Isomer-specific bioactivation and toxicity of dichlorophenyl methylsulphone in rat olfactory mucosa.
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 (14)C-labeled 2,6-isomer to rat olfactory microsomes was demonstrated. In contrast, no significant covalent binding of the (14)C-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.
Franzén
Anna
A
Department of Pharmaceutical Biosciences, Uppsala University, Box 594, SE-751 24 Uppsala, Sweden.
Carlsson
Carina
C
Brandt
Ingvar
I
Brittebo
Eva B
EB
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000187:drug effects; D001345:Autoradiography; D001711:Biotransformation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005978:Glutathione / Q000494:pharmacology; D007536:Isomerism; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D009336:Necrosis; D009831:Olfactory Mucosa / Q000187:drug effects* / Q000473:pathology; D011078:Polychlorinated Biphenyls / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013250:Steroid Hydroxylases / Q000187:drug effects; D013997:Time Factors
D004791:Enzyme Inhibitors; D011078:Polychlorinated Biphenyls; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C029009:steroid hormone 7-alpha-hydroxylase; D005978:Glutathione