Isomer-specific Bioactivation and Toxicity of Dichlorophenyl Methylsulphone in Rat Olfactory Mucosa
2003 (English)In: Toxicologic pathology (Print), ISSN 0192-6233, E-ISSN 1533-1601, Vol. 31, no 4, 364-372 p.Article in journal (Refereed) Published
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 C-14-labeled 2,6-isomer to rat olfactory microsomes was demonstrated. In contrast, no significant covalent binding of the C-14-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.
Place, publisher, year, edition, pages
2003. Vol. 31, no 4, 364-372 p.
Bowman's gland, olfactory epithelium, 2, 6-dichlorophenyl methylsulphone, covalent binding, CYP2A, olfactory mucosa, rat, nasal toxicity
Pharmacology and Toxicology
IdentifiersURN: urn:nbn:se:uu:diva-93786DOI: 10.1080/01926230390201075PubMedID: 12851101OAI: oai:DiVA.org:uu-93786DiVA: diva2:167375