Intrathyroidal iodine metabolism in the rat. The influence of diet and the administration of thyroid-stimulating hormone

1. Ratios of mono[¹³¹I]iodotyrosine and di[¹³¹I]iodotyrosine (R values) and the incorporation of ¹³¹I into iodothyronines have been estimated in rat thyroid glands from 30min. to 38hr. after the administration of [¹³¹I]iodide. 2. In rats receiving a powdered low-iodine diet the R values were close to unity and did not change with time after the administration of [¹³¹I]iodide. In rats receiving a commercial pellet diet the R values fell from a mean of 0·8 at 30min. after [¹³¹I]iodide administration to 0·49 at 38hr. 3. Administration of 0·5–2·0i.u. of thyroid-stimulating hormone before giving the injection of [¹³¹I]iodide caused a small diminution in the R value when the time between injecting [¹³¹I]iodide and killing the animal was 16hr. or more. 4. Iodothyronines represented a greater percentage of the total thyroid-gland radioactivity in the iodine-deficient animals than in animals fed on the pellet diet. Thyroid-stimulating hormone had little effect, if any, on the iodothyronine contents.     

Disturbance of thyroidal iodine metabolism in BB/W rat.

To investigate the thyroid function in Bio-Breeding Worcester (BB/W) rats, we have examined the iodine metabolism, serum TSH and thyroid hormone levels in 8- and 16-week-old BB/W and normal Wistar (W) rats. At 8 weeks of age, serum TSH levels were significantly higher in BB/W rats than in W rats, although there was no difference in the serum levels of free T3 and free T4. Furthermore, the thyroidal radioactive iodine incorporation at 48 h was significantly lower in BB/W rats, suggesting that they might have some defects in iodine organification. At 16 weeks of age, serum TSH levels were also significantly higher in BB/W rats than in W rats. Furthermore, serum TSH levels in 16-week-old BB/W rats were significantly higher than in 8-week-old BB/W rats. The thyroid weight was significantly greater in BB/W rats, probably due to the increased serum TSH. The thyroidal radioactive iodine uptake at 48 h and the iodine content in the thyroid homogenates were significantly lower in BB/W rats. These results suggest that BB/W rats have some defect in iodine metabolism resulting in impaired thyroid hormone synthesis.     

The metabolism of acetamidothiazoles in the rat. 2-Acetamido-4-chloromethylthiazole

2-Acetamido-4-chloromethylthiazole is metabolized in the rat to (2-acetamido-4-thiazolylmethyl)mercapturic acid and 2-acetamidothiazole-4-carboxylic acid. 2-Acetamido-4-methylthiomethylthiazole and the corresponding sulphoxide and sulphone are also produced as minor metabolites. The identification of the metabolites is described and their formation investigated. Quantitative results on the excretion of the metabolites labelled with (14)C are reported.     

The intracellular metabolism of iodine in carcinogenesis

Research from this laboratory and others have concluded that significant glandular atypia, and often neoplasia, occurs in the breast tissues of rodents and humans under conditions of iodine deprivation. These cellular changes caused by iodine deficiency are intensified, by aging, steroid hormones, and pituitary hormones. There has been controversy concerning the effect of iodine deficiency on stimulation and maintenance of cancer of the breast in rodents when the cancer is induced chemically or by transplantation. However, neither within this induced neoplastic framework nor with the dysplastic changes seen by deficiency alone have laboratory studies of thepathway of intracellular iodine been previously possible. The new research data addresses the question of whether organification occurs and whether iodine significantly affects the intracellular structures. An hypothesis will be presented that places the inorganic element, iodine, into association with receptor protein complexes that may be responsible for intracellular sex hormone activity. The relationship of this mechanism to carcinogenesis in breast tissue will be considered.     

The metabolism of cyclohexanecarboxylate in the rat.

In the rat, cyclohexanecarboxylate was metabolized and excreted (mostly in the urine) as hippurate, hexahydrohippurate, 3,4,5,6-tetrahydrohippurate and benzoyl and cyclohexylcarbonyl beta-glucuronides. The pattern of metabolism is dose-dependent. With decreasing dose a progressive increase in the conversion into hippurate occurred. This was largely at the expense of glucuronide formation, although the proportions of hexahydro- and tetrahydro-hippurate were also decreased. The observed formation of hexahydrohippurate and 3,4,5,5-tetrahydrohippurate substantiates the proposed mechanism of aromatization of cyclohexanecarboxylate. It appears that these compounds arise via glycine conjugation of active intermediates in the aromatization process. Hexahydrohippurate and 3,4,5,6-tetrahydrohippurate may occur in the urine of rats as new mitabolities of shikimate, dependent for their formation on microbial metabolism.     

The metabolism of shikimate in the rat.

