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

Abstract

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.

Nasal Cytotoxic and Carcinogenic Activities of Systemically Distributed Organic Chemicals

“…However, 1,4-DCB produced epithelial necrosis of the nasal turbinates in male and female rats when given by gavage for 13 weeks at 1,200 and 1,500 mg/kg (National Toxicology Program, 1987). In a study of a wide range of 2,6-DCBs, 2,6-dichloronitrobenzene and dichlorobenzaldehyde were identified as having OM toxicity, but a simple explanation of nasal toxicity based on structure activity relationships could not be identified (Carlsson et al, 2004). CYP activity of the NM underlies the toxicities of these compounds, mediating selective covalent binding of the toxicants to the NM, especially the dorsal medial meatus (Brittebo, 1997).…”

Cyp2a5-Mediated Activation and Early Ultrastructural Changes in the Olfactory Mucosa: Studies on 2,6-Dichlorophenyl Methylsulfone

“…1) is a potent olfactory toxicant in rodents, and similar 2,6-dichlorobenzene derivatives with a large, polar, and strong electron-withdrawing substituent in the primary position have recently been reported as potential olfactory toxicants in mice (Brandt et al, 1990;Bahrami et al, 1999Bahrami et al, , 2000aCarlsson et al, 2004). The 2,6-diClPh-MeSO 2 -induced olfactory toxicity is markedly reduced in animals pretreated with the broad-spectrum P450 inhibitor metyrapone, and this inhibitor also abolishes the extensive bioactivation of 2,6-diClPh-MeSO 2 to a reactive, tissue-binding metabolite in rat olfactory microsomes (Bahrami et al, 2000b.…”

Structure-activity relationship study of rutaecarpine analogous active against central nervous system cancer

“…31,32 For each class, a model is set up according to correlation ĉ = T . q, where T is a matrix with the PLS scores obtained from the original data and q is a vector, the length equaling the number of significant latent variables (LVs), and ĉ is a class membership function; this is obtained by PLS regression from an original c vector, whose elements are called dummy variables, i.e., they have values of 1 if an object is a member of a class (active) and 0 otherwise (inactive), and an X matrix consisting of the original preprocessed data.…”