Metabolic activation of the herbicide dichlobenil in the olfactory mucosa of mice and rats

Eriksson, Catarina; Brittebo, Eva B.

doi:10.1016/0009-2797(91)90080-q

Cited by 37 publications

(20 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Olfactory toxicity is often related to a tissue-specific and cytochrome P450 (CYP) -dependent metabolic activation of the chemicals into reactive intermediates (Eriksson and Brittebo 1991;Brittebo et al 1992;Brittebo 1995;Ding et al 1996;Eriksson et al 1996;Bergman and Brittebo 1999). The olfactory toxicants dichlobenil (a herbicide) and methimazole (a drug used in hyperthyroidism) were selected for this study.…”

Section: Introductionmentioning

confidence: 99%

Differential effects of olfactory toxicants on olfactory regeneration

Bergman

Östergren²,

Gustafson

et al. 2002

Archives of Toxicology

View full text Add to dashboard Cite

The aim was to study the long-term response in the olfactory mucosa of NMRI mice after exposure to the olfactory toxicants dichlobenil (a herbicide) or methimazole (an antithyroid drug). Three and six months after exposure to dichlobenil (2x or 1 x 25 mg/kg i.p.), the dorsomedial part of the olfactory region showed a respiratory metaplasia with abundant invaginations and a fibrotic lamina propria. In contrast, 3 months after exposure to a toxic dose of methimazole (2 x 50 mg/kg i.p.), the olfactory neuroepithelium and lamina propria had been restored. To study the regenerative events, we used an antibody derived against growth-associated protein 43 (GAP-43), which stains immature neurons. To study epithelial differentiation and horizontal basal cells (HBCs) we used an antibody derived against some cytokeratins. Two weeks after methimazole treatment, there was a marked increase of GAP-43-stained cells in the whole olfactory region, which correlated with the observed regeneration at that time. Two weeks after dichlobenil treatment, the damaged atypical epithelium in the olfactory region showed a distinct keratin staining of basal and columnar cells whereas GAP-43-stained cells were not found. Despite a transient increase of GAP-43-stained cells in the border zone between damaged and undamaged olfactory mucosa, an expansion of a normal neuroepithelium into the damaged olfactory region was not detected in the dichlobenil-treated mice. An intact lamina propria is suggested as a prerequisite for repopulation of the neuroepithelium after toxicant-induced injury.

show abstract

Section: Introductionmentioning

confidence: 99%

Differential effects of olfactory toxicants on olfactory regeneration

Bergman

Östergren²,

Gustafson

et al. 2002

Archives of Toxicology

View full text Add to dashboard Cite

show abstract

“…Vacuolations, most likely due to hydropic swelling of the SER cistemae, were frequently observed in the Bowman's glands. SER is known as the primary site of cytochrome P-450s, and a cytochrome P-450-dependent activation of dichlobenil to reactive products has previously been demonstrated in olfactory microsomes (11,12). The dichlobenil metabolites are covalently bound to all major proteins in olfactory microsomes and are confined to the Bowman's glands in the olfactory mucosa (4,13 (32).…”

Section: Vehicle-treated Mice and Untreated Mice Light Microscopy Andmentioning

confidence: 95%

“…2). More specifically, the dichlobenil-induced necrosis in the olfactory mucosa is related to an extensive cytochrome P-450-dependent oxidative metabolism of dichlobenil to a reactive species, leading to depletion of glutathione and covalent binding of metabolites in the olfactory mucosa (6,11,12).…”

Section: Introductionmentioning

confidence: 99%

Effects of Dichlobenil on Ultrastructural Morphology and Cell Replication in the Mouse Olfactory Mucosa

