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

Franzén, Anna; Carlsson, Carina; Brandt, Ingvar; Brittebo, Eva B.

doi:10.1080/01926230390201075

Cited by 12 publications

(2 citation statements)

References 22 publications

(32 reference statements)

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“…Aryl methyl sulfones (Figure 4) are biotransformants formed from chloro aryl hydrocarbons derived from compounds such as 1,1,1-trichloro-2,2-bis( p -chlorophenyl)ethane (DDT) and polychlorinated biphenyls (PCBs) following conjugation with glutathione (GSH) and degradation via mercapturic acid derivatives. 2,6-dichlorophenyl methylsulfone, as a single ip dose, produced necrosis preferentially in the BG and neuroepithelium in the dorsomedial olfactory region (Franzén et al, 2003), probably mediated by CYP2A5 activation, one of the prominent CYPs in the mouse (Zhuo et al, 2004; Franzén et al, 2006). By contrast, only minor damage occurred at this site in rats dosed with the 2,5-chlorinated isomer.…”

Section: Rodent Nasal Cytotoxinsmentioning

confidence: 99%

Nasal Cytotoxic and Carcinogenic Activities of Systemically Distributed Organic Chemicals

2006

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Toxicity and carcinogenicity in the mucosa of the nasal passages in rodents has been produced by a variety of organic chemicals which are systemically distributed. In this review, 14 such chemicals or classes were identified that produced rodent nasal cytotoxicity, but not carcinogenicity, and 11 were identified that produced nasal carcinogenicity. Most chemicals that affect the nasal mucosa were either concentrated in that tissue or readily activated there, or both. All chemicals with effects in the nasal mucosa that were DNA-reactive, were also carcinogenic, if adequately tested. None of the rodent nasal cytotoxins has been identified as a human systemic nasal toxin. This may reflect the lesser biotransformation activity of human nasal mucosa compared to rodent and the much lower levels of human exposures. None of the rodent carcinogens lacking DNA reactivity has been identified as a nasal carcinogen or other cancer hazard to humans. Some DNA-reactive rodent carcinogens that affect the nasal mucosa, as well as other tissues, have been associated with cancer at various sites in humans, but not the nasal cavity. Thus, findings in only the rodent nasal mucosa do not necessarily predict either a toxic or carcinogenic hazard to that tissue in humans.

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Section: Rodent Nasal Cytotoxinsmentioning

confidence: 99%

Nasal Cytotoxic and Carcinogenic Activities of Systemically Distributed Organic Chemicals

2006

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“…We have recently reported that 2,6‐diClPh‐MeSO 2 is rapidly metabolised to a covalently bound metabolite in rat olfactory microsomes and Bowman's glands, while covalent binding of the 2,5‐chlorinated isomer is very low (Franzén et al 2003). Accordingly, the 2,6‐dichlorinated isomer caused necrosis in the Bowman's glands and degeneration of the olfactory epithelium 24 hr after dosing also in rats (Franzen et al 2003). As expected from the lack of covalent binding, the 2,5‐dichlorinated isomer did not cause any histological changes in the olfactory mucosa in rats.…”

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2,6‐Dichlorophenyl Methylsulphone Induced Behavioural Impairments in Rats and Mice in Relation to Olfactory Mucosal Metaplasia

Carlsson

Fredriksson

Brandt

2003

Pharmacology & Toxicology

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2,6-Dichlorophenyl methylsulphone (2,6-diClPh-MeSO 2 ) induces persistent olfactory mucosal metaplasia and a strong glial fibrillary acidic protein increase in the olfactory bulb of mice. Furthermore, 2,6-diClPh-MeSO 2 gives rise to a long-lasting hyperactivity along with an impaired radial arm maze performance. To study cause-effect relationships, olfactory mucosal histopathology, glial fibrillary acidic protein induction and neurobehavioural deficits were re-examined in mice and rats of both sexes given a single intraperitoneal dose of 2,6-diClPh-MeSO 2 (16 and 65 mg/kg). There was a clear difference in the character of the olfactory mucosal lesions in the two species. In mice, an extensive metaplasia characterised by severe fibrosis, cartilage and bone formation accompanied with large polyps filling the nasal lumen was confirmed. In rats, a dose-dependent weak metaplasia with patchy loss of olfactory epithelium was observed three weeks after dosing, preferentially at the dorsal meatus, nasal septum, and the tips of the middle ethmoturbinates. Large areas of intact olfactory epithelium remained in all animals, particularly in the low dose rats. In both species, 2,6-diClPhMeSO 2 gave rise to significantly increased motor-activities, impaired performance in the radial arm maze, and glial fibrillary acidic protein-induction. Only rats showed hyperactivity at the low dose. Performance in the Morris water maze was unaffected in rats of both sexes indicating that a general impairment in spatial learning could not be supported. We propose that the observed hyperactivity and radial arm maze acquisition deficits originated from a direct effect of 2,6-diClPh-MeSO 2 in the brain rather than being a consequence of the olfactory mucosal lesion.The olfactory mucosa has a high metabolic capacity. Several substances including the herbicides dichlobenil (2,6-dichlorobenzonitrile), chlorthiamid (2,6-dichlorothiobenzamide) and the environmental dichlobenil metabolite 2,6-dichlorobenzamide, induce olfactory mucosal toxicity following metabolic activation and covalent binding in the Bowman's glands (Brandt et al. 1990) (Brittebo et al. & 1992. Methylsulphonyl-2,6-dichlorobenzene (2,6-diClPh-MeSO 2 ) is another olfactory toxicant sharing the 2,6-dichlorinated benzene structure (Bahrami et al. 1999(Bahrami et al. & 2000b. Based on the high toxic potency, 2,6-diClPh-MeSO 2 has been used as a model compound to examine the mechanism of action and the longterm toxicity in the olfactory system in rodents. The nontoxic 2,5-dichlorinated isomer (2,5-diClPh-MeSO 2 ) has served as a negative control. Following a single toxic dose of 2,6-diClPh-MeSO 2 (Ø4 mg/kg), degeneration and necrosis of the Bowman' s glands will develop. Subsequent to this primary toxic event, degeneration and shedding of the olfactory neuroepithelium is observed (Ø8 mg/kg), followed by a repopulation of the basement membrane with an atypical, respiratory-like epithelium. Within two weeks after dos-

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

et al. 2004

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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.

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

Cited by 12 publications

References 22 publications

Nasal Cytotoxic and Carcinogenic Activities of Systemically Distributed Organic Chemicals

Nasal Cytotoxic and Carcinogenic Activities of Systemically Distributed Organic Chemicals

2,6‐Dichlorophenyl Methylsulphone Induced Behavioural Impairments in Rats and Mice in Relation to Olfactory Mucosal Metaplasia

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

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