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PubMed1982

Effects of iodide and propylthiouracil on the release of 3,5,3'-triiodothyronine and of cyclic adenosine 3',5'-monophosphate from perifused rat thyroids.

We have established a perifusion system using rat thyroid. With this system, we analyzed the effects of TSH, 3-isobutyl-1-methylxanthine (IBMX) and iodide on the release of T3 and of cAMP, paying special attention to the relation between the release of the two substances. During perifusion, which was continued for 7 h, T3 release increased progressively with time and in a dose-related manner when TSH was added at concentrations of 0.1-10 mU/ml. However, cAMP release was unappreciable even in the presence of 10 mU/ml TSH. The release of T3 and cAMP was markedly enhanced by 3 x 10(-4) M IBMX. When iodide was added, a marked increase in cAMP release was unexpectedly observed. However, a slight but significant suppression of TSH-stimulated T3 release was shown with 1 x 10(-3) M iodide. TSH-stimulated T3 release was almost completely inhibited by 1 x 10(-3) M 6-n-propyl-2-thiouracil, but such a complete inhibition did not occur with 2-mercapto-1-methylimidazole. The cAMP release stimulated by IBMX was not affected by 6-n-propyl-2-thiouracil, but that stimulated by iodide was effectively inhibited. The present studies indicate that TSH and IBMX enhance T3 release, but only IBMX increases cAMP release. Iodide also results in a marked increase in cAMP release but does not affect T3 release from unstimulated thyroid and inhibits T3 release from TSH-stimulated thyroid. We suggest that there is not necessarily any close correlation between T3 release and cAMP release into perifusates of the rat thyroid.

1-Methyl-3-isobutylxanthine↗
PubMed1983

Mechanism of action of thioureylene antithyroid drugs in the rat: possible inactivation of thyroid peroxidase by propylthiouracil.

We have previously shown that the thioureylene antithyroid drugs 6-propyl-2-thiouracil (PTU) and 1-methyl-2-mercaptoimidazole (MMI) can inactivate thyroid peroxidase (TPO) in a model iodination system containing relatively high concentrations of iodide. The purpose of the present study was to determine whether these drugs may also inactivate TPO in vivo in rats. Assays for total TPO activity after injection of PTU or MMI did not prove to be a valid approach. As TPO inactivation might be expected to result in a relatively prolonged inhibition of enzyme activity, most of our experiments involved measurement of the duration of the inhibitory effect of a single injection of drug. Young rats were injected with low doses of PTU or MMI, and the effect on thyroidal organic iodine formation was determined at intervals after injection, either by 1-h pulse labeling with 131I- in vivo or by incubation of excised thyroid lobes in a medium containing 131I-. Results of both types of experiment demonstrated that the inhibitory effect of a small dose of PTU (1 mumol/100 g BW) was still very marked 17-18 h after injection. Moreover, an inhibitory effect of this small dose of PTU on the metabolism of [35S]MMI could also be demonstrated. Administration of MMI to rats, on the other hand, did not show the prolonged inhibitory effect observed with PTU. This is most likely attributable to the much lower thyroidal uptake of MMI than of PTU in rats. Intrathyroidal metabolism of [35S]PTU and [35S]MMI was also investigated. In contrast to the rapid disappearance of 35S from plasma, both drugs showed accumulation and retention of 35S in the thyroid. However, we obtained no evidence that thyroidal accumulation of PTU or one of its metabolites could explain the prolonged inhibitory effect of this drug. It seemed more likely that this was attributable to TPO inactivation. The clinical implications of our findings are discussed with relation to the dosage schedule commonly employed in the treatment of Graves' disease with antithyroid drugs.

Animals↗
PubMed1989

Effects of propylthiouracil on the biliary clearance of thyroxine (T4) in rats: decreased excretion of 3,5,3'-triiodothyronine glucuronide and increased excretion of 3,3',5'-triiodothyronine glucuronide and T4 sulfate.

