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

Bergström, Ulrika; Giovanetti, Anna; Piras, Elena; Brittebo, Eva B.

doi:10.1080/01926230309720

Cited by 18 publications

(27 citation statements)

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“…Nasal toxicants often induce rapid depletion of NPSH in the OM, with maximal depletion seen usually within 2 to 4 h after an intraperitoneal injection (Brittebo et al, 1992; Bergstrom et al, 2003). Thus, we examined the potential impact of DCBN treatment on NPSH levels in the OM of the Cyp2a5 -null and WT mice (male, 2–3 month old), at 2 h following DCBN treatment.…”

Section: Resultsmentioning

confidence: 99%

Mechanisms of olfactory toxicity of the herbicide 2,6-dichlorobenzonitrile: Essential roles of CYP2A5 and target-tissue metabolic activation

Xie

Zhou

Behr

et al. 2010

Toxicology and Applied Pharmacology

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The herbicide 2,6-dichlorobenzonitril (DCBN) is a potent and tissue-specific toxicant to the olfactory mucosa (OM). The toxicity of DCBN is mediated by cytochrome P450 (P450)-catalyzed bioactivation; however, it is not known whether target-tissue metabolic activation is essential for toxicity. CYP2A5, expressed abundantly in both liver and OM, was previously found to be one of the P450 enzymes active in DCBN bioactivation in vitro. The aims of this study were to determine the role of CYP2A5 in DCBN toxicity in vivo, by comparing the extents of DCBN toxicity between Cyp2a5-null and wild-type (WT) mice, and to determine whether hepatic microsomal P450 enzymes (including CYP2A5) are essential for the DCBN toxicity, by comparing the extents of DCBN toxicity between liver-Cpr-null (LCN) mice, which have little P450 activity in hepatocytes, and WT mice. We show that the loss of CYP2A5 expression did not alter systemic clearance of DCBN (at 25 mg/kg); but it did inhibit DCBN-induced non-protein thiol depletion and cytotoxicity in the OM. Thus, CYP2A5 plays an essential role in mediating DCBN toxicity in the OM. In contrast to the results seen in the Cyp2a5-null mice, the rates of systemic DCBN clearance were substantially reduced, while the extents of DCBN-induced nasal toxicity were increased, rather than decreased, in the LCN mice, compared to WT mice. Therefore, hepatic P450 enzymes, although essential for DCBN clearance, are not necessary for DCBN-induced OM toxicity. Our findings form the basis for a mechanism-based approach to assessing the potential risks of DCBN nasal toxicity in humans.

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Section: Resultsmentioning

confidence: 99%

Mechanisms of olfactory toxicity of the herbicide 2,6-dichlorobenzonitrile: Essential roles of CYP2A5 and target-tissue metabolic activation

Xie

Zhou

Behr

et al. 2010

Toxicology and Applied Pharmacology

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“…Previous studies have demonstrated that methimazole is metabolized by a cytochrome P450 in sustentacular cells and Bowman glands, causing massive apoptosis and promoting the degeneration of OE supportive cells [6], [51], [52]. This leads to detachment of OSNs while progenitor cells remain intact [53].…”

Section: Discussionmentioning

confidence: 99%

Odor Memory Stability after Reinnervation of the Olfactory Bulb

et al. 2012

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The olfactory system, particularly the olfactory epithelium, presents a unique opportunity to study the regenerative capabilities of the brain, because of its ability to recover after damage. In this study, we ablated olfactory sensory neurons with methimazole and followed the anatomical and functional recovery of circuits expressing genetic markers for I7 and M72 receptors (M72-IRES-tau-LacZ and I7-IRES-tau-GFP). Our results show that 45 days after methimazole-induced lesion, axonal projections to the bulb of M72 and I7 populations are largely reestablished. Furthermore, regenerated glomeruli are re-formed within the same areas as those of control, unexposed mice. This anatomical regeneration correlates with functional recovery of a previously learned odorant-discrimination task, dependent on the cognate ligands for M72 and I7. Following regeneration, mice also recover innate responsiveness to TMT and urine. Our findings show that regeneration of neuronal circuits in the olfactory system can be achieved with remarkable precision and underscore the importance of glomerular organization to evoke memory traces stored in the brain.

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“…Mice were sacrificed 24h after the injection. Methimazole is metabolized in Bowman’s gland duct cells and sustentacular cells by a cytochrome P450-dependent pathway leading to the production of reactive intermediates that cause dose- and time-dependent apoptosis of OSNs (Bergman and Brittebo, 1999; Bergstrom et al, 2003). The methimazole experiment was done at age P10–P11 and again at age P21–P22.…”

Section: Methodsmentioning

confidence: 99%

Chemical stress induces the unfolded protein response in olfactory sensory neurons

Sammeta

McClintock

2010

J of Comparative Neurology

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More than any other neuron, olfactory sensory neurons are exposed to environmental insults. Surprisingly, their only documented response to damaging stress is apoptosis and subsequent replacement by new neurons. However, they expressed unfolded protein response genes, a transcriptionally regulated defense mechanism activated by many types of insults. The unfolded protein response transcripts Xbp1, spliced Xbp1, Chop (Ddit3), and BiP (Hspa5) were decreased when external access of stressors was reduced by blocking a nostril (naris occlusion). They, and Nrf2 (Nfe2l2), were increased by systemic application of tunicamycin or the selective olfactotoxic chemical, methimazole. Methimazole's effects overcame naris occlusion and the unfolded protein response was independent of odor-evoked neuronal activity. Chemical stress is therefore a major and chronic activator of the unfolded protein response in olfactory sensory neurons. Stressdependent repression of the anti-apoptotic gene Bcl2 was absent, however, suggesting a mechanism for disconnecting the UPR from apoptosis and tolerating a chronic unfolded protein response. Environmental stressors also affect both the sustentacular cells that support the neurons and respiratory epithelia because naris occlusion decreased expression of the xenobiotic chemical transformation enzyme Cyp2a5 in sustentacular cells and both naris occlusion and methimazole altered the abundance of the antibacterial lectin Reg3g in respiratory epithelia.

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

Cited by 18 publications

References 0 publications

Mechanisms of olfactory toxicity of the herbicide 2,6-dichlorobenzonitrile: Essential roles of CYP2A5 and target-tissue metabolic activation

Mechanisms of olfactory toxicity of the herbicide 2,6-dichlorobenzonitrile: Essential roles of CYP2A5 and target-tissue metabolic activation

Odor Memory Stability after Reinnervation of the Olfactory Bulb

Chemical stress induces the unfolded protein response in olfactory sensory neurons

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