important intramolecular interaction between 3' and 4' substituents, and those 3' substituents that most favor both 4' OH orientation trans to the 3' group and a more acidic OH group substantially increase binding and biological activity; and (c) support the concept that there is a direct correlation between the conformational free energy of the aromatic rings and biological activity.

Animals↗
PubMed1979

Thyrotropin suppression by 3,5-dimethyl-3'-isopropyl-L-thyronine in man.

The thyromimetic activity of 3,5-dimethyl-3'-isopropyl-L-thyronine (DIMIT), a nonhalogenated thyroid analog, was studied in adult men using suppression of TRH-induced TSH release to assess this activity. In nine men, aged 30-58 yr, the TSH increment after 500 microgram TRH iv was compared to the TSH response to TRH 24 h after oral administration of 1 mg DIMIT. Eight euthyroid subjects had normal baseline TSH levels of 1.5 +/- 0.2 (SE) microunit/ml that fell significantly to 0.7 +/- 0.2 microunit/ml 24 h after DIMIT (P less than 0.005). Their TSH increments after TRH fell from 15.3 +/- 2.8 to 6.7 +/- 1.6 microunit/ml 24 h after DIMIT (P less than 0.001). One subject with probable Hashimoto's thyroditis had an elevated TSH of 18 microunit/ml, with an exaggerated TSH response to TRH of 72 microunit/ml. His basal TSH fell to 7.6 and his TSH increment fell to 14.3 microunit/ml 24 h after DIMIT. The suppression of TSH was relatively prolonged. In four subjects, the TSH response to TRH was still blunted from 5-12 days after DIMIT. In one subject, the TSH increment returned to normal 15 days after DIMIT. DIMIT had no significant effect on PRL secretion. There was no evidence of toxicity in patients receiving DIMIT. DIMIT has effective thyromimetic activity in man, as shown by its significant and prolonged suppression of TSH secretion.

Adult↗
PubMed1979

Angiotensin II analogues. 13. Role of the hydroxyl group of position 4 tyrosine in pressor activity.

In order to determine the features of the phenolic ring in position 4 of [Asn1,Ile5]angiotensin II that contribute to pressor activity, analogues with selected aromatic substituents were synthesized by the solid-phase method. They showed pressor activities in the rat: [Asn1,Phe(4-NH2)4]AII, 24%; [Asn1,Phe(4-NO2)4AII, 0.1%; [Asn1,Tyr(3,5-Me2)4]AII, 2.2%; [Asn1,D-Tyr(3,5-Me2)4]AII, 1.4%. These results indicate that the activity contributed by the aromatic character of the phenyl ring in the side chain of position 4 is enhanced by a group in the para position that may function as a proton donor in hydrogen-bond formation. Bulky substituents ortho to this hydrogen-bonding group decrease activity by steric interference with hydrogen-bond formation. Bulky groups than cannot act as hydrogen donors in the para position of the aromatic ring drastically decrease the activating effect of the aromatic ring on pressor activity.

Angiotensin I↗
PubMed1978

Effects of a thyroid hormone analog on fetal rat hepatocyte ultrastructure and microsomal function.

The effects of an analog of thyroxine, 3,5-dimethyl-3'-isopropyl-L-thyronine (DIMIT), on fetal rat hepatocyte ultrastructure and microsomal function were investigated by using the techniques of quantitative electron microscopy and enzyme assays. Rats were injected with DIMIT (10 microgram/100 g BW) or vehicle daily from the 15th through the 19th day of pregnancy. Fetuses were sacrificed on the 20th day of gestation. In comparison with controls, DIMIT-treated livers 1) were devoid of glycogen; 2) contained smaller hepatocytes; 3) contained a greater number of hepatocytes; 4) had an increased volume density of mitochondria; and 5) had increased NADPH-cytochrome c reductase and glucose-6-phosphatase activities. Surface areas of rough and smooth surfaced endoplasmic reticulum were unaffected by the hormone analog, and cytochrome P-450 was not induced. All of the changes that were produced by DIMIT in the 20-day-old fetal rat, as well as smooth endoplasmic reticulum and cytochrome P-450 development, are observed in normal animals within the first 3 days after birth. The data suggest that thyroid hormone may be a physiological stimulus for certain aspects of early hepatic development, but that it acts in combination or in sequence with other factor(s) to produce the full complement of structural and functional changes that occur perinatally in the rat.

Animals↗
PubMed1978

Thyroid hormone analogs and fetal goiter.

Transfer of iodothyronine across the placenta in most species occurs only with difficulty. Recently, biologically active, nonhalogenated thyroid hormone analogs have been synthesized with properties which might favor placental transfer. To test this possibility, we compared the doses of T4, T3, and thyroid hormone analogs necessary to prevent propylthiouracil-induced goiter formation in rat fetuses. T4 and T3 prevented fetal goiter, but in doses that caused maternal hyperthyroidism; in contrast, the thyroid hormone analogs prevented fetal goiter in doses that were not thyrotoxic to the mother.

Animals↗