Target cells for methylsulphonyl-2,6-dichlorobenzene in the olfactory mucosa in mice.
Previously we reported that methylsulphonyl-2,6-dichlorobenzene, 2, 6-(diCl-MeSO(2)-B), was irreversibly bound to the olfactory mucosa of mice and induced necrosis of the Bowman's glands with subsequent neuroepithelial degeneration and detachment. In this study, autoradiography and histopathology were used to determine tissue-localization and toxicity of 2,6-(diCl-MeSO(2)-B) in the olfactory mucosa of control mice and animals pretreated with cytochrome P450 (CYP) and glutathione (GSH) modulators. The Bowman's glands of the olfactory mucosa were the major target sites of non-extractable binding of 2,6-(diCl-(14)C-MeSO(2)-B), whereas the olfactory neuroepithelium and nerve bundles showed only background levels of silver grains. Metyrapone pretreatment slightly decreased binding in the Bowman's glands and markedly decreased toxicity in the olfactory mucosa after 2,6-(diCl-MeSO(2)-B) administration. These results support that a CYP-mediated activation of 2, 6-(diCl-MeSO(2)-B) takes place in the Bowman's glands giving rise to toxic reactive intermediates. In mice pretreated with the GSH-depleting agent phorone, a marked increase of irreversible binding of 2,6-(diCl-(14)C-MeSO(2)-B) in the Bowman's glands was observed. Tape-section autoradiograms also revealed a significant increase of uptake of radioactivity in the olfactory bulb. As determined by histopathology, GSH-depletion increased both the extent and severity of the lesion in the mucosa. These results imply that 2,6-(diCl-MeSO(2)-B)-reactive intermediates are conjugated with GSH. The amount of irreversible binding and toxicity in the olfactory mucosa seems to be associated with the level of 2, 6-(diCl-MeSO(2)-B)-reactive intermediates.
Bahrami
F
F
Department of Environmental Toxicology, Uppsala University, Norbyvägen 18A, S-752 36, Uppsala, Sweden.
van Hezik
C
C
Bergman
A
A
Brandt
I
I
D000818:Animals; D001345:Autoradiography; D001555:Benzene Derivatives / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D001711:Biotransformation; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000378:metabolism; D007659:Ketones / Q000494:pharmacology; D008797:Metyrapone / Q000494:pharmacology; D051379:Mice; D008853:Microscopy; D009831:Olfactory Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019324:beta-Naphthoflavone / Q000494:pharmacology
D001555:Benzene Derivatives; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007659:Ketones; C120875:methylsulfonyl-2,6-dichlorobenzene; D019324:beta-Naphthoflavone; C018637:phorone; D003577:Cytochrome P-450 Enzyme System; D005978:Glutathione; D008797:Metyrapone