Metabolism of /sup 35/S- and /sup 14/C-labeled propylthiouracil in a model in vitro system containing thyroid peroxidase
In previous communications we described an in vitro model system containing highly purified thyroid peroxidase (TPO) for studying the mechanism of inhibition of thyroid hormone biosynthesis by the antithyroid drugs, 6-propylthiouracil (PTU) and 1-methyl-2-mercaptoimidazole (MMI). We showed that inhibition of iodination of thyroglobulin in this system may be reversible or irreversible depending on the relative concentrations of iodide and drug and the TPO concentration. Metabolism of the drugs occurred under both conditions, but was more limited under irreversible conditions of inhibition. It was of interest to examine the nature of the drug metabolites associated with reversible and irreversible conditions of inhibition. For this purpose we have employed the 35S- and 14C-labeled drugs and a recently developed reverse phase HPLC procedure. Results of a similar study with MMI were reported in an earlier communication. In the present study we report our findings with PTU. Under conditions of reversible inhibition, PTU was readily metabolized and by 15 min was reduced to a few percent of the starting value. The earliest detectable metabolite with both (35S)- and (14C)PTU was the disulfide, which reached a peak in about 15 min and then slowly declined. Coincident with the decline in the disulfide was the appearance of more polar metabolites. In the case of (35S)PTU, these corresponded to sulfate/sulfite, PTU sulfonate, and a product tentatively identified as PTU sulfinate. The latter two were also observed as 14C-labeled metabolites produced from (14C)PTU. Two nonpolar desulfurated 14C-labeled metabolites were also observed. Surprisingly, these did not correspond to either propyluracil or propyldeoxyuracil, the anticipated most likely products of PTU desulfuration. The identity of these desulfurated metabolites of PTU in the TPO model system remains to be determined.
- Research Organization:
- Univ. of Texas Southwestern Medical Center, Dallas (USA)
- OSTI ID:
- 5879000
- Journal Information:
- Endocrinology; (United States), Vol. 124:6
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
PEROXIDASES
ENZYME ACTIVITY
THIOURACIL
METABOLISM
THYROGLOBULIN
BIOSYNTHESIS
CARBON 14 COMPOUNDS
INHIBITION
ISOTOPE DILUTION
LIQUID COLUMN CHROMATOGRAPHY
METABOLITES
RATS
SULFUR 35
THYROID
ANIMALS
ANTIMETABOLITES
ANTITHYROID DRUGS
AZINES
BETA DECAY RADIOISOTOPES
BETA-MINUS DECAY RADIOISOTOPES
BODY
CHROMATOGRAPHY
DAYS LIVING RADIOISOTOPES
DRUGS
ENDOCRINE GLANDS
ENZYMES
EVEN-ODD NUCLEI
GLANDS
GLOBULINS
HETEROCYCLIC COMPOUNDS
HORMONE ANTAGONISTS
HYDROXY COMPOUNDS
ISOTOPE APPLICATIONS
ISOTOPES
LABELLED COMPOUNDS
LIGHT NUCLEI
MAMMALS
NUCLEI
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANIC SULFUR COMPOUNDS
ORGANS
OXIDOREDUCTASES
PROTEINS
PYRIMIDINES
RADIOISOTOPES
RODENTS
SEPARATION PROCESSES
SULFUR ISOTOPES
SYNTHESIS
THIOLS
TRACER TECHNIQUES
URACILS
VERTEBRATES
550501* - Metabolism- Tracer Techniques