1997

View full text Add to dashboard Cite

The herbicide dichlobenil (2,6-dichlorobenzonitrile) is a tissue-specific toxicant inducing necrosis in the olfactory mucosa. Transmission electron microscopy showed vacuolations (1 hr) and necrosis (4 hr) in the Bowman's glands following intraperitoneal injection of dichlobenil (25 mg/kg) in C57B1 mice, whereas no lesions were noted in the olfactory neuroepithelium at these timepoints. Twentyfour hr following injection (25 mg/kg), most of the lamina propria and the olfactory epithelium were severely damaged; the basal lamina, nerves, and blood vessels in the lamina propria, however, remained intact. Following a lower dose (12 mg/kg), the lesions were not as pronounced. The effects of dichlobenil (6, 12, and 25 mg/kg) on cell replication in the olfactory mucosa, as determined by incorporation of 3H-thymidine 3 days later, were more pronounced in the lamina propria than in the neuroepithelium and occurred at a lower dose in the lamina propria than in the neuroepithelium. Together these studies support the previous proposal that dichlobenil induces a primary damage in the Bowman's glands.

show abstract

“…The Bowman's glands in the lamina propria express high levels of various cytochrome P450 (CYP) forms and are therefore a sensitive target for certain CYP-activated toxicants. The herbicides dichlobenil (2,6-dichlorobenzonitrile) and chlorthiamide (2,6-dichlorothiobenzamide) and the environmental dichlobenil metabolite 2,6-dichlorobenzamide all induce toxicity in the OM following covalent binding in the Bowman's glands Eriksson and Brittebo 1991). Dichlobenil, one of the most extensively studied nasal toxicants, gives rise to a tissue-specific toxicity predominately in the dorsomedial region of the OM in mice and rats (Brandt et al 1990).…”

Section: Introductionmentioning

confidence: 98%

Olfactory mucosal toxicity screening and multivariate QSAR modeling for chlorinated benzene derivatives

et al. 2004

View full text Add to dashboard Cite

The olfactory mucosa (OM) is an important target for metabolism-dependent toxicity of drugs and chemicals. Several OM toxicants share a 2,6-dichlorinated benzene structure. The herbicides dichlobenil (2,6-dichlorobenzonitrile) and chlorthiamide (2,6-dichlorothiobenzamide) and the environmental dichlobenil metabolite 2,6-dichlorobenzamide all induce toxicity in the OM following covalent binding in the Bowman's glands. In addition, we have shown that 2,6-dichlorophenyl methylsulfone targets the Bowman's glands and is probably the most potent OM toxicant so far described. These findings suggest that the 2,6-positioning of chlorines in combination with an electron-withdrawing group in the primary position of the benzene ring is an arrangement that facilitates OM toxicity. This study examined the physicochemical characteristics of the 2,6-dichlorinated OM toxicants. A number of 2,6-dichlorinated benzene derivatives with various types of substituents in primary position were tested for OM toxicity in mice. In addition, some other 2,6- and 2,5-substituted benzene derivatives were examined. Two novel OM toxicants, 2,6-dichlorobenzaldehyde oxime and 2,6-dichloronitrobenzene, were identified. By the use of partial least squares projection to latent structures with discriminant analysis (PLS-DA) a preliminary quantitative structure-activity relationship (QSAR) model was built also using reported OM toxicity data. Physicochemical properties positively correlated with olfactory mucosal toxicity were identified as molecular dipolar momentum and the electronic properties of the substituent. Inversely correlated descriptors were variables describing the hydrophobicity, electronic properties of the molecule such as electron affinity and the electronic charge on the primary carbon. In conclusion, this preliminary PLS-DA model shows that a 2,6-dichlorinated benzene derivative with a large, polar, and strong electron-withdrawing substituent in the primary position has the potential of being a potent OM toxicant in mice.

show abstract

Metabolic activation of the herbicide dichlobenil in the olfactory mucosa of mice and rats

Cited by 37 publications

References 29 publications

Differential effects of olfactory toxicants on olfactory regeneration

Differential effects of olfactory toxicants on olfactory regeneration

Effects of Dichlobenil on Ultrastructural Morphology and Cell Replication in the Mouse Olfactory Mucosa

Olfactory mucosal toxicity screening and multivariate QSAR modeling for chlorinated benzene derivatives

Contact Info

Product

Resources

About