Tetraiodothyroformic Acid Research Articles

REDUCTION OF SERUM CHOLESTEROL BY TETRAIODOTHYROFORMIC ACID

Reduction of Serum Cholesterol by Tetraiodothyroformic Acid Get access Nutrition Reviews, Volume 19, Issue 7, July 1961, Pages 209–211, https://doi.org/10.1111/j.1753-4887.1961.tb01973.x Published: 01 July 1961

The identification of 3,3', 5,5',-tetraiodothyroformic acid within the rat liver.

Homogenized rat livers were extracted with organic solvents and the extracts converted into more readily volatile derivatives (trimethylsilylmethyl esters and permethyl esters). Combined g.l.c.-mass-spectrometric analysis identified the presence of tetraiodothyroformate. It is postulated that mitochondrial beta-oxidation of tetraiodothyropyruvate results in the formation of this apparently undescribed metabolite.

THE EFFECT OF THYROID HORMONES ON WATER PERMEABILITY OF THE ISOLATED BLADDER OF THE TOAD BUFO BUFO.

SUMMARY Thyroxine at 10−6m concentration enhances water movement from the mucosal to the serosal surface of the isolated toad bladder in the absence of an osmotic gradient. It is suggested that this is caused by the effect of thyroxine on sodium transport which creates a driving force for the increased water movement. Thyroxine caused this effect when applied on either side of the membrane, but was more effective when applied to the serosal surface. Incubation of different bladders successively in the same triiodothyronine solution indicated that triiodothyronine may be rapidly utilized. A mixture of thyroxine and triiodothyronine caused a diphasic effect on water loss down an osmotic gradient. The analogues tetraiodothyroproprionic acid and tetraiodothyroformic acid had no effect on water movement down an osmotic gradient across the isolated toad bladder nor did they affect oxygen uptake or sodium transport. The results support the concept that thyroxine and triiodothyronine act on permeability processes in and across cell membranes.

Effect of thyroxine analogue TFA-4 on serum cholesterol.

The role of thyroxine in the control of serum cholesterol has long been recognized clinically. In hypothyroidism hypercholesteremia assumes some diagnostic importance; whereas, a tendency to hypocholesteremia is often recorded in hyperthyroidism. The administration of desiccated thyroid and thyroid extracts will reduce the serum cholesterol and phospholipid. 1 At the present time a rather voluminous literature points to the probability that elevated lipids constitute one of the factors involved in atherogenesis. Therefore, if thyroxine could be altered so as to maintain its cholesterol-lowering effect without altering general body metabolism a useful research and possible therapeutic tool would be available. It is the purpose of this paper to present a clinical experience with one of these thyroxine analogues. Tetraiodothyroformic acid (TFA-4) is formulated by substituting a carboxyl group for the alanine side-chain of thyroxine (Fig. 1). Duncan and Best 2-4 studied this compound in rats and found that, when compared to

Abnormalities of cholesterol metabolism in hypothyroidism and the effects of treatment with thyroid hormones and thyroxin analogues

Knowledge of the metabolism of cholesterol in conditions of deranged function of the thyroid gland has been reviewed, and clinical correlations between serum lipids, basal metabolic rate, and thyroid status surveyed. The effects of the thyroid hormones, L-thyroxin and 3,5,3′-triiodo-L-thyronine (L-T 3) on circulating lipids, particularly in hypothyroidism, were summarized. They were compared with the following thyroxin analogues: D-thyroxin and 3,5,3′-triiodo-D-thyronine (D-T 3); 3,5-diiodo-L-thyronine (L-T 2) and D-T 2; 3,5,3′,5′-tetraiodothyroformic acid (Tetraform) and 3,5,3′-triiodothyroformic acid (Triform); 3,5,3′-triiodothyroacetic acid (Triac) and 3,5,3′,5′-tetraiodothyroacetic acid (Tetrac) ; 3,5,3′-triiodothyropropionic acid (Triprop) and 3,5,3′,5′-tetraiodothyropropionic acid (Tetraprop); 3,5-diiodothyroacetic acid (Diac); and 3,3′,5′-triiodo-DL-thyronine (3,3′,5′-T 3). Except for 3,3′,5′-T 3, which appears to antagonize some thyroid hormone effects peripherally, these analogues are thyroactive to greater or lesser degrees. Their cholesterol-lowering potency has been compared with other actions, and the significance of apparent dissociation of cholesterol-lowering and calorigenic effects has been assessed. Therapeutic implications have been briefly explored.

Tissue distribution of thyroxin analogues and their effects on cholesterol metabolism.

