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 an d taste in humans, The aim of the present study was to examine the distribu tion and effects of methimazole on the olfactory system in rodents. Autorad iography showed a selective covalent binding of H-3-labeled methimazole in the Bowman's glands in the olfactory mucosa, bronchial epithelium in the lu ngs, and centrilobular parts of the liver following an iv injection in mice , Histopathology showed an extensive lesion in the olfactory mucosa that wa s efficiently repaired 3 months after two consecutive ip doses of methimazo le. The effect of methimazole on various brain regions was studied by deter mining levels and location of glial fibrillary acidic protein (GFAP), The r esults showed a threefold increase of GFAP in the olfactory bulb 2 weeks af ter 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 prev ented the covalent binding and toxicity of methimazole in the olfactory muc osa and bulb. The present results suggest that the methimazole-induced toxi city in the olfactory mucosa is mediated by a cytochrome P450-dependent met abolic 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 seconda ry phenomenon due to the primary damage in the olfactory mucosa, (C) 1999 A cademic Press.