Olfactory Toxicity of Methimazole: Dose-Response and Structure-Activity Studies and Characterization of Flavin-Containing Monooxygenase Activity in the Long-Evans Rat Olfactory Mucosa

Genter, Mary Beth; Deamer, Nora J.; Blake, Bonita L.; Wesley, Deborah S.; Levi, Patricia E.

doi:10.1177/019262339502300404

Cited by 99 publications

(89 citation statements)

References 28 publications

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“…However, the specific P450 enzymes responsible for microsomal MMZ metabolism in either liver or OM have not been identified. In that connection, FMO1 and FMO2, as well as many P450s, are known to be expressed in the OM (Genter et al, 1995;Shehin-Johnson et al, 1995;Ling et al, 2004). Further studies are needed to determine the contributions of these FMOs and P450 enzymes (other than CYP2A5) to MMZ toxicity in the OM.…”

Section: Downloaded Frommentioning

confidence: 99%

“…Methimazole (1-methyl-2-mercaptoimidazole; Tapazole) (MMZ), a drug commonly used for treating hyperthyroidism, and also often used as a model substrate, as well as an inhibitor, for the flavin-containing monooxygenases (FMO), is known to cause tissue-selective toxicity in rodent olfactory mucosa (OM) (Brittebo, 1995;Genter et al, 1995;Bergman and Brittebo, 1999;Bergström et al, 2003;Casallo Blanco et al, 2007). MMZ-induced olfactory deficits have also been reported in human patients (Bandyopadhyay et al, 2002;Woeber, 2002).…”

Section: Introductionmentioning

confidence: 99%

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The Tissue-Specific Toxicity of Methimazole in the Mouse Olfactory Mucosa Is Partly Mediated through Target-Tissue Metabolic Activation by CYP2A5

Xie¹,

Zhou²,

Genter³

et al. 2011

Drug Metab Dispos

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ABSTRACT:The antithyroid drug methimazole (MMZ) can cause severe, tissuespecific toxicity in mouse olfactory mucosa (OM), presumably through a sequential metabolic activation of MMZ by cytochrome P450 (P450) and flavin monooxygenases (FMO). The aims of this study were to determine whether CYP2A5, one of the most abundant P450 enzymes in the mouse OM, is involved in MMZ metabolic activation, by comparing Cyp2a5-null with wild-type (WT) mice, and whether hepatic microsomal P450 enzymes, including CYP2A5, are essential for MMZ-induced OM toxicity, by comparing liver-Cpr-null (LCN) mice, which have little P450 activity in hepatocytes, with WT mice. We showed that the loss of CYP2A5 expression did not alter systemic clearance of MMZ (at 50 mg/kg, i.p.); but it did significantly decrease the rates of MMZ metabolism in the OM, whereas FMO expression in the OM was not reduced. MMZ induced depletion of nonprotein thiols, as well as pathological changes, in the OM of WT mice; the extent of these changes was much reduced in the Cyp2a5-null mice. Thus, CYP2A5 plays an important role in mediating MMZ toxicity in the OM. In contrast, the rate of systemic clearance of MMZ was significantly reduced in the LCN mice, compared to WT mice, whereas the MMZ-induced OM toxicity was not prevented. Therefore, hepatic P450 enzymes are essential for systemic MMZ clearance, but they are not required for MMZ-induced OM toxicity. We conclude that the tissue-specific toxicity of MMZ is mediated by target tissue metabolic activation, and the reaction is partly catalyzed by CYP2A5 in the OM.

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Section: Downloaded Frommentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Tissue-Specific Toxicity of Methimazole in the Mouse Olfactory Mucosa Is Partly Mediated through Target-Tissue Metabolic Activation by CYP2A5

Xie¹,

Zhou²,

Genter³

et al. 2011

Drug Metab Dispos

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“…The methimazole-induced olfactory lesion model (25) has been widely used to study neuroregeneration in the OE. The death of OSNs in this model is considered to occur secondary to the degeneration of Bowman's glands and sustentacular cells.…”

Section: Olfactory Neuroregeneration Is Accompanied By An Acute Inflamentioning

confidence: 99%

Acute inflammation regulates neuroregeneration through the NF-κB pathway in olfactory epithelium

Chen

Reed

Lane

2017

Proc. Natl. Acad. Sci. U.S.A.

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Adult neural stem cells/progenitor cells residing in the basal layer of the olfactory epithelium are capable of reconstituting the neuroepithelium even after severe damage. The molecular events underlying this regenerative capacity remain elusive. Here we show that the repair of neuroepithelium after lesioning is accompanied by an acute, but self-limited, inflammatory process. Attenuation of inflammatory cell recruitment and cytokine production by dexamethasone impairs proliferation of progenitor horizontal basal cells (HBCs) and subsequent neuronal differentiation. Using TNF-α receptor-deficient mice, we identify TNF-α signaling as an important contributor to this inflammatory and reparative process, mainly through TNF-α receptor 1. HBC-selective genetic ablation of RelA (p65), the transcriptional activator of the NF-κB pathway, retards inflammation and impedes proliferation at the early stages of regeneration and suggests HBCs directly participate in cross-talk between immune response and neurogenesis. Loss of RelA in the regenerating neuroepithelium perturbs the homeostasis between proliferation and apoptosis while enhancing JNK signaling. Together, our results support a model in which acute inflammation after injury initiates important regenerative signals in part through NF-κB-mediated signaling that activates neural stem cells to reconstitute the olfactory epithelium.neuroregeneration | inflammation | olfactory stem cells | NF-κB

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“…Also carbimazole, a precursor of methimazole, may induce hyposmia (loss of sense of smell) in humans (9,27). Both of these drugs are olfactory toxicants in rodents (4,6,(12)(13)(14). For instance, in mice given a single IP injection of methimazole (50 mg/kg) there is necrosis throughout the olfactory region 1 day later, whereas the nasal respiratory mucosa and the liver are spared (6).…”

Section: Introductionmentioning

confidence: 99%

Methimazole-Induced Damage in the Olfactory Mucosa: Effects on Ultrastructure and Glutathione Levels

et al. 2003

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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.

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Olfactory Toxicity of Methimazole: Dose-Response and Structure-Activity Studies and Characterization of Flavin-Containing Monooxygenase Activity in the Long-Evans Rat Olfactory Mucosa

Cited by 99 publications

References 28 publications

The Tissue-Specific Toxicity of Methimazole in the Mouse Olfactory Mucosa Is Partly Mediated through Target-Tissue Metabolic Activation by CYP2A5

The Tissue-Specific Toxicity of Methimazole in the Mouse Olfactory Mucosa Is Partly Mediated through Target-Tissue Metabolic Activation by CYP2A5

Acute inflammation regulates neuroregeneration through the NF-κB pathway in olfactory epithelium

Methimazole-Induced Damage in the Olfactory Mucosa: Effects on Ultrastructure and Glutathione Levels

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