Four thyroxin analogues, l-triiodothyronine, d-triiodothyronine, tetraiodothyropropionic acid, and tetraiodothyroformic acid, labeled with I131, were injected intravenously into male rats and the tissue distributions of radioactivity determined at intervals of 40 min, 2 hr, and 6 hr. Of the two analogues that have been shown to exert an effect on cholesterol metabolism, which is accentuated relative to their other metabolic activities, d-triiodothyronine and tetraiodothyroformic acid, only the former was disproportionately concentrated by the liver. The liver to skeletal muscle concentration ratio of tetraiodothyroformic acid did not differ appreciably from those of l-triiodothyronine and tetraiodothyropropionic acid, which do not display an accentuated effect on cholesterol metabolism. It is concluded that the effect on cholesterol metabolism relative to other metabolic activities of thyroxine analogues is not determined solely by their tissue distributions.

Comparative Effects of Thyroxin Analogues as Hypocholesteremic Agents

L-thyroxin and four thyroxin analogues were administered to a group of hypercholesteremic euthyroid patients, the majority with arteriosclerotic heart disease, and the effects on serum total cholesterol compared. L-thyroxin and each of the analogues studied, tetraiodothyroformic acid, dimethyldiiodothyroformic acid, D-thyroxin and D-triiodothyronine, were given to four to nine patients for periods up to 10 months. At the doses employed each of the analogues resulted in a reduction in the mean level of serum cholesterol without obvious evidence of hypermetabolism or aggravation of angina pectoris or congestive heart failure. The reduced level of serum cholesterol was sustained throughout the period of hormone administration, and upon the substitution of a placebo returned to the pretreatment range. L-thyroxin, at the dose employed, also effected a modest sustained reduction in serum cholesterol but both patients with angina included in this group experienced an increase in severity of symptoms. Except for four patients who developed acneiform dermatitis, salivary gland swelling, or gastrointestinal symptoms during the administration of the formic acid analogues, no toxic or undesirable effects were observed from any of the analogues. To evaluate better the general metabolic effects of the analogues each was administered to three or more of a group of seven myxedematous patients for periods of 6 to 12 months. Given in sufficient amount all were observed to increase basal metabolic rate and to maintain a clinically euthyroid state. From these observations, it is concluded that the D-isomers of thyroxin and triiodothyronine, while not without general metabolic effects, are tolerated by the majority of euthyroid patients with coronary atherosclerosis in amounts sufficient to maintain a reduced serum cholesterol level.

Effect of certain thyroxine analogues on liver cholesterol

l-Thyroxine, l-triiodothyronine, their d-isomers, and their formic, acetic, propionic and butyric acid analogues were given to cholesterol-thiouracil-fed rats and the effect on thyroid weight and serum and liver cholesterol determined. l-Thyroxine, d-thyroxine and tetraiodothyroformic acid were also given to cholesterol-fed rats and the effect on oxygen use and serum and liver cholesterol measured. The substitution of either d-alanine or a carboxyl group for the l-alanine side chain of thyroxine and triiodothyronine resulted in a degree of dissociation of goiter-inhibiting and liver cholesterol effects. Thus, these substituted compounds at doses having equal or less goiter-inhibiting effects resulted in significantly lower liver cholesterol levels than did l-thyroxine or l-triiodothyronine. The effect of d-thyroxine and tetraiodothyroformic acid on liver cholesterol was also disproportionate to their calorigenic activity as compared to l-thyroxine.

Hypocholesterolemic effect of tetraiodothyroformic acid on brittle coronary patients.

The inverse relationship of lipemia and the body metabolism has been established.1-9Hurxthal, in 1934, demonstrated that, within limits, the blood cholesterol level reflects the thyroid activity.9Thyroid deficiency is accompanied by an elevated blood cholesterol level, while in hyperthyroidism, the blood cholesterol level is usually below normal. There are many studies which suggest a relationship between the incidence of arteriosclerosis and hypercholesterolemia.10-12The search for hypocholesterolemic agents which might prevent arteriosclerotic narrowing of the blood vessels has been exhaustive and frustrating. While it has long been recognized that desiccated thyroid will reduce blood cholesterol levels in the hypercholesterolemic patient, the amount of thyroid which must be administered is of such a magnitude that it often induces a strong calorigenic or adrenergic effect. It is also difficult to administer thyroxin in sufficient amounts to lower the hyperlipemia without the induction of adverse effects such as palpitation due

