Metabolic activation of the olfactory toxicant, dichlobenil, in rat olfactory microsomes: comparative studies with p-nitrophenol.
The tissue-specific toxicity of the herbicide, dichlobenil (2,6-dichlorobenzonitrile), in the olfactory mucosa is related to a cytochrome P450 (P450)-dependent metabolism, depletion of glutathione and covalent binding of metabolites. Pretreatment of mice with diethyldithiocarbamate (DEDTC) protected against the dichlobenil-induced necrosis. Addition of DEDTC abolished the covalent binding of [14C]-dichlobenil to rat olfactory microsomes, whereas P4502E1-substrates such as ethanol, acetone or p-nitrophenol (NP) had no effect. The NP-hydroxylation in olfactory microsomes was > 6 times higher than that in liver microsomes and was markedly decreased following addition of dichlobenil, DEDTC or metyrapone. In liver microsomes of acetone-treated rats the NP-hydroxylation was markedly decreased following addition of DEDTC, whereas metyrapone and dichlobenil had no effect. In acetone-treated rats, the NP-hydroxylation and the metabolic activation of [14C]-dichlobenil in olfactory microsomes were decreased to 50 and 73% of untreated controls, respectively, whereas in liver microsomes these activities increased > 6 and 3.5-fold, respectively. An antibody to P4502E1 had no effect on the NP-hydroxylation or metabolic activation of [14C]-dichlobenil in olfactory microsomes, whereas the NP-hydroxylation in liver microsomes of acetone-treated rats was markedly decreased. In conclusion, the results do not support a major role for P4502E1 in the metabolic activation of dichlobenil or hydroxylation of NP in rat olfactory microsomes and suggest that these catalytic activities in the olfactory mucosa may represent a common form of P450.
Eriksson
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Department of Pharmacology and Toxicology, Uppsala Biomedical Center, Sweden.
Brittebo
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EB
D000096:Acetone / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000493:pharmacokinetics* / Q000633:toxicity; D001711:Biotransformation; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004050:Ditiocarb / Q000494:pharmacology; D005260:Female; D006540:Herbicides / Q000493:pharmacokinetics*; D006900:Hydroxylation; D051379:Mice; D008810:Mice, Inbred C57BL; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism*; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009570:Nitriles; D009596:Nitrophenols / Q000493:pharmacokinetics*; D009831:Olfactory Mucosa / Q000648:ultrastructure*; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D001549:Benzamides; D006540:Herbicides; D009570:Nitriles; D009596:Nitrophenols; D000096:Acetone; D003577:Cytochrome P-450 Enzyme System; D004050:Ditiocarb; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating; C055869:dichlobanil; C024836:4-nitrophenol