Metabolic activation of the herbicide dichlobenil in the olfactory mucosa of mice and rats.
The metabolic activation of the herbicide dichlobenil (2,6-dichloro[ring-14C]benzonitrile) in the olfactory mucosa of C57BL mice and Sprague-Dawley rats was examined. In homogenates of the olfactory mucosa (mouse 1000 x g supernatants; rat microsomes), dichlobenil was metabolized and covalently bound to protein. The apparent Km, Vmax and V/K values showed that the olfactory mucosa had both a higher affinity for dichlobenil and a higher capacity/mg protein to activate dichlobenil in comparison to the liver. The covalent binding was dependent on NADPH and was inhibited by the addition of dithionite, metyrapone and glutathione indicating an oxidative cytochrome P-450 dependent activation of dichlobenil into an electrophilic intermediate. The covalent binding was also inhibited by the addition of superoxide dismutase whereas catalase, mannitol or dimethylsulfoxide had no effect indicating the involvement of O2- but not of H2O2 or OH. in the activation. In explants of the olfactory mucosa incubated with [14C]dichlobenil a preferential covalent binding was observed in the Bowman's glands suggesting an activation of dichlobenil in these structures. The highly efficient metabolic activation of dichlobenil to reactive intermediates in the olfactory mucosa is suggested to be of importance for the potent dichlobenil-induced toxicity in this tissue.
Eriksson
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Department of Pharmacology and Toxicology, Swedish University of Agricultural Sciences, Uppsala Biomedial Centre.
Brittebo
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EB
D000818:Animals; D001549:Benzamides / Q000493:pharmacokinetics*; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D006540:Herbicides / Q000493:pharmacokinetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009570:Nitriles; D009831:Olfactory Mucosa / Q000187:drug effects / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D013347:Subcellular Fractions / Q000378:metabolism
D001549:Benzamides; D006540:Herbicides; D009570:Nitriles; D003577:Cytochrome P-450 Enzyme System; C055869:dichlobanil; D010100:Oxygen