Methimazole toxicity in rodents: covalent binding in the olfactory mucosa and detection of glial fibrillary acidic protein in the olfactory bulb.
Methimazole is an antithyroid drug reported to affect the sense of smell and taste in humans. The aim of the present study was to examine the distribution and effects of methimazole on the olfactory system in rodents. Autoradiography showed a selective covalent binding of 3H-labeled methimazole in the Bowman's glands in the olfactory mucosa, bronchial epithelium in the lungs, and centrilobular parts of the liver following an iv injection in mice. Histopathology showed an extensive lesion in the olfactory mucosa that was efficiently repaired 3 months after two consecutive ip doses of methimazole. The effect of methimazole on various brain regions was studied by determining levels and location of glial fibrillary acidic protein (GFAP). The results showed a threefold increase of GFAP in the olfactory bulb 2 weeks after treatment with methimazole whereas no change was observed 4 days after treatment. Pretreatment of mice with thyroxine did not protect against the methimazole-induced toxicity in the olfactory mucosa and bulb. In contrast, pretreatment with the cytochrome P450 inhibitor metyrapone completely prevented the covalent binding and toxicity of methimazole in the olfactory mucosa and bulb. The present results suggest that the methimazole-induced toxicity in the olfactory mucosa is mediated by a cytochrome P450-dependent metabolic activation of the compound into reactive metabolites that are bound to various tissues including the olfactory mucosa. The increase of GFAP in the olfactory bulb of methimazole-treated mice is suggested to be a secondary phenomenon due to the primary damage in the olfactory mucosa.
Department of Pharmacology and Toxicology, Swedish University of Agricultural Sciences, Uppsala, S-751 23, Sweden.
U
U
Bergman
E B
EB
Brittebo
D000818:Animals; D013956:Antithyroid Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D001345:Autoradiography; D001549:Benzamides / Q000493:pharmacokinetics / Q000633:toxicity; D001665:Binding Sites / Q000187:drug effects; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000276:immunology / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D008713:Methimazole / Q000493:pharmacokinetics / Q000633:toxicity*; D051379:Mice; D008853:Microscopy; D009570:Nitriles; D009830:Olfactory Bulb / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009831:Olfactory Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley
D013956:Antithyroid Agents; D001549:Benzamides; D005904:Glial Fibrillary Acidic Protein; D009570:Nitriles; D008713:Methimazole; C055869:dichlobanil