Effects of slimming and composition of diets on VO2 and thyroid hormones in healthy subjects.

Oxygen consumption and plasma thyroid hormone concentrations are modified by both low- and high-calorie diets. It has been suggested that the trigger may be changes in weight ("adipostatic" hypothesis involving the difference between the actual weight and the "set point") or changes in amount of carbohydrate in the diet ("carbohydrate" hypothesis). Two experiments were performed in order to test both hypotheses. Fourteen young healthy volunteers were studied: 1) at their spontaneous stable weight; 2) while losing weight rapidly on a calorically restricted diet; 3) and then at their stable new weight when consuming a refeeding diet. The calorie restricted diet resulted in decrease of VO2, and T3, and an increase of rT3; the refeeding diet resulted in values of VO2, T3, and rT3 intermediate between those of the spontaneous diet and those of the restricted diet. Another group of nine subjects were studied at their spontaneous caloric and proteic levels, comparing a diet containing only protein and carbohydrate with a diet containing only protein and fat. During the low carbohydrate diet rT3 increased and T3 decreased but they remained unchanged during the carbohydrate-rich diet. Thus neither the adipostatic hypothesis nor the carbohydrate hypothesis is sufficient alone to explain the observed changes in serum T3 and rT3.

Changes in thyroid hormone and thyrotrophin in the serum and thyroid glands of developing genetically obese male and female Zucker rats.

In a first experiment, serum thyroxine (T4), 3,5,3'-triiodothyronine (T3) and thyrotrophin (TSH) concentrations as well as thyroid gland T4 and T3 contents were measured in developing lean and obese Zucker male and female rats of 4-16 weeks of age. The rats were bred in our laboratory and always treated in sex-matched pairs of one lean and one obese rat from the same litter. Serum T4 was not different in any phenotype/sex group at 4 weeks. In male rats, it became progressively lower (27 and 37% at 12 and 16 weeks respectively) in obese than in lean rats. In females, similar levels of serum T4 were maintained in both obese and lean developing rats. Serum T3 was similar in obese and lean male 4-week-old rats whereas it was lower (28%) in obese than in lean females. It became progressively lower (39 and 49% at 12 and 16 weeks respectively) in obese than in lean developing male rats. In females, lower levels of serum T3 were maintained (25 and 43% at 12 and 16 weeks respectively) in obese than in lean rats. Serum TSH was not different in any phenotype/sex group at 4 weeks. It rose in both obese and lean male rats with age, but became progressively lower (33 and 23% at 12 and 16 weeks respectively) in obese compared with lean rats. In females, similar levels of serum TSH were maintained in both obese and lean developing rats. Thyroid gland weight was not different in any phenotype/sex group at 4 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of iodotyrosines, thyronines, iodothyroacetic acids and thyromimetic analogues on in vitro copper-induced oxidation of low-density lipoproteins.

We studied the effect of different thyroid compounds [(I2, monoiodo-L-tyrosine (MIT), diiodo-L-tyrosine (DIT), L-thyronine (T0), 3,5-diiodo-L-thyronine (T2), 3,5,3'-triiodo-L-thyronine (T3), 3,3',5'-triiodo-L-thyronine (rT3), 3,5,3',5'-tetraiodo-L-thyronine (T4), 3,5-diiodothyroacetic acid (TA2), 3,5,3'-triiodothyroacetic acid (TA3) and 3,5,3',5'-tetraiodothyroacetic acid (TA4)] or thyromimetics [(3,5-dimethyl-3'-isopropyl-L-thyronine (DIMIT) and 3,5-diiodo-3'-isopropyl-thyroacetic acid (IpTA2)] on in vitro copper-induced oxidation of low-density lipoproteins (LDL). Human native LDL (0.05 g protein/L) oxidation was induced by 2.5 micromol/L of CuCl2. Conjugated dienes were measured spectrophotometrically for up to 10 hr. The length of the lag phase (Tlag), maximum velocity of the reaction (Vmax) and the maximum amount of generated dienes were obtained from kinetic data. T3 increased Tlag and decreased Vmax with a dependence upon concentration (0 to 3 micromol/L). There was no difference between the Dmax obtained with Cu2+ alone or in the presence of the various compounds (1 micromol/L). I2, MIT and DIT did not modify any parameter of the oxidation kinetic. T0 and T2 had the same antioxidant efficiency as T3, whereas T4 only decreased Vmax. rT3 increased Tlag less than did T3, whereas DIMIT was the thyronine that had the most important effect. TA2 and TA, were the most efficient antioxidant compounds. TA4 decreased Tlag less than TA3 did, whereas IpTA2 had an effect weaker than that of the physiological acetic derivatives. The data suggest that thyroid hormones and derivatives have LDL-antioxidant properties, their importance being related to their 4'-hydroxy diphenyl ether structure and depending upon the nature and the position of substituents in this structure.