THE EFFECT OF CERTAIN THYROXINE ANALOGUES ON THE SERUM LIPIDS IN HUMAN SUBJECTS

SUMMARY 1. Certain analogues of thyroxine have been administered to twenty-six hypothyroid patients and 132 euthyroid hypercholesterolaemic men with coronary heart disease. The analogues studied were d-thyroxine, 3:5:3′:5′-tetraiodothyroformic acid, 3:5:3′:5′-tetraiodothyronamine, 3:5:3′-triiodo-l-thyronine, 3:5:3′-triiodo-d-thyronine, 3:5:3′-triiodothyroacetic acid, 3:5-diiodo-l-thyronine, 3:5-diiodo-d-thyronine and 3:5-diiodothyroacetic acid. 2. In both hypothyroid and euthyroid patients, most of these analogues reduced the serum cholesterol without necessarily elevating the basal metabolic rate (b.m.r.). Nevertheless, in euthyroid patients with coronary heart disease several produced angina in the absence of any change in b.m.r. and this has been regarded as a sign of increased myocardial metabolism insufficient to be reflected in the overall measure of b.m.r. of all tissues. The possible differential effect of these analogues on the oxygen requirements of various tissues is discussed. 3. Although it has been possible to maintain low cholesterol levels for periods up to 3 months during the administration of several of these analogues, the dose required for this purpose was often so close to the dose which provoked angina that most cannot be recommended for widespread administration for the reduction of the hypercholesterolaemia frequently found in patients who have coronary heart disease. d-Thyroxine may prove to be an exception and requires further clinical assessment.

The formation of thyroxine metabolites by Escherichia coli.

ABSTRACT A »wild« strain of Escherichia coli was incubated with labelled and non-labelled l-thyroxine. Chromatographic and electrophoretic studies demonstrated that several iodinated compounds were formed during incubation. One of the compounds seems fairly certainly to be tetra-iodothyroacetic acid (Tetrac, T A4), others may be tri-iodothyroacetic acid (Triac, TA3) and tetra-iodothyroformic acid (TFform4, Tetraform) but the identification of these substances requires further studies. An unknown compound stainable with diazotised sulphanilic acid and with a great mobility on chromatography was observed. The findings may have some bearing on the enterohepatic circulation of the thyroid hormones. The usefulness of microbial techniques in the elucidation of the tissue metabolism of thyroid hormones and in the preparation of thyroxine analogues is pointed out.

THYROXINE ANALOGUES AND CHOLESTEROL METABOLISM: THE RELATIVE EFFECTS OF VARIOUS THYROXINE DERIVATIVES ON GROWTH, OXYGEN CONSUMPTION AND TISSUE CHOLESTEROL CONCENTRATIONS IN THE RAT

A number of thyroxinc analogues have been tested for their relative effects on tissue cholesterol concentrations, oxygen consumption, and growth in the hypercholesterolemic rat. Of the compounds studied, diiodothyroacetic (Diac) and diiodothyroformic acid (T2 FA) appear to have the greatest effect in reducing tissue cholesterol concentrations without affecting growth or basal metabolism. Other derivatives such as tri- and tetraiodothyroacetic acids, triiodothyropropionic acid and tetraiodothyroformic acid have been shown by others to exert some preferential effect on tissue cholesterol concentrations. However, when compared on an equal molar basis in the present study, these compounds were not nearly as effective as Diac and T2 FA in lowering cholesterol levels.

Effect of tetraiodothyroformic acid on oxygen consumption of the cholesterol-thiouracil-fed rat.

The formic acid analogue of thyroxine, tetraiodothyroformic acid, was found to have 0.086% the goiter inhibiting activity of l-thyroxine in the thiouracil-cholesterol-fed rat. With regard to oxygen consumption its activity was 0.084% that of l-thyroxine. In amounts having equal effect on thyroid weight and oxygen consumption, tetraiodothyroformic acid resulted in significantly lower mean liver cholesterol.

Thyroxinelike compounds and cholesterol metabolism: differences in the effects of thyroxine, triiodothyronine and their formic acid analogues.

The biologic activity of l–thyroxine, l–triiodothyronine, and their formic acid analogues, tetraiodothyroformic acid and triiodothyroformic acid have been studied in the rat. By thiouracil-goitre inhibition assay they were found to have the following relative activities (on a molar basis): l-thjToxine, 100%; l–triiodothyronine, 333%; tetraiodothyroformic acid, 0.08% and triiodothyro-formic acid 0.27%. In addition to this quantitative difference, the physiologic activity of tetra-iodothyroformic acid was also found to differ in other respects from that of l–thyroxine. When administered in amounts having equal goitre inhibiting ac-tivity, the formic acid analogue exerted significantly greater effect on cholesterol metabolism than didl–thyroxine. As compared to l–thyroxine, tetraiodothyro-formic acid also exerted relatively greater effect on cholesterol metabolism than on growth.