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Mass Spectrometry and Luminogenic-based Approaches to Characterize Phase I Metabolic Competency of In Vitro Cell Cultures
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Metabolism of methimazole by rat liver cytochrome P-450-containing monoxygenases

P W Lee, R A Neal

    Drug Metabolism and Disposition: the Biological Fate of Chemicals
    |September 1, 1978
    PubMed

    Insights

    Methimazole (MMI) metabolism in rat liver microsomes produces N-methylimidazole and binds to proteins. This binding involves atomic sulfur, suggesting a novel mechanism for MMI-protein interactions.

    Area of Science:

    • Biochemistry
    • Pharmacology
    • Toxicology

    Background:

    • Methimazole (MMI) is an antithyroid drug used to treat hyperthyroidism.
    • Its metabolism and potential interactions with cellular components are not fully understood.

    Purpose of the Study:

    • To investigate the metabolic pathways of methimazole (MMI) in rat hepatic microsomes.
    • To elucidate the mechanism of MMI binding to microsomal macromolecules.

    Main Methods:

    • Incubation of [14C]- and [35S]-labeled methimazole (MMI) with rat hepatic microsomes.
    • Analysis of metabolites using chromatography and mass spectrometry.
    • Assessment of NADPH-dependency and cytochrome P450 involvement.
    • Investigation of bound radioactivity release under different conditions.

    Main Results:

    • MMI metabolism yielded 3-methyl-2-thiohydantoin and N-methylimidazole.
    • NADPH-stimulated binding of MMI-derived radioactivity to microsomal proteins was observed.
    • Cytochrome P450 enzymes largely catalyzed these reactions.
    • Bound MMI could be released as unchanged drug or 35SCN-, indicating strong covalent binding.
    • Data suggest atomic sulfur binding to cysteine residues forming hydrodisulfides.

    Conclusions:

    • Rat hepatic microsomes metabolize MMI via cytochrome P450 enzymes.
    • A portion of MMI metabolism involves the release of atomic sulfur, which covalently binds to microsomal proteins.
    • This binding mechanism, forming hydrodisulfides, provides insight into MMI-protein interactions and potential toxicity.

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