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.

Influence of prolonged fasting on thyroid hormone modulation of lipolysis in isolated epididymal adipocytes of Wistar rats.

Male Wistar rats, 3 weeks old, were thyroidectomized surgically, kept for 1 month at 25 degrees C and then fasted for 3 days, with or without daily intraperitoneal injection of 3,5,3'-triiodo-L-thyronine (4.6 nmol T3/100 g body weight). Age-matched fed euthyroid rats were used as controls. All the experiments were carried out using isolated epididymal adipocytes. Basal lipolysis was higher during fasting in euthyroid or T3-treated adipocytes than in hypothyroid adipocytes. Adipocytes of fed hypothyroid rats were quite unresponsive to theophylline alone or combined with adrenaline or isoproterenol, whereas lipolysis was stimulated by these drugs in euthyroid or T3-treated adipocytes. Such a stimulated lipolysis was increased partially by fasting in hypothyroid adipocytes and was restored to a euthyroid level in T3-treated adipocytes. Lipolysis was more stimulated by adenosine deaminase in fasted euthyroid adipocytes than in fed ones. Hypothyroid and T3-treated adipocytes were unresponsive to adenosine deaminase except in fasted T3-treated rats. In these adipocytes, lipolysis was activated by the combination of adenosine deaminase plus theophylline. Finally, lipolysis was inhibited strongly in hypothyroidism while it was activated weakly by fasting. Lipolysis was inhibited slightly in fasted hypothyroid rats and thyroid hormone restored lipolysis. The findings are discussed in terms of the dual regulation of lipolysis by fasting and thyroid hormones.

Influence of prolonged fasting and thyroid hormone on the alpha 2-adrenergic response in isolated epididymal adipocytes of Wistar rats.

Fasting and thyroid hormone have been reported to modulate the beta-adrenergic pathway of lipolysis in rat, but their effects on the alpha 2-adrenergic response are not well known. The purpose of the present study was to investigate this point. Male Wistar rats, 3 weeks old, were thyroidectomized surgically, kept for 1 month at 25 degrees C and then fasted or not fasted for 3 days with or without daily intraperitoneal injection of 3,5,3'-tri-iodo-L-thyronine (T3; 4.6 nmol/100 g body weight). Age-matched, sham-operated, fed and fasted euthyroid rats were used as controls. The experiments were carried out using isolated epididymal adipocytes. The alpha 2-adrenergic agonist UK 14304 (UK) inhibited the stimulated lipolysis more in fed than in fasted euthyroid rats whereas it had no effect in hypothyroid or T3-treated hypothyroid rats. The alpha 2-adrenergic antagonist idazoxan reversed the antilipolytic effect of UK more in fasted than in fed euthyroid rats. The alpha 2-adrenergic antagonist RX 821002 (RX) did so, but at lower concentrations than those of idazoxan. Idazoxan slightly increased the glycerol release in hypothyroid and especially T3-treated hypothyroid rats. RX had practically no effect on the production of glycerol in these animals. The findings suggest that (a) fasting and probably hypothyroidism decrease the alpha 2-adrenergic response in adipocytes from rats, (b) T3 treatment of hypothyroid rats has no effect on the alpha 2 response, and (c) thyroid hormone does not directly modulate the alpha 2-adrenergic response in rat adipocytes.

Evaluation of the effect of furosemide on ultrafilterable platinum kinetics in patients treated with cis-diamminedichloroplatinum.

