A new class of propylthiouracil analogs: comparison of 5'-deiodinase inhibition and antithyroid activity.

After in vivo administration, propylthiouracil (PTU) inhibits not only thyroid iodide uptake and organification, but also T4 5'-deiodinase activity in most peripheral organs. The present report describes the effects of some previously untested 6-substituted 2-thiouracil derivatives on in vivo and in vitro iodide uptake and organification, and on T4 5'-deiodinase activity in liver and pituitary homogenates. When added to homogenates, many analogs were as potent or more potent than PTU in inhibiting hepatic T4 5'-deiodinase activity. Three derivatives, 6-anilino-2-thiouracil (A compound), 6-(p-ethylanilino)2-thiouracil (B compound), and 6-(p-n-butylanilino) 2-thiouracil (C compound), which were among the most potent inhibitors of hepatic T4 5'-deiodinase, when added in vitro inhibited T4 5'-deiodinase activity in liver homogenates after in vivo administration. When added to pituitary homogenates prepared from hypothyroid rats, these compounds also significantly inhibited pituitary T4 5'-deiodinase activity. In a concentration of 1 mM in the presence of 20 mM dithiothreitol, the percent inhibition of pituitary T4 5'-deiodinase activity was 19.7 +/- 7.4 (mean +/- SE), 34.0 +/- 3.2, 47.3 +/- 3.1, and 89.0 +/- 1.0 for PTU and the A, B, and C compounds, respectively (P less than 0.05 for all groups vs. one another and vehicle). Despite their ability to inhibit hepatic T4 5'-deiodinase activity, none of the 13 analogs tested altered thyroid iodide uptake or organification after administration of 0.1 mg/rat. PTU, in the same dose, inhibited thyroid iodide uptake by 78.2 +/- 2.4% (P less than 0.001) and thyroid iodide organification by 36.4 +/- 7.3% (P less than 0.01). Furthermore, the A, B, and C compounds did not inhibit thyroid iodide uptake or iodide organification when administered in higher doses of 5, 5, and 1 mg/rat, respectively. In contrast to these in vivo results, the A, B, and C compounds were more potent than PTU in inhibiting iodide organification in a purified thyroid peroxidase system and in porcine thyroid slices. The concentrations causing 50% inhibition of iodide organification in the purified thyroid peroxidase system were 30, 7, 8, and 14 microM for PTU and the A, B, and C compounds, respectively. However, PTU was far more potent in inhibiting iodide organification in intact incubated thyroid lobes compared to the A, B, and C compounds.(ABSTRACT TRUNCATED AT 400 WORDS)