Influence of Dietary Iodine on Drug-induced Hypothyroidism in the Rat

Abstract

Several compounds of pharmaceutical importance from a variety of chemical families, for example chlorpromazine and clomipramine, have been found to form charge-transfer complexes with iodine. We have investigated the influence of dietary iodine on thyroid-gland dysfunction induced by clomipramine, chlorpromazine or 2-thiazoline-2-thiol. We suggest that iodine is partly diverted from its metabolic pathway by complexation with drugs, and so the urinary concentration of iodide is increased. Both chlorpromazine and clomipramine, at doses which do not inhibit thyroperoxidase, enhanced urinary iodine excretion when dietary iodine was restricted (3.944+/-0.96 microg/day for chlorpromazine-tested rats, 3.43+/-1.33 microg/day for clomipramine-tested rats, compared with 2.34+/-0.11 microg/day in control rats). Concurrently, these pharmaceutical compounds increased the level of free thyroid-stimulating hormone (TSH) in comparison with controls and induced histological modifications in, and enlargement of, the thyroid gland. We have demonstrated that drug-induced loss of iodine in the urine was associated with antithyroid action when iodine intake was limited.

Antithyroid Action of Tamoxifen in the Rat

“…The other countries have regions with mild-to-severe iodine deficiency. We came to the same conclusions for the action of T2T (antithyroid action by inhibition of thyroid peroxidase and formation of charge transfer complexes with molecular iodine) [5]. Thus, the antiestrogen TAM has potential thyroid toxicity.…”

“…The disturbances of thyroid metabolism induced by TAM were observed in our rats under all diets tested. On the other hand, it has been shown that molecules with strong electrodonor power towards molecular iodine but with no inhibitory action on thyroid peroxidase only exert antithyroid activity when exogenous sources of iodine are restricted, such as on the LID/KI diet or in the LID diet [5,6]. When dietary iodine is normal or elevated, the thyroid gland adapts, and when the diet is deficient in iodine, complexes do not form.…”

“…The technique described in a preceding publication [5] was based on the Sandell Kolthoff reaction [7], using a modified method described by Dunn et al [8]. In brief, urine was digested with chloric acid under mild conditions and iodine determined manually from its catalytic activity on the reduction of ceric ammonium sulfate in the presence of arsenious acid.…”

“…Since the majority of drugs exerting antithyroid activity act by inhibiting thyroid peroxidase, we investigated whether this molecule interfered with thyroid function, as there is evidence that TAM modifies various thyroid parameters [3,4]. The action of molecules inhibiting or altering the activity of thyroid peroxidase, the key enzyme in thyroid hormonogenesis, is not found to be markedly influenced by the iodine content of the diet [5]. A wide variety of substances have been found to exert an action on thyroid peroxidase.…”

“…It has also shown that the formation of these complexes disrupts thyroid metabolism by decreasing the availability of iodine in the gland. Alterations in thyroid metabolism only become apparent when supplies of iodine are limited, as we have shown with chlorpromazine (CPZ) and clomipramine (CMP) [5]. In the light of these observations, we were prompted to investigate the potential hypothyroid action of TAM, by comparing the response of thyroid glands of rats receiving different amounts of iodine in the diet and treated chronically with TAM.…”