Metabolism-dependent toxicity of methimazole in the olfactory nasal mucosa

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.