TRIIODOTHYRONINE RECEPTORS AND NONTHYROIDAL DISEASES

We will continue to study the rat bearing the transplantable Walker 256 carcinoma (T) with decreased serum T4 and T3 but normal TSH as a model for patients with nonthyroidal disease who have decreased serum T3. We propose to determine whether the previously described decrease in hepatic nuclear T3 receptors reflects a specific or general change in nonhistone protein synthesis, whether other aspects of hepatic protein synthesis are altered in T rats and whether anterior pituitary nuclear T3 receptor and GH content are changed in these animals. We will characterize the dose-response curve for pituitary GH content in relation to the saturation of pituitary nuclear receptors. Hepatic nuclear T3 receptor forms will be characterized by means of a T3 photoaffinity probe and the t 1/2 of receptor will be determined. The response of the thyroid to endogenous TSH will also be measured. Additional studies will examine the influence of nonthyroidal disease on experimental thyrotoxicosis. Walker 256 carcinoma and experimental laparotomy will be used in rats with acute and chronic experimental thyrotoxicosis. Biological responses to T3 such as hepatic-glycerophosphate dehydrogenase and malic enzyme activity and pituitary GH content will be assessed. We propose to study further tumor products in serum from T rats and conditioned medium from cultured cloned Walker 256 carcinoma which decrease nuclear T3 receptor levels in cultured GC cells. Tumor product effects on receptor synthesis and turnover in GC cells, on receptor synthesis in relation to GC cell nonhistone protein synthesis, and on T3 action (receptor depletion, GH induction, growth, amino acid transport will be examined. Lastly, we will continue to study the interaction between 5,5'-diphenylhydantoin (DPH) and the thyroid hormone system. We will explore the possible use of DPH in experimental thyrotoxicosis and we will test the effect of DPH on the rate of growth and GH production of GC cell tumors transplanted subcutaneously in rats.