Effect of 3,5,3′-Triiodothyronine-Induced Hyperthyroidism on Iodothyronine Metabolism in the Rat: Evidence for Tissue Differences in Metabolic Responses*

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Abstract
The effect was studied of T3[triiodothyronine]-induced hyperthyroidism on the outer ring (5'' or 3'') monodeiodination of T4 [thyroxine] (to T3) and 3'',5''-diiodothyronine [3'',5''-T2; to 3''-monoiodothyronine (3''-T1)] and on the inner ring (3 or 5) monodeiodination of 3,5-T2 (to 3-T1) by various rat tissues. Weight-matched pairs of male Sprague Dawley rats were given either saline or T3 (20 .mu.g/100 g BW [body weight] daily) i.p. for 3 days. The metabolism of the iodothyronines was studied on day 4 in homogenates of the tissues in the presence of 25 mM dithiothreitol. Hyperthyroidism was associated with a significant (P < 0.05) increase in T4 to T3 monodeiodinating activity in the liver (mean, 95%), kidney (mean, 60%) and heart (mean, 153%), but not in skeletal muscle, small intestine, spleen, testis, cerebral cortex, or cerebellum. The monodeiodinating activity converting 3'',5''-T2 to 3''-T1 was greatly increased (P < 0.05) in the heart (mean, 750%), spleen (mean, 462%) and skeletal muscle (mean, 167%), but not in liver, kidney, small intestine, testis, cerebral cortex, or cerebellum. In the case of liver and kidney, however, there was evidence of an activation of 3'',5''-T2 monodeiodinating activity, as suggested by a significant increase in the activity in the absence of added dithiothreitol. The monodeiodination of 3,5-T2 to 3-T1 increased significantly only in the cerebral cortex (mean, 525%) and liver (mean, 69%), and not in any other tissue. The time course of the above-mentioned changes in iodothyronine metabolism was studied in groups of rats (5 per group) given T3 (20 .mu.g 100 g BW-1 day-1) 6-72 h before death. Significant increases in 3'',5''-T2 (to 3''-T1) monodeiodination in the heart and 3,5-T2 (to 3-T1) monodeiodination in the cerebral cortex were evident within 6 h of T3 administration. Changes in T4 to T3 monodeiodinating activity in the kidney and liver, however, did not become statistically significant until 24 and 72 h, respectively. The various effects of T3 on the tissues became maximal between 48 and 72 h after the initiation of T3 treatment. Most tissues, including some that have been considered unresponsive to thyroid hormones, e.g., brain and spleen, demonstrate substantial metabolic changes after T3 administration. The tissue responses are variable in degree; in some instances, they are specific for the substrate and type of tissue. Differences in the degree of change in T4 and 3'',5''-T2 outer ring monodeiodinating activities of various tissues of the hyperthyroid rat suggest that either the monodeiodinases involved are distinct or that there are substantial differences in the factors that regulate monodeiodinations of different substrates.