METABOLISM-DEPENDENT TOXICITY OF METHIMAZOLE IN THE OLFACTORY NASAL-MUCOSA

In mice given a single intraperitoneal injection of the antithyroid dr ug methimazole (0.44 mmol/kg; 50 mg/kg) detachment of the olfactory ne uroepithelium and necrosis of the Bowman' glands in the lamina propria was observed 24 hr after administration. Three days after administrat ion there was an atypical epithelium throughout the olfactory region a nd the Bowman's glands had disappeared. Pretreatment with the olfactor y cytochrome P450 inhibitor metyrapone protected against the methimazo le-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 re sults suggest that methimazole-induced toxicity in the olfactory mucos a is related to metabolism-dependent changes of the thiol group.