Mechanism of action of thioureylene antithyroid drugs in the rat: possible inactivation of thyroid peroxidase by propylthiouracil
It has been shown previously 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 /sup 131/I- in vivo or by incubation of excised thyroid lobes in a medium containing /sup 131/I-. 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 (/sup 35/S)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 (/sup 35/S)PTU and (/sup 35/S)MMI was also investigated. In contrast to the rapid disappearance of /sup 35/S from plasma, both drugs showed accumulation and retention of /sup 35/S 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.
- Research Organization:
- Univ. of Texas Health Science Center, Dallas
- OSTI ID:
- 5099056
- Journal Information:
- Endocrinology; (United States), Vol. 113:1
- Country of Publication:
- United States
- Language:
- English
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63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ANTITHYROID DRUGS
BIOLOGICAL EFFECTS
IODINE 131
RETENTION
LABELLED COMPOUNDS
PEROXIDASES
INACTIVATION
SULFUR 35
IN VIVO
RATS
THIOURACIL
THYROID
ANIMALS
ANTIMETABOLITES
AZINES
BETA DECAY RADIOISOTOPES
BETA-MINUS DECAY RADIOISOTOPES
BODY
CARBOXYLIC ACIDS
DAYS LIVING RADIOISOTOPES
DRUGS
ENDOCRINE GLANDS
ENZYMES
EVEN-ODD NUCLEI
GLANDS
HETEROCYCLIC ACIDS
HETEROCYCLIC COMPOUNDS
HORMONE ANTAGONISTS
HYDROXY COMPOUNDS
INTERMEDIATE MASS NUCLEI
IODINE ISOTOPES
ISOTOPES
LIGHT NUCLEI
MAMMALS
NUCLEI
ODD-EVEN NUCLEI
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANIC SULFUR COMPOUNDS
ORGANS
OXIDOREDUCTASES
PORPHYRINS
PYRIMIDINES
RADIOISOTOPES
RODENTS
SULFUR ISOTOPES
THIOLS
URACILS
VERTEBRATES
550201* - Biochemistry- Tracer Techniques
560172 - Radiation Effects- Nuclide Kinetics & Toxicology- Animals- (-1987)