Effects of glutathione-modulating agents on the covalent binding and toxicity of dichlobenil in the mouse olfactory mucosa.
Twenty-four hours following injection of a single dose of the herbicide dichlobenil (2,6-dichlorobenzonitrile) in C57Bl/6 mice a steep dose-response curve for the histopathological toxicity in the olfactory mucosa was observed. Four hours following injection of a toxic dose of [ring-14C]dichlobenil (12 mg/kg) the covalent binding in the olfactory mucosa was 26 times higher than that in the liver. A dose-dependent decrease of nonprotein sulfhydryls (mainly glutathione, GSH) in the olfactory mucosa was observed 2.5 hr following injection of dichlobenil (6, 12, 25 mg/kg). The synthetic GSH precursor N-acetyl-L-cysteine decreased both the dichlobenil-induced toxicity and the covalent binding, whereas N-acetyl-D-cysteine had no effect. No protective effects of the cyanide antidotes nitrite, thiosulfate, or superoxide dismutase on the dichlobenil-induced toxicity were observed. In mice given the GSH-depleting agent phorone and a subtoxic dose of dichlobenil (6 mg/kg), an extensive toxicity and an increased covalent binding in the olfactory mucosa were demonstrated. Autoradiography showed no change in the distribution of covalent [14C]dichlobenil binding to nontarget tissues of phorone-treated mice. In conclusion, the results demonstrate a relationship between the degrees of covalent binding, GSH depletion, and toxicity of dichlobenil in the olfactory mucosa. Hence, the level of GSH appears to be of importance for the dichlobenil-induced toxicity in the olfactory mucosa.
Brittebo
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EB
Department of Pharmacology and Toxicology, SLU, Uppsala, Sweden.
Eriksson
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C
Brandt
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I
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D001345:Autoradiography; D001549:Benzamides / Q000378:metabolism / Q000633:toxicity*; D005260:Female; D005978:Glutathione / Q000378:metabolism*; D006540:Herbicides / Q000633:toxicity*; D007659:Ketones / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009297:Nasal Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009570:Nitriles; D009573:Nitrites / Q000494:pharmacology; D010503:Periodic Acid-Schiff Reaction; D013482:Superoxide Dismutase / Q000494:pharmacology
D001549:Benzamides; D006540:Herbicides; D007659:Ketones; D009570:Nitriles; D009573:Nitrites; C018637:phorone; D013482:Superoxide Dismutase; D005978:Glutathione; C055869:dichlobanil; D000111:Acetylcysteine