Peers 2sareRIE Sescan ath) fe cele December 1967 ADULT HYPERTHYROIDISM Our interest in the possibility that the thyroid hormone mightbe acting to stimulate protein biosynthesis, a process which utilizes energy rather than wastes it, first arose from observations in the nervous system, where the thyroid hormone plays an important role in maturation and development. Wehad been surprised to find that in adult man hyperthyroidism has no effect on the O, consumption of the brain (5). Actually, we should not have been surprised, for Gordon and Heming (6) had previously surveyed a variety of organs and found only three in which O, consumption was unaffected in hyperthyroidism, the brain, testis and spleen. It seemed to us to be more than coincidence that of these three, two, the brain and testis, have the unique characteristic of ‘having a respiratory quotient of approximately unity (7, 8). A respiratory quotient of unity indicates that the respiratory gas @ oxchance reflects mainly carbohydrate utilization. It appeared then that the thyroid hormone might havenoeffect on metabolic rate in tissues in which protein and/or lipid turnover were negligible compared to that of carbohydrate. On the other hand, in the immature brain undergoing growth and development, protein synthesis is markedly greater than in the mature brain. During this developmental period, Fazekas and co-workers (9) found that thyroxine does in fact stimulate cerebral consumption of O.; once maturation was achieved, the oxygen consumption of the brain no longer responded to thyroxine. It was observations such as these and many others which led us to study the action of thyroid hormones on protein biosynthesis. These investigations led to the finding that thyroxine and physiologically active analogues do indeed stimulate pro- tein synthesis, not only in vivo but also when added directly to cell-free prepara- tions in vitro (10-12). Inhibition of protein synthesis, and therefore also the effect of thyroxine on protein synthesis, by means of an agent which blocks protein synthesis, i.e., puromycin, results in an immediate SUF S101 * HRae aeaden ae Vatahbetoat meer2 or 1765 inhibition of the stimulation by thyroxine of O, consumption and restores the meta- bolic rate of hyperthyroid animals to the level of euthyroid controls (13). This result suggests that the effect of thyroid hormone on QO, consumption may well be secondary to its effect on protein biosynthesis. Indeed, the effect on biosynthesis of protein with its possible consequences on the cellular levels of many enzymes might well be the basic action responsible for many of the diverse physiological and bio- chemical manifestations of the action of thyroid hormones. The finding of an effect of thyroxine in vitro in cell-free systems from liver and other tissues has permitted studies of the chemical mechanism of the effect on protein biosynthesis. Our studies thus far clearly implicate the mitochondria in the mechanism of the effect. Thyroxine first interacts with the mitochondria to produce a soluble product or change in the soluble milieu, which in turn causes the ribosomes to increase their activity in protein synthesis (14, 15). We are currently investigating the nature and consequences of the thyroxine-mitochondrial interaction. There is no longer any question about whether thyroid hormones stimulate protein biosynthesis. There is, however, some controversy about the mechanism of the effect. The work of Tata and his associates (16) tends to implicate an action at the gene level resulting in the increased synthesis of messenger RNA, which in turn could result in increased protein synthesis. These studies were, however, carried out in vivo in thyroidectomized animals. Such chronically thyroid-deficient animals have low nuclear RNA polymeraseactivity, and thyroid replacement therapy raises the activity back toward normal. Is this increase a cause or a consequent of other actions of the thyroid hormone? Tata claims that the effect on the RNA polymerase activity is the earliest one he observes, but his assay system does not contain mitochondria. On the other hand, we have observed with our assay system,