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Methimazole-induced damage in the olfactory mucosa: effects on ultrastructure and glutathione levels
Ulrika Bergström1, Anna Giovanetti, Elena Piras
1Department of Pharmacology and Toxicology, SLU, Box 573, SE-751 23 Uppsala, Sweden. Ulrika.Bergstrom@ebc.uu.se
Abstract:
Methimazole is an antithyroid drug that can induce loss of smell and taste in humans. It is also an olfactory toxicant in rodents. The aim of the present study was to examine involvement of glutathione in methimazole-induced damage of the olfactory mucosa (OM) of mice, and to study early onset of this damage using transmission electron microscopy (TEM). We found that an intraperitoneal dose of methimazole induced a dose-dependent decrease of nonprotein sulfhydryl groups (NP-SH; mainly glutathione) in the OM. Hepatic NP-SH was not decreased. One hour after administration (50 mg/kg), TEM demonstrated an extensive damage to acinar and intraepithelial excretory duct cells of Bowman's glands (BG) including dilatation of the endoplasmic reticulum and mitochondrial swelling. Furthermore, large vacuoles were noted in basal intraepithelial duct cells. After 2 hours there were ruptures of secretory granule membranes in BG and mitochondrial swelling and degeneration of sustentacular cells. The basal cells were less damaged. After four hours the neuroepithelium was disorganized although the columnar organization of neurons was largely intact. The acinar organization of the BG was frequently lost. The subsequent detachment of the neuroepithelium is suggested to be secondary to extensive damage of BG excretory ducts and sustentacular cells.
Insights
Methimazole, an antithyroid drug, depletes glutathione in the olfactory mucosa, causing significant cellular damage. This damage, observed via electron microscopy, affects Bowman's glands and sustentacular cells, leading to neuroepithelium disorganization.
Area of Science:
- Toxicology
- Neuroscience
- Cell Biology
Background:
- Methimazole is an antithyroid drug known to cause olfactory dysfunction in humans and rodents.
- Glutathione is a key cellular antioxidant, and its depletion can lead to oxidative stress and cell damage.
Purpose of the Study:
- To investigate the role of glutathione in methimazole-induced olfactory mucosa damage in mice.
- To characterize the early cellular changes in the olfactory mucosa following methimazole administration using transmission electron microscopy (TEM).
Main Methods:
- Mice were administered varying doses of methimazole intraperitoneally.
- Olfactory mucosa (OM) and liver nonprotein sulfhydryl groups (NP-SH), primarily glutathione, were measured.
- Transmission electron microscopy (TEM) was used to examine cellular damage in the OM at 1, 2, and 4 hours post-administration.
Main Results:
- Methimazole induced a dose-dependent decrease in OM NP-SH levels, while hepatic NP-SH remained unaffected.
- TEM revealed early damage to Bowman's glands (BG) excretory duct cells, including endoplasmic reticulum dilation and mitochondrial swelling, within 1 hour.
- Sustentacular cell degeneration and disorganization of the neuroepithelium were observed at later time points, with damage to BG appearing secondary to duct and sustentacular cell injury.
Conclusions:
- Glutathione depletion in the olfactory mucosa is a key mechanism in methimazole-induced toxicity.
- Early and severe damage to Bowman's glands and sustentacular cells precedes neuroepithelial disorganization.
- Methimazole serves as an olfactory toxicant, with its effects mediated by glutathione depletion and subsequent cellular damage in the olfactory system.
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