Studies on the mechanism of inhibition of thyroid function by lithium.

Abstract

The effect of dietary lithium on the rate of thyroglobulin degradation was investigated using both in vivo and in vitro experimental models. The in vivo experiments utilized a modification of the double isotopic method of estimation of protein turnover (Arias, I.M., Doyle, D and Schminke, R.T. (1969) J. Biol. Chem. 244, 3303–3315) injecting isotopes of iodine, 131 I and 125 I, to label thyroglobulin 27 h and 3 h respectively before killing. Faster rates of thyroglobulin hydrolysis were associated with lower activity of 131 I as compared to 125 I and thus resulted in higher 125 I/ 131 I isotopic ratios in thyroglobulin. The isotopic ratio in the 1000 × g supernatant fraction of thyroid gland homogenate closely approximated the isotopic ratio in the isolated thyroglobulin and was used as an estimate of the rate of thyroglobulin degradation. Treatment with lithium had no direct effect on the rate of thyroglobulin degradation. The only exception was observed in states of extreme iodine deficiency, presumably through suppression of thyrotropin release by the pituitary. Experiments in vitro were carried out by labeling of the thyroglobulin pool in vivo with an injection of 131 I and subsequent culture of the isolated glands for 6 h in vitro under conditions where deiodination of iodotyrosines was prevented (Bagchi, N., Brown, T.R., Shivers, B. and Mack, R.E. (1977) Endocrinology 100, 1002–1008). The rate of thyroglobulin degradation, as measured by the percent 131 I released as iodotyrosines and iodothyronines, was not altered by lithium administration. However, lithium-treated animals demonstrated a marked decrease in the rate of release of 131 I-iodothyronines. The effect of lithium on thyroglobulin iodination was investigated in parallel in vivo experiments. Lithium administration resulted in a decreased content of iodothyronines and a lower moniodotyrosine/diiodotyrosine ratio. These studies suggest that lithium acts primarily by inhibition of the coupling of iodotyrosines and has no direct effect on thyroglobulin degradation. Hydrolysis of such iodothyronine-poor thyroglobulin would account for the observed decreases of hormonal release from the gland.