It has been reported that furosemide can prevent platinum nephrotoxicity by dilution of the toxic drug in the tubule or by another unknown mechanism. To evaluate its influence on ultrafilterable platinum pharmacokinetics, we undertook a randomized prospective trial of cis-diamminedichloroplatinum (CDDP) (80 mg/m2 by a 20-min infusion) administered to 20 patients with hydration-induced diuresis. Ten patients received 20 mg/m2 furosemide 1 h before CDDP administration, and 10 patients received no diuretic drug. Plasma and urinary pharmacokinetics of platinum and creatinine were compared in both groups of patients. Plasma total and ultrafilterable platinum was always higher in the furosemide group. However, protein binding, urinary concentrations, cumulative urinary excretion, renal clearance and creatinine clearance/renal clearance ratio (fractional clearance) were not statistically different. Moreover, the fractional clearance was successively lower, equal and higher than one in both groups. These results suggest that: (1) furosemide probably causes water depletion leading to a rise in plasma concentrations; (2) its protection by a pharmacokinetic interaction is doubtful, since all other parameters (especially urinary parameters) are not significantly modified; (3) renal clearance and fractional clearance suggest a bidirectional transport of platinum in the tubule not influenced by the diuretic drug.

Influence of hydration on ultrafilterable platinum kinetics and kidney function in patients treated with cis-diamminedichloroplatinum(II).

It has been reported that hypertonic saline provides protection against the renal toxicity of cisplatin (CDDP). We therefore evaluated its influence on the plasma and urinary pharmacokinetics of ultrafilterable platinum and kidney function as estimated by creatinine, inulin and PAH clearance. We undertook a randomized trial including two groups of ten patients receiving 100 mg/m2 CDDP in isotonic (group 1) or hypertonic saline (group 2) by a 20-min infusion. The hydration consisted of dextrose in group 1 and isotonic saline in group 2. Maximal concentration (Cmax), protein binding and cumulative urinary excretion were significantly higher in the dextrose group. Urinary flow decreased in this group but not in the other one. Inulin clearance was higher in the dextrose group than in the saline group and P-aminohippuric acid (PAH) clearance was not significantly different in these groups of patients. Hyponatremia was observed in the dextrose group. These results suggest that hypertonic saline infusion and saline hydration may enhance the diffusion of CDDP into tissues, lowering Cmax and renal excretion of platinum. The reduction of protein binding may indicate a diminution of aquation of CDDP in plasma. Our results suggest that the infusion of CDDP in hypertonic saline with salt hydration could exert a protective effect on the kidney. Moreover, there is a lessening of the risk of cellular hyperhydration. However, the better influence of dextrose hydration on glomerular filtration leads us to recommend a combination of the two methods of hydration for better tolerance and efficacy.

[Effects of methylcyclopentadienyl manganese tricarbonyl (MMT) of rat liver mitochondria. I. Effects, in vitro, on the oxidative phosphorylation (author's transl)]. / Action du manganese methylcyclopentadienyle tricarbonyle (MMT) sur les mitochondries I. Effets du MMT, in vitro, sur la phosphorylation oxydative des mitochondries hepatiques de rats

Methylcyclopentadienyl manganese tricarbonyl (MMT) is an effective inhibitor of mitochondrial respiration associated with NAD+-linked substrates. At concentrations which inhibit glutamate-malate oxidation (over 80% inhibition) succinate and tetramethylphenylenediamine (TMPD)-ascorbate are inhibited less than 25%. MMT inhibits both electron and energy transfer in mitochondria as revealed by the partial release of MMT inhibition by 2,4-dinitrophenol (DNP). The data indicated that the effects of MMT are supported by energy conservation at site I of the respiratory chain.

[Effects of methylcyclopentadienyl manganese tricarbonyl (MMT) on rat liver mitochondria. II. Activity-structure relation (author's transl)]. / Action du manganese methylcyclopentadienyle tricarbonyle (MMT) sur les mitochondries. II. Relation activite-structure.

The action of various manganese organic compounds, which are structural analogs of methylcyclopentadienyl manganese tricarbonyl (MMT), was investigated. Only the cyclopentadienyl manganese tricarbonyl compounds are effective inhibitors of mitochondrial respiration, but only when associated with NAD+-linked substrates. The manganese tricarbonyl group is required for this mitochondrial respiration inhibition. The substitutions operated on the cyclopentadienyl cycle also interfere and increase the inhibitory effect. Meanwhile, the benzoyl and thenoyl groups are more effective than the methyl group. The effects of the various compounds result from their special electronic configuration.

