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Title: Metabolism of /sup 35/S- and /sup 14/C-labeled 1-methyl-2-mercaptoimidazole in vitro and in vivo

Abstract

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, MMImore » 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.« less

Authors:
; ;
Publication Date:
Research Org.:
Univ. of Texas Southwestern Medical Center, Dallas (USA)
OSTI Identifier:
6568957
Resource Type:
Journal Article
Journal Name:
Endocrinology; (United States)
Additional Journal Information:
Journal Volume: 124:1
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 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

Citation Formats

Taurog, A, Dorris, M L, and Guziec, Jr, F S. Metabolism of /sup 35/S- and /sup 14/C-labeled 1-methyl-2-mercaptoimidazole in vitro and in vivo. United States: N. p., 1989. Web.
Taurog, A, Dorris, M L, & Guziec, Jr, F S. Metabolism of /sup 35/S- and /sup 14/C-labeled 1-methyl-2-mercaptoimidazole in vitro and in vivo. United States.
Taurog, A, Dorris, M L, and Guziec, Jr, F S. 1989. "Metabolism of /sup 35/S- and /sup 14/C-labeled 1-methyl-2-mercaptoimidazole in vitro and in vivo". United States.
@article{osti_6568957,
title = {Metabolism of /sup 35/S- and /sup 14/C-labeled 1-methyl-2-mercaptoimidazole in vitro and in vivo},
author = {Taurog, A and Dorris, M L and Guziec, Jr, F S},
abstractNote = {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.},
doi = {},
url = {https://www.osti.gov/biblio/6568957}, journal = {Endocrinology; (United States)},
number = ,
volume = 124:1,
place = {United States},
year = {Sun Jan 01 00:00:00 EST 1989},
month = {Sun Jan 01 00:00:00 EST 1989}
}