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 [C-14]-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 [C-14]-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 [C-14]-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.