Dopamine and norepinephrine turnover in various regions of the rat brain after chronic manganese chloride administration.

Rats were treated with MnCl2 X 4H2O (1 mg/100 g/day, i.p.) for a period of 4 months. The turnover of dopamine (DA) and norepinephrine (NE) was measured in several brain regions (brain stem, hypothalamus, corpus striatum and "rest of the brain") by the decay in endogenous DA and NE after inhibition of tyrosine hydroxylase by alpha-methylparatyrosine. Monoamine oxidase (MAO) activity and manganese levels were also estimated. Manganese treatment produced a decrease in DA level and turnover in the corpus striatum but not in the rest of the brain. An increase in contents of NE was observed both in the brain stem and hypothalamus. NE turnover was found to be increased in the brain stem, decreased in the hypothalamus and unaltered in the rest of the brain. MAO activity was not significantly altered in all the brain regions studied. These results which show that chronic administration of manganese may cause regionally different changes in catecholamine turnover were discussed in relation to the accumulation of manganese in the brain regions and to other metabolic changes associated with manganese toxicity.

Serum concentrations of total and free thyroid hormones in moderately obese women during a six-week slimming cure.

Successive determinations of serum total (T4) and free (FT4) thyroxine, total (T3) and free (FT3) 3,5,3'-triiodothyronine and total 3,3',5'-triiodothyronine (rT3) concentrations were performed by radioimmunoassay in 17 moderately obese women during a 6-week slimming cure. The 2.09 MJ/d (500 kcal/d) diet (50 per cent protein, 25 per cent carbohydrate and 25 per cent lipid) was given as three daily meals of general foods. During the cure, the body mass index (BMI) decreased by about 10 per cent, with a gradual decrease in the rate of weight loss. Moreover, the patients with the highest basal overweight had the largest subsequent weight loss. A decrease of about 15 per cent in serum T4 was observed from the second week to the end of the diet period. Inversely, serum FT4 increased transiently on day 3, then returned to the baseline. The fall in serum T3 and FT3 was obvious on day 3 and an approximate 20 per cent decrease in the two hormonal forms remained from the second to the last week of diet. Serum rT3 increased by 30 per cent during the first week, then returned to the baseline on the third week. The largest decreases in serum T4, T3 and FT3 observed during the cure occurred in the patients with the highest corresponding basal values. These findings suggest that (i) the rapid changes of the serum thyroid hormone concentrations observed during the slimming cure may be an adaptive mechanism against a further weight loss, and (ii) these changes would be related to the initial state of the thyroid hormone metabolism.

Influence of frusemide on cis-dichlorodiammineplatinum (II) pharmaco-kinetics.

Cis-dichlorodiammineplatinum (CDDP) pharmacokinetics were evaluated in eighteen patients with cancer who received 80 mg/m2 CDDP as a 20 min infusion. One hour before, 10 of them had 20 mg/m2 frusemide. Fifteen blood samples and fifteen urine samples were collected over the 5 hours following the infusion of CDDP. Platinum was assayed by flameless atomic absorption. The data did not detect any difference between patients with or without frusemide for the following platinum parameters: plasma concentration, urinary concentration, cumulative urinary excretion, renal clearance. These results suggest that frusemide has no influence upon cisplatin (CDDP) pharmacokinetics and if it protects the kidneys, it is not via kinetic modifications.

Measurement of thyroid hormone in the rat thyroid gland by radioimmunoassay.

The present paper describes (i) a hydrolysis technique with Pronase and leucine aminopeptidase using one rat thyroid gland, resulting in maximum release of thyroid hormones and minimum deiodination, and (ii) a simple and rapid procedure for thyroid hormone radioimmunoassays in thyroid hydrolysates using commercial kits intended for serum thyroid hormone determinations. The procedure is used to determine T4, T3, and rT3 concentrations and hormonal molar ratios in a thyroid gland from a male Wistar rat. The reliability of the method is also studied.