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Metabolism of ³⁵S- and ¹⁴C-Labeled l-Methyl-2 Mercaptoimidazole in Vitro and in Vivo^*

ALVIN TAUROG, MARTHA L. DORRIS and FRANK S. GUZIEC, JR.

Department of Pharmacology, University of Texas Southwestern Medical Center (A.T., M.L.D.) Dallas, Texas 75235
Department of Chemistry, New Mexico State University (F.S.G.) Las Cruces, New Mexico 88003

Address all correspondence and requests for reprints to: Dr. Alvin Taurog, Department of Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75235.

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 l-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 ¹⁴ C - 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. The difference in metabolic pattern between the reversible and irreversible conditions is primarily related to the rapid inactivation of TPO that occurs under irreversible conditions.

The metabolism of [³⁵S]MMI in thyroids of rats injected with the labeled drug resembles more closely conditions of reversible inhibition, since sulfate/sulfite is the only 35S-labeled metabolite. Neither [³⁵S]MMI disulfide nor the 7.5 min component was detected in rat thyroids in vivo. However, it was demonstrated that these components do not survive homogenization with thyroid tissue, and failure to detect them in vivo does not exclude them as likely intermediates in intrathyroidal MMI metabolism.

Based on the observations reported in this study, we present a revised scheme for the mechanism of inhibition of TPOcatalyzed iodination by MMI. (Endocrinology 124: 30–39,1989)

Footnotes

^* This work was supported by USPHS Grant DK-03612.

USPHS career research awardee.

Received June 8, 1988.

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