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Toxicologic Pathology, Vol. 31, No. 4, 364-372 (2003)
DOI: 10.1080/01926230390201075

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

Anna Franzén

Department of Pharmaceutical Biosciences, Uppsala University, Box 594, SE-751 24 Uppsala, Sweden

Carina Carlsson

Department of Environmental Toxicology, Uppsala University Norbyvägen 18A, SE-752 36 Uppsala, Sweden

Ingvar Brandt

Department of Environmental Toxicology, Uppsala University Norbyvägen 18A, SE-752 36 Uppsala, Sweden

Eva B. Brittebo

Department of Pharmaceutical Biosciences, Uppsala University, Box 594, SE-751 24 Uppsala, Sweden, Eva.Brittebo{at}farmbio.uu.se

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 concentration-and time-dependent covalent binding of the 14C-labeled 2,6-isomer to rat olfactory microsomes was demonstrated. In contrast, no significant covalent binding of the 14C-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.

Key Words: Bowman's gland • olfactory epithelium • 2,6-dichlorophenyl methylsulphone • covalent binding • CYP2A • olfactory mucosa • rat • nasal toxicity.


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[Abstract] [Full Text] [PDF]