Metabolism of /sup 35/S- and /sup 14/C-labeled 1-methyl-2-mercaptoimidazole in vitro and in vivo
We previously described an in vitro incubation system for studying the mechanism of inhibition of thyroid peroxidase (TPO)-catalyzed iodination by the antithyroid drug 1-methyl-2-mercaptoimidazole (MMI). Inhibition of iodination in this system may be reversible or irreversible, depending on the relative concentrations of iodide and MMI and on the TPO concentration. Metabolism of the drug occurs under both conditions, and in the present investigation we used 35S- and 14C-labeled MMI together with reverse phase HPLC to examine the metabolic products associated with reversible and irreversible inhibition of iodination by MMI. Under conditions of reversible inhibition, MMI was rapidly metabolized and disappeared completely from the incubation mixture. With (35S)MMI, the earliest detectable 35S-labeled product was MMI disulfide, which reached a peak after a few minutes and then declined to undetectable levels. Coincident with the decrease in disulfide was the appearance of two 35S peaks, the major one corresponding to sulfate/sulfite, and the other to a component eluting at 7.5 min. Similar results were obtained for the disulfide and for the 7.5 min metabolite with (14C)MMI. The major 14C-labeled metabolite containing no S appeared to be 1-methylimidazole. Under conditions of irreversible inhibition, MMI disulfide was also the earliest detectable 35S-labeled metabolite. However, MMI decreased more slowly, and after reaching a nadir at about 6 min returned gradually to a level about halfway between the initial and the minimum value. The reformation of MMI appeared to involve the nonenzymatic disproportionation of MMI disulfide. Formation of the 7.5 min peak was also observed, but there was no formation of sulfate/sulfite.
- Research Organization:
- Univ. of Texas Southwestern Medical Center, Dallas (USA)
- OSTI ID:
- 6568957
- Journal Information:
- Endocrinology; (United States), Vol. 124:1
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
IMIDAZOLES
METABOLISM
CARBON 14 COMPOUNDS
DISULFIDES
IN VITRO
IN VIVO
IODIDES
IODINATION
LIQUID COLUMN CHROMATOGRAPHY
METABOLITES
RATS
SULFUR 35
TRACER TECHNIQUES
TYROSINE
AMINO ACIDS
ANIMALS
AZOLES
BETA DECAY RADIOISOTOPES
BETA-MINUS DECAY RADIOISOTOPES
CARBOXYLIC ACIDS
CHEMICAL REACTIONS
CHROMATOGRAPHY
DAYS LIVING RADIOISOTOPES
EVEN-ODD NUCLEI
HALIDES
HALOGEN COMPOUNDS
HALOGENATION
HETEROCYCLIC COMPOUNDS
HYDROXY ACIDS
IODINE COMPOUNDS
ISOTOPE APPLICATIONS
ISOTOPES
LABELLED COMPOUNDS
LIGHT NUCLEI
MAMMALS
NUCLEI
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANIC SULFUR COMPOUNDS
RADIOISOTOPES
RODENTS
SEPARATION PROCESSES
SULFUR ISOTOPES
VERTEBRATES
550501* - Metabolism- Tracer Techniques