C. Eriksson et Eb. Brittebo, METABOLIC-ACTIVATION OF THE OLFACTORY TOXICANT, DICHLOBENIL, IN RAT OLFACTORY MICROSOMES - COMPARATIVE-STUDIES WITH P-NITROPHENOL, Chemico-biological interactions, 94(3), 1995, pp. 183-196
The tissue-specific toxicity of the herbicide, dichlobenil (2,6-dichlo
robenzonitrile), in the olfactory mucosa is related to a cytochrome P4
50 (P450)-dependent metabolism, depletion of glutathione and covalent
binding of metabolites. Pretreatment of mice with diethyldithiocarbama
te (DEDTC) protected against the dichlobenil-induced necrosis. Additio
n of DEDTC abolished the covalent binding of [C-14]-dichlobenil to rat
olfactory microsomes, whereas P4502E1-substrates such as ethanol, ace
tone or p-nitrophenol (NP) had no effect. The NP-hydroxylation in olfa
ctory microsomes was >6 times higher than that in liver microsomes and
was markedly decreased following addition of dichlobenil, DEDTC or me
tyrapone. In liver microsomes of acetone-treated rats the NP-hydroxyla
tion was markedly decreased following addition of DEDTC, whereas metyr
apone and dichlobenil had no effect. In acetone-treated rats, the NP-h
ydroxylation and the metabolic activation of [C-14]-dichlobenil in olf
actory 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 re
sults do not support a major role for P4502E1 in the metabolic activat
ion of dichlobenil or hydroxylation of NP in rat olfactory microsomes
and suggest that these catalytic activities in the olfactory mucosa ma
y represent a common form of P450.