Drug effects on triiodothyronine uptake by rat anterior pituitary cells in vitro

Summary

In nonthyroidal illness, numerous drugs such as glucocorticoids, dopamine, fenclofenac, furosemide and diphenylhydantoin may modify the close inverse-feedback relationship between circulating thyroid hormones and TSH. Such effects could involve altered hypothalamic TRH secretion, a direct effect on TSH production by the thyrotroph, alterations in circulating free thyroid hormone concentrations, or changes in thyroid hormone uptake by the thyrotroph. We therefore examined the effect of nonsteroidal antiinflammatory drugs (NSAID), diuretics, the synthetic flavonoid EMD 21388, and diphenylhydantoin, on [¹²⁵I]T₃ cellular uptake in rat pituitary primary cell cultures. Uptake of [¹²⁵I]T₃ (cell-associated counts of washed cells) was measured at 15 min after the addition of 50 pmol/L [¹²⁵I]T₃ in protein-free medium (37 ^°C, pH 7.4).

Uptake of [¹²⁵I]T₃ by pituitary cells was 6.0 ± 1.7% of total counts (mean ± SD, n = 18). Unlabeled T₃ (10 μmol/L) displaced 92% of total uptake. The IC₅₀ of unlabeled T₃ for the displacement of [¹²⁵I]T₃ was 1.2 μmol/ L. T₄ and rT₃ were approximately 10% as effective as T₃ itself in inhibiting [¹²⁵I]T₃ uptake, while triac did not affect cellular [¹²⁵I]T₃ uptake. Inhibition of [¹²⁵I]T₃ uptake at drug concentrations of 100 μmol/L was seen with the diuretics, furosemide (9%), bumetanide (14%), piretan-ide (12%) and ethacrynic acid (76%), the NSAID, meclo-fenamic acid (35%) and fenclofenac (52%), EMD 21388 (49%), and the anticonvulsant, diphenylhydantoin (23%). Aspirin, up to 500 μmol/L, had no effect on [¹²⁵I]T₃ uptake.

Our results indicate that ethacrynic acid, meclofen-amic acid, fenclofenac, EMD 21388 and diphenylhydantoin affect plasma membrane T₃ uptake in the pituitary. This potential influence on TSH release will be contrary to the previously-demonstrated direct inhibitory effect of these drugs on TSH release.

Key words

Drugs - T₃ uptake - anterior pituitary