Mechanism of Action of Neomercazole (Methimazole)
Methimazole inhibits thyroid peroxidase (TPO), thereby blocking both the iodination of tyrosine residues on thyroglobulin and the coupling of iodotyrosines (MIT and DIT) into thyroid hormones (T3 and T4). 1
Primary Mechanism: Thyroid Peroxidase Inhibition
- Methimazole directly targets thyroid peroxidase, the enzyme responsible for catalyzing thyroid hormone synthesis 1, 2
- The drug blocks the oxidation and organification of iodide, preventing iodine from being incorporated into tyrosine residues on thyroglobulin 2
- Methimazole inhibits the coupling reaction where iodotyrosines (monoiodotyrosine and diiodotyrosine) combine to form T3 and T4 3, 2
Key Pharmacological Properties
- Methimazole does not inactivate pre-existing thyroid hormones already stored in the thyroid gland or circulating in the bloodstream 1
- The drug does not interfere with exogenously administered thyroid hormones given orally or by injection 1
- Methimazole is readily absorbed from the gastrointestinal tract, metabolized in the liver, and excreted in the urine 1
Comparative Inhibitory Potency
- Methimazole is more potent than propylthiouracil (PTU) at inhibiting TPO-mediated iodination, demonstrating distinctly greater efficacy in blocking the iodination step 3
- However, both methimazole and PTU have similar potencies in inhibiting the TPO-catalyzed coupling reaction, suggesting different inhibitory mechanisms may be involved in the two distinct steps of thyroid hormone synthesis 3
Additional Mechanisms Beyond TPO Inhibition
- Methimazole suppresses iodotyrosine deiodinase 1 (Dehal1) expression, which is responsible for recycling iodine from MIT and DIT 4
- The drug inhibits redistribution of Dehal1 protein into lysosomes following thyroglobulin endocytosis, further affecting thyroid hormone metabolism 4
- Methimazole may have immunomodulatory effects in Graves' disease by reducing thyroid iodine content (which decreases antigen expression) and scavenging reactive oxygen species generated during peroxidation 2
Paradoxical Effect on TPO Expression
- At therapeutic concentrations (1-10 μM), methimazole actually increases cellular TPO activity and TPO mRNA levels in cultured thyroid follicles, though it simultaneously inhibits the TPO-H2O2-mediated catalytic reaction 5
- This increase in TPO expression requires new protein synthesis and is enhanced by cAMP-generating systems 5
- Only at very high concentrations (100 μM) does methimazole directly inhibit cellular TPO activity 5
Clinical Implications
- The therapeutic effect depends on depleting stored thyroid hormones since methimazole only blocks new hormone synthesis 1
- Clinical response typically takes several weeks as pre-existing thyroid hormones are gradually metabolized and depleted
- The drug's immunomodulatory properties may contribute to remission in Graves' disease when maintained for at least 12 months, achieving cure in approximately 50% of patients 2