PANEL DISCUSSION ON HYPERTHYROIDISM 1766 which contains mitochondria, that tri- iodothyronine administration to animals stimulates protein biosynthesis within two hours, several hours earlier than the reported effect on the polymerase activity. Also, the in vitro effect of thyroxine on protein biosynthesis has been observed to occur independently of any effect on DNAdependent RNA synthesis and, in fact, in the absence of nuclei (17). The question obviously still remains to be resolved, but it is our present view that the primary effect of thyroxine is in the mitochondria, which in turn leads to increased protein synthesis, possibly also RNA synthesis, and eventually all the other consequences attributed to the hormone. DR. WERNER:Thereis a recent paper in Science in which kidneycells in tissue culture were exposed to '*I-thyroxine placed in the medium (18). The nucleus became labeled. Would this suggest that the hormone might be acting at the chromosomal or gene level? DR. SOKOLOFF: The studies to which you refer would at first glance appear to offer evidence of an effect at the gene level and to be in conflict with our finding in cell-free systems that thyroxine stimulates protein synthesis independently of any action at the gene level but secondarily to an interaction with mitochondria. In the tissue culture studies, one is dealing with intact cells. All the cellular organelles are present, and an effect on the nuclei could conceivably be secondary to effects elsewhere. Also, in the particular studies to which you are referring (18), the added thyroid hormone was labeled with radioactive iodine, and only the radioactivity was shown to be associated to a greater degree but not exclusively with the nucleus. It may have been only the iodine ora metabolite, not the hormoneitself, which was concentrated in the nucleus. At any rate, the results you refer to are certainly consistent with a possible action in the JULSi02 nucleus, but they can hardly be considered} more than suggestive at the present time.; DR. J. MAXWELL McKENZIE, Depart-; ment of Medicine, McGill University’ Medical School, Montreal: Dr. Werner,’ I would like to ask a question of Dr.” Sokoloff. Hyperthyroidism is classically a wasting 9 disease, and if you give too much thyroid hormoneto the experimental animal, there 3 is body wasting, including depletion of protein. How does this tie in with thyroxine 9 as a stimulator of protein synthesis? DR. SOKOLOFF: In growing or develop- § ing animals or tissues, thyroxine may actually accelerate growth and development (9, 16, 19, 20). In the fully grown adult,it is not possible to accumulate large amounts of protein. Protein is not stored like fat. Therefore, increased protein synthesis would probably result also in increased protein breakdown. Under such circum- stances, one can conceive of a cycle of increased protein synthesis and increased protein breakdown, resulting in an increased utilization of energy. I believe there is ample evidence in theliterature to indicate that increased caloric intake supplemented with adequate vitamins and minerals, particularly magnesium, results in a reduction or elimination of the negative nitrogen balance or the wasting effects associated with hyperthyroidism (21, 22). One might, perhaps, consider thyrotoxicosis as a disease characterized by an excessive or toxic stimulation of protein turnover, which results in an excessive rate of energy utilization to support this turnover. In the absence of a sufficiently increased caloric intake to meet the increased 4 energy demand, materials normally utilized § to maintain normal body structure and functions may then be drained to provide, 4 in a sense, fuel for the toxic protein turn- 4 over; wasting then ensues. Adequate ' dietary intake may prevent or minimize it It is also possible that the same mechanism “yal qe