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Metabolism-dependent toxicity of methimazole in the olfactory nasal mucosa
1Department of Pharmacology, University of Lund, Sweden.
Abstract:
In mice given a single intraperitoneal injection of the antithyroid drug methimazole (0.44 mmol/kg; 50 mg/kg) detachment of the olfactory neuroepithelium and necrosis of the Bowman's glands in the lamina propria was observed 24 hr after administration. Three days after administration there was an atypical epithelium throughout the olfactory region and the Bowman's glands had disappeared. Pretreatment with the olfactory cytochrome P450 inhibitor metyrapone protected against the methimazole-induced changes at this site. In mice injected with the methimazole analogues 1-methylimidazole or 4-methylimidazole (0.44 mmol/kg; 36 mg/kg) or the antithyroid drug propylthiuracil (0.22 mmol/kg; 38 mg/kg) no morphological changes were observed in the olfactory mucosa. The results suggest that methimazole-induced toxicity in the olfactory mucosa is related to metabolism-dependent changes of the thiol group.
Insights
Methimazole causes olfactory tissue damage in mice, affecting the olfactory neuroepithelium and Bowman's glands. This toxicity is linked to its metabolism, specifically thiol group changes.
Area of Science:
- Toxicology
- Histopathology
- Pharmacology
Background:
- Antithyroid drugs like methimazole are crucial for treating hyperthyroidism.
- Understanding drug-induced toxicity is essential for patient safety.
- The olfactory system's response to xenobiotics requires further investigation.
Purpose of the Study:
- To investigate the toxic effects of methimazole on the mouse olfactory mucosa.
- To determine if methimazole's toxicity is metabolism-dependent.
- To explore the role of cytochrome P450 in methimazole-induced olfactory damage.
Main Methods:
- Mice received intraperitoneal injections of methimazole, methimazole analogues, or propylthiouracil.
- Olfactory tissues were examined 24 hours and 3 days post-administration.
- Pretreatment with metyrapone, a cytochrome P450 inhibitor, was used to assess metabolic involvement.
Main Results:
- Methimazole induced olfactory neuroepithelium detachment and Bowman's gland necrosis within 24 hours.
- Atypical epithelium and loss of Bowman's glands were observed three days after methimazole administration.
- Metyrapone pretreatment protected against these methimazole-induced olfactory changes, while analogues and propylthiouracil did not cause similar damage.
Conclusions:
- Methimazole causes significant, metabolism-dependent toxicity in the olfactory mucosa.
- The thiol group's metabolism appears critical for methimazole-induced olfactory damage.
- Olfactory cytochrome P450 plays a role in mediating methimazole toxicity in this tissue.