DIPHENYLHYDANTOIN STIMULATES THE INTRAPITUITARY CONVERSION OF THYROXINE TO TRIIODOTHYRONINE IN THE RAT

Treatment of normal rats with diphenylhydantoin (DPH) decreases serum thyroxine (T4) and triiodothyronine (T3) levels without the anticipated rise in serum thyrotropin (TSH). The present work has studied the intrapituitary conversion of T4 to T3 in male Wistar rats, 200-250 g body weight (BW), treated with DPH 5 mg/100 g BW/day for 8 days. A tracer dose of 3',5'-[I-125]T4 (150 muCi) was injected intravenously, and 2 h later hypophyses were removed and homogenized individually at 4-degrees-C in ice-cold PBS buffer (pH 7.4). T4 and T3 were extracted in 400 mul n-butanol:2 N HCl (9:1) and chromatographed in tertiary amyl alcohol:hexane: 1 N ammonia (5:1:6). In 11 untreated control rats, [I-125]T3 generated from [I-125]T4 deiodination was 35 +/- 6% and intact [I-125]T4 was 49 +/- 9% of total chromatographic radioactivity. In 11 DPH-treated rats [I-125]T3 increased (p < 0.001) and [I-125]T4 decreased (p < 0.02). The DPH effect was blocked in rats treated for 2 days with iopanoic acid 10 mg/100 g BW, though blocking was not seen in rats treated with half the dose of iopanoic acid. In normal rats receiving supplemental doses of T4 (2 mug/100 g BW/day for 8 days), DPH similarly increased pituitary 5'-deiodination. Administration of propylthiouracil (PTU) to T4-supplemented rats had no effect on pituitary 5'-deiodination of T4, whereas the addition of DPH to PTU treatment increased [I-125]T3 production (p < 0.01). Serum T4 (p < 0.001) and T3 (p < 0.01) were decreased after DPH therapy, while serum and pituitary TSH were not altered. The DPH-stimulated deiodination of T4 to T3 may contribute to depress the feedback response of the pituitary gland to low serum thyroid hormone levels.