The rat with transplantable Walker 256 carcinoma (T) with decreased serum T?4? and T?3? but normalserum TSH and liver alpha-glycerophosphate dehydrogenase (alpha-GPD) activity will be studied further as a model for patients with nonthyroidal disease with decreased serum T?3?. We intend to determine whether the described decrease in nuclear T?3? receptors reflects a specific or general change in nonhistone protein synthesis, whether other aspects of protein synthesis are altered in T rats, and whether pituitary nuclear T?3? receptors and growth hormone (GH) content are changed in these animals. We have recently defined the T?3? dose response curves for liver alpha-GPD, malic enzyme (ME), and pituitary GH to develop an in vitro model where tumor products may reproduce in cultured cells the effects observed in intact animal-bearing tumors. In this in vitro system, we have demonstrated that tumor products decrease the nuclear receptor levels of cultured GC cells and will now define the chemical nature of tumor products that affect nuclear T?3? receptor and thyroid hormone action. Initial studies suggest 5,5'-diphenylhydantoin (DPH) inhibits TSH secretion, decreases specific nuclear binding of T?3?, and increases hepatic ME and pituitary GH. We have now determined the dose-response relationship between T?3? and pituitary TSH and GH secretion in intact rats and cultured anterior pituitary cells. We have demonstrated that DPH causes a dose-dependent and reversible decrease in nuclear T3 receptor complexes and results in parallel changes in growth rate, GH in RNA and GH production. We will determine whether the above changes reflect new protein synthesis resulting from altered gene transcription. If so, we will determine whether DPH or analogues to be developed may be useful in the management of thyrotoxicosis. (C)
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