Effects of glutathione-modulating agents on the covalent binding and toxicity of dichlobenil in the mouse olfactory mucosa

Brittebo, Eva B.; Eriksson, Catarina; Brandt, Ingvar

doi:10.1016/0041-008x(92)90093-8

Cited by 29 publications

(20 citation statements)

References 25 publications

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“…In addition, experimental GSH depletion in vivo can increase the olfactory toxicity of some compounds (2,7). Preliminary results from our laboratory showed that there was a markedly increased susceptibility to methimazole in mice depleted of GSH by phorone-pretreatment.…”

Section: Discussionmentioning

confidence: 91%

“…A tissue-selective decrease of NP-SH in the olfactory mucosa has previously been observed following exposure to other olfactory toxicants such as dichlobenil and methyl iodide (7,8). In addition, experimental GSH depletion in vivo can increase the olfactory toxicity of some compounds (2,7).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that in vivo GSH-depletion can potentiate the olfactory toxicity of some compounds (2,7). In GSH-depleted mice, methimazole exposure will induce a centrilobular hepatic necrosis (23,24).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

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

et al. 2003

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“…Consequently, there was a discrepancy between the localized binding of the radiolabeled 2,6-isomer in the Bowman's glands and the lesion in both the olfactory epithelium and in the Bowman's glands in the dorsomedial part of the olfactory region. As previously suggested for the nasal toxicant dichlobenil (11), this discrepancy implies that a primary necrosis in the Bowman's glands is followed by a secondary lesion characterized by degeneration and detachment of the olfactory epithelium. The localization of the 2,6-diClPh-MeSO 2 -induced lesion in the rat olfactory mucosa was similar to that previously reported in mice, but the extent of the lesion was less pronounced (2).…”

Section: Discussionmentioning

confidence: 64%

“…One day after a single dose (8)(9)(10)(11)(12)(13)(14)(15)(16) mg/kg) administered IP to mice there is necrosis in the dorsomedial part of the olfactory region. Later on, a metaplastic remodelling of the olfactory mucosa with permanent loss of olfactory epithelium will occur.…”

Section: Introductionmentioning

confidence: 99%

Isomer-Specific Bioactivation and Toxicity of Dichlorophenyl Methylsulphone in Rat Olfactory Mucosa

et al. 2003

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This study aimed to explain the isomer-and site-specific toxic effects of dichlorophenyl methylsulphone in the olfactory mucosa of rats. A single ip dose of the 2,6-chlorinated isomer (16 or 65 mg/kg) induced necrosis preferentially in the Bowman's glands and neuroepithelium in the dorsomedial part of the olfactory region. Only minor damage occurred at this site in rats dosed with the 2,5-chlorinated isomer (65 mg/kg). A strong concentrationand time-dependent covalent binding of the 14 C-labeled 2,6-isomer to rat olfactory microsomes was demonstrated. In contrast, no significant covalent binding of the 14 C-labeled 2,5-isomer was observed. The cytochrome P450 (CYP) inhibitors metyrapone, tranylcypromine and acetonitrile inhibited covalent binding of the 2,6-isomer to olfactory microsomes. Glutathione (GSH) appeared to play a protective role as a scavenger of a reactive intermediate whereas methyl-GSH did not alter covalent binding to olfactory microsomes. As determined by microautoradiography, binding of the 2,6-chlorinated isomer in the olfactory mucosa was confined to the Bowman's glands. Both isomers showed a low binding to liver microsomes and caused no liver injury. We suggest that a CYP2A-catalyzed activation of the 2,6-chlorinated dichlorophenyl methylsulphone to a reactive intermediate and adduct formation in the Bowman's glands will initiate a site-specific toxicity of this isomer in the olfactory mucosa.

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2015

Hamilton &Amp; Hardy's Industrial Toxicology

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Effects of glutathione-modulating agents on the covalent binding and toxicity of dichlobenil in the mouse olfactory mucosa

Cited by 29 publications

References 25 publications

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

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

Isomer-Specific Bioactivation and Toxicity of Dichlorophenyl Methylsulphone in Rat Olfactory Mucosa

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