In the rat, shikimate was metabolized and excreted as hippurate, hexahydrohippurate, 3,4,5,6-tetrahydrohippurate, t-3,t-4-dihydroxycyclohexane-r-1-carboxylate and c-3,t-4-dihydroxycyclophexane-r-1-carboxylate, conjugates of catechol and CO2. The metabolism was entirely dependent on various initial microbial transformations in the gut, metabolite formation being suppressed in animals pretreated with antibiotics. Shikimate was not metabolized by mammalian tissues, and products of microbial metabolism were excreted either unchanged or after further biotransformation in the animal tissues.     

The effect of Mn2+ on thyroid iodine metabolism in rats]

Injection into rats of manganous chloride (2 mg/100 g) showed, after a 24-hr period, a marked depression of thyroidal 131I uptake. There is a decrease in serum T3 and T4 levels and an increase in I- level. These results demonstrate that the action of manganous ions is to block uptake of I- by the thyroid.     

The metabolism of 4-methyl-2-oxopentanoate in rat pancreatic islets.

1. Radioactively labelled 4-methyl-2-oxopentanoate was taken up by isolated pancreatic islets in a concentration- and pH-dependent manner and led to the intracellular accumulation of labelled amino acid and to a decrease in the intracellular pH. Uptake of 4-methyl-2-oxopentanoate did not appear to be either electrogenic or Na+-dependent. The islet content of 2-oxo acid radioactivity was not affected by either 2-cyano-3-hydroxy-cinnamate (10mM) or pyruvate (10mM), although both these substances inhibited the oxidation of [U-14C]4-methyl-2-oxopentanoate by islet tissue. 2. 4-Methyl-2-oxopentanoate markedly stimulated islet-cell respiration, ketone-body formation and biosynthetic activity. The metabolism of endogenous nutrients by islets appeared to be little affected by the compound. 3. Studies with the 3H- and 14C-labelled substrate revealed that 4-methyl-2-oxopentanoate was incorporated by islets into CO2, water, acetoacetate, L-leucine and to a lesser extent into islet protein and lipid. Carbon atoms C-2, C-3 and C-4 of the acetoacetate produced were derived from the carbon skeleton of the 4-methyl-2-oxopentanoate, but the acetoacetate carboxy group was derived from the incorporation of CO2. These results, and consideration of the relative rates of 14CO2 and acetoacetate formation from 1-14C-labelled as opposed to U-14C-labelled 4-methyl-2-oxopentanoate, led to the conclusion that the pathway of catabolism of this 2-oxo acid in pancreatic islets is identical with that described in other tissues. The amination of 4-methyl-2-oxopentanoate by islets was attributed to the presence of a branched-chain amino acid aminotransferase (EC 2.6.1.42) activity in the tissue. Although glutamate dehydrogenase activity was demonstrated in islet tissue, the reductive amination of 2-oxoacids did not seem to be of importance in the formation of leucine from 4-methyl-2-oxopentanoate. 4. The results of experiments with respiratory inhibitors and uncouplers, and the finding that 14CO2 production and islet respiration were linked in a 1:1 stoicheiometry suggested that 4-methyl-2-oxopentanoate catabolism was coupled to mitochondrial oxidative phosphorylation. The catabolism of 4-methyl-2-oxopentanoate in islet tissue appeared to be regulated at the level of the initial 2-oxo acid dehydrogenase (EC 1.2.1.25) reaction.     

The effect of iodothyronines on the conversion of thyroxine into 3,3''-5-tri-iodothyronine in isolated rat renal tubules.

Isolated rat renal tubules prepared by collagenase digestion were used to study the effects of 3,3',5'-tri-iodothyronine ('reverse T3', rT3) and other iodothyronines on the formation of 3,3',5-tri-iodothyronine (T3) from thyroxine (T4). rT3 inhibited the conversion with a dose response over the concentration range 1.5nM-1.5microM. The inhibition was competitive in nature. Both 3,3'-di-iodothyronine and 3',5'-di-iodothyronine also inhibited the production of T3 and T4 in isolated rat renal tubules, but tetraiodothyroacetic acid and 3,5-di-iodothyronine were found to have no effect. These experiments demonstrate in an intact cell system that some naturally occurring iodothyronines have significant effects on T4 deiodination.     

The perinatal thyroid in iodine deficient regions: risks of radioiodines--hazards of stable iodine overload. A study in the newborn rat.

Administration of large quantities of stable iodine is an effective means of reducing the radiation burden on the thyroid in the event of a nuclear power-plant accident. Such administration may involve countries with low baseline dietary iodine intake. It is questioned whether stable iodine overload is safe, and in particular, what are its effects in newborn infants? Iodine-deficient newborn rats were submitted to a single acute administration of stable iodine (100 microg) on the second day of life. The effects on thyroid structure were studied, after 24 hr and after 7 days, using light microscopy. Compared to controls, the thyroids of animals submitted to stable iodine overload showed, 7 days after treatment, signs of acute toxicity including marked desquamation of epithelial cells and rupture of a large number of thyroid follicles. Our findings in iodine deficient newborn rats suggest that stable iodine overload may have side effects during perinatal life. This prophylactic measure should, therefore, be accompanied by follow-up of thyroid function. Thyroid hormones are critical for brain development, during the first period of life.