Effects of TSH on the adenylate cyclase-cAMP system and some parameters of intermediary metabolism were investigated in human thyroid carcinoma and adjacent normal thyroid tissue. Basal adenylate cyclase activity and cAMP concentrations were significantly higher in carcinomatous tissue. Basal [1-14C]glucose oxidation, 32Pi incorporation into phospholipids, and organification of iodide were similar in both tissues. Stimulation of cAMP by TSH was significantly greater in normal compared to carcinomatous tissue. In neither tissue was there a good correlation between TSH stimulation of adenylate cyclase activity and cAMP concentrations. The TSH stimulation of 32Pi incorporation into phospholipids by TSH was significantly greater in normal tissue. The mean effect of TSH on iodide organification and glucose oxidation was similar in normal and carcinomatous tissue. Although specific binding of TSH was demonstrated in both normal and carcinomatous tissue, it did not correlate very well with stimulation of adenylate cyclase activity. Hormones other than TSH also augmented adenylate cyclase activity in two of the carcinomas. In individual patients, the relative responsivity of carcinomatous tissue compared to normal was not always consistent when all of the metabolic parameters were considered.
A B S T R A C T Earlier studies indicated that initial exposure of thyroid slices to thyrotropin diminished responsiveness of the adenylate cyclase-cyclic AMP system, glucose oxidation, and 32Pi incorporation into phospholipids upon readdition of the hormone. The present studies demonstrate that slices from dog, beef, and human thyroid glands initially incubated with thyrotropin (TSH) were less responsive to subsequent addition of the hormone when organification of iodide was examined. Increasing the amount of TSH did not overcome the refractoriness induced by the initial exposure to the hormone. Furthermore, the stimulatory effects of dibutyryl cyclic AMP and prostagladin E1 were abolished in slices previously incubated with TSH. Development of such refractoriness did not depend upon new protein synthesis and was not abolished by 1 mM prophylthiouracil in the first incubation. Addition of 0.1 ,uM thyroxine or triiodothyronine or 1.5 ,M iodide during all three incubations did not modify the response to TSH, added for the first time in the third incubation. However, 1 mM iodide in the buffer during all three incubations inhibited the response to TSH during the third incubation. During the refractory period, effects of TSH on colloid droplet formation were also diminished. The in vivo effect of TSH on serum 1-triiodothyronine in rats was significantly reduced when the rats had been injected with TSH 8 h earlier. These studies demonstrate that TSH-induced refractoriness also includes effects on organification of iodine and secretion of thyroid hormone. The results cannot be adequately explained by unresponsiveness of adenylate cyclase because effects of dibutyryl cyclic AMP and prostagladin E1 were also inhibited by prior exposure to TSH.
Chicken eggs incubated under hatchery conditions for 19 days show significant decreases in the total content of water and organic nitrogen, but not of sodium or potassium. The hypothesis is discussed that the formation of gaseous nitrogen is responsible for the nitrogen loss.Metabolic production of elemental nitrogen by germfree mice and by man has been suggested by data obtained in our laboratory. We used a closed svstem that could be flushed practically free from preexisting N2 and in which atmospheric contamination was excluded with confidence (1-3). Attempts to further document the pathway using [15N]amino acids were unsuccessful mostly because of the technical difficulties involved.This problem, which has obvious implications vis-a-vis nutritional concepts on one side, and gas exchange theory and measurement on the other, has received recent attention from respiratory physiologists, who have reinvestigated the Lavoisier-Haldane postulate of equality between inspiratory and expiratory N2 (4-10). The most careful of these experiments (9) have found an excess of expiratory N2 of the order of 0.59-4.4 ml/min; this is a quantity nearly identical to the one reported by us with a totally different technique (3). Such amounts of N2 are sufficiently small to be negligible in the usual respiratory calculations, although not negligible from a metabolic standpoint. The volumes involved approach the limit of the sensitivity of the respiratory balance method; therefore, the authors could not decide whether the excess expiratory N2 represented metabolic production or persistent nitrogen washout.Clearly, definitive answers, obtained through a multitude of approaches, to this important problem are needed.The avian egg represents an actively metabolizing and differentiating system permeable to gases or vapors (11,12). It thus provides a technically simple model and a new approach. We have measured total "Kjeldahl" § nitrogen in groups of fertilized chicken eggs before incubation and 2 days before hatching, and have demonstrated significant nitrogen loss, associated with growth and maturation of the embryo. § The meaning of the term "Kjeldahl" nitrogen is well known and indicates the nitrogen measurable with the Kjeldahl method, i.e., that in protein, amino acids, urea, ammonia, nucleic acids, uric acid, and the like. Inorganic nitrogen such as nitrates, N2, and nitrogen oxides are not measured by the Kjeldahl method (13).The hypothesis that the loss of "organic" nitrogen is due to formation of N2, which then diffuses out of the egg, is discussed. METHOD AND MATERIALSFertilized eggs from chickens (Gallus domesticus) were selected at the hatchery from those laid within the previous 24 hr.The eggs were then randomlyF allocated to two groups of at least 60 each, numbered, and weighed. The control group was frozen and analyzed at once. The other group was incubated for 19 days in the hatchery, under supervision of the hatchery personnel. On the morning of the nineteenth day, most of the incubated eggs were removed from th...
A B S T R A C T Prior exposure ofthyroid slices to thyrotropin (TSH) induced refractoriness to subsequent stimulation of the cyclic AMP system by the hormone. Although the inhibition is incomplete, we examined whether the reduction in cyclic AMP was sufficient to alter other metabolic effects of TSH. Bovine or dog thyroid slices were incubated with or without 5-100 mU/ml TSH for 1-2h, washed, and then incubated without hormone for 1-2 h. Half of the slices not exposed to TSH initially were then incubated with buffer and half were exposed to 5-100 mU/ml TSH. Slices initially incubated with TSH were also incubated with or without TSH in the third incubation. During the refractory period, TSH activation of protein kinase was inhibited even though the hormone still caused some increase in cyclic AMP concentrations. However, protein kinase activity was fully responsive to dibutyryl cyclic AMP when slices were incubated with it during the third incubation. Stimulation of glucose oxidation by TSH was significantly decreased in thyroid slices previously incubated with the hormone. During refractoriness, stimulation of glucose oxidation caused by prostaglandin E1 and dibutyryl cyclic AMP was also significantly diminished but that due to acetylcholine was not. Thus even though dibutyryl cyclic AMP could fully activate protein kinase activity during refractoriness, its effect on glucose oxidation was still inhibited, suggesting that the metabolic block responsible for this refractoriness was distal to activation of protein kinase. Stimulation of 32P, incorporation into phospholipid by TSH and acetylcholine was Received for publication 23 August 1976 and in revised form 29 November 1976. also inhibited during refractoriness. Despite reduction of the stimulatory effect of TSH, binding of 125I1 TSH was not modified by prior incubation of thyroid slices with TSH. These results indicate that changes in the TSH receptor are not responsible for the development of refractoriness and other metabolic sites besides activation of adenylate cyclase appear to be involved.
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