The liver metabolizes T4 by deiodination and conjugation to T4 glucuronide (T4G), but little information exists about the formation of T4 sulfate (T4S) in vivo. We have examined the excretion of T4G, T4S, T3 and rT3 glucuronide (T3G and rT3G) in bile, collected under pentobarbital anesthesia 0-8 h or 17-18 h after iv [125I]T4 injection to control and 6-propyl-2-thiouracil (PTU)-treated rats. Radioactivity in bile, plasma, feces, and urine was analyzed by Sephadex LH-20 chromatography and HPLC. PTU induced a 2-fold increase in the biliary excretion of total radioactivity (26.6% vs. 15.0% dose between 0-8 h; 2.0% vs. 1.0% dose between 17-18 h). Biliary metabolites, 17-18 h after T4 injection, in control vs. PTU rats amounted to (percent dose): T4G, 0.44 vs. 0.75; T3G, 0.19 vs. 0.07; rT3G, 0.02 vs. 0.15; and T4S, 0.06 vs. 0.32. Similar results were obtained for control rats when bile was collected between 7-8 h after iv T4. The excretion rate of T3G was lower and that of rT3G higher when bile was continuously collected for 8 h immediately after T4 administration, probably due to prolonged experimental stress. However, regardless of the period of bile collection, PTU induced a more than 24-fold decrease in the T3G/rT3G ratio and a 5-fold increase in T4S excretion. In the animals killed 18 h after T4 injection, PTU treatment increased plasma T4 retention by 50%, reduced urinary I- excretion by 74%, and increased fecal radioactivity by 47%. No conjugates were detected in feces, and the distribution of fecal T4:T3:rT3 was 70:18:2 in control and 68:7:6 in PTU-treated rats. The results indicate that 1) the glucuronidative clearance of T4 is not affected by PTU; 2) the T3G/rT3G ratio in bile is a sensitive indicator of type I deiodinase inhibition; 3) T4 undergoes significant sulfation in rats in vivo, and 4) biliary excretion of T4S is enhanced if its type I deiodination is inhibited.

Animals↗
PubMed1989

Ligand-induced inactivation of type I iodothyronine 5'-deiodinase: protection by propylthiouracil in vivo and reversibility in vitro.

The inactivation of the phenolic ring deiodinases by natural substrates and iodinated contrast agents such as iopanoic acid (IOP) is a principal mechanism regulating the peripheral metabolism of thyroid hormones. The present studies were designed to investigate the cellular and biochemical mechanisms mediating this effect on type I 5'-deiodinase (5'DI) in rat liver and kidney. We reasoned that if inactivation requires the direct interaction of ligand (e.g. IOP) with 5'DI, then this effect should be blocked by a prior injection of 6n-propyl-2-thiouracil (PTU), which binds to an essential sulfhydryl group at the enzyme's active site and inhibits catalytic cycling. Experiments were performed using liver and kidney microsomes prepared from male rats injected 2.5 or 6 h earlier with various combinations of PTU, IOP, and/or vehicle. In initial studies, conditions were defined whereby active 5'DI could be regenerated in vitro from PTU-injected animals. This involved the treatment of microsomes with 50 mM dithiothreitol, pH 7.0, before assay. After this reductive treatment, 5'DI activity in both liver and kidney microsomes from rats previously injected with PTU, or the combination of PTU followed 30 min later by IOP, was equivalent to that in vehicle-injected control animals, whereas activity was decreased 60% in microsomes from animals injected with only IOP. This demonstrates that PTU protects 5'DI against ligand-induced inactivation, suggesting that this process is initiated by substrate binding to the enzyme's active site. In other experiments, liver microsomes from IOP-injected animals were pretreated with 100 mM dithiothreitol, pH 9.0, then washed, and 5'DI activity was determined. Under these stringent reducing conditions, 5'DI activity was completely recovered in microsomes from rats injected with IOP 2.5 h earlier, but only partially recovered 6 h after the IOP injection. Thus, ligand-induced inactivation of 5'DI may involve initially a reversible oxidation of the enzyme, followed by its irreversible inactivation.

Animals↗