Eriksson C, Brittebo E B
Department of Pharmacology and Toxicology, Uppsala Biomedical Center, Sweden.
Chem Biol Interact. 1995 Mar 18;94(3):183-96. doi: 10.1016/0009-2797(94)03333-4.
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.
除草剂二氯苯腈（2,6 - 二氯苯甲腈）对嗅觉黏膜的组织特异性毒性与细胞色素P450（P450）依赖性代谢、谷胱甘肽耗竭以及代谢产物的共价结合有关。用二乙基二硫代氨基甲酸盐（DEDTC）预处理小鼠可预防二氯苯腈诱导的坏死。添加DEDTC可消除[14C] - 二氯苯腈与大鼠嗅觉微粒体的共价结合，而乙醇、丙酮或对硝基苯酚（NP）等P4502E1底物则无此作用。嗅觉微粒体中的NP羟基化比肝微粒体中的高6倍以上，添加二氯苯腈、DEDTC或甲吡酮后显著降低。在丙酮处理大鼠的肝微粒体中，添加DEDTC后NP羟基化显著降低，而甲吡酮和二氯苯腈则无作用。在丙酮处理的大鼠中，嗅觉微粒体中NP羟基化和[14C] - 二氯苯腈的代谢活化分别降至未处理对照的50%和73%，而在肝微粒体中这些活性分别增加了6倍和3.5倍以上。抗P4502E1抗体对嗅觉微粒体中[14C] - 二氯苯腈的NP羟基化或代谢活化无影响，而丙酮处理大鼠肝微粒体中的NP羟基化则显著降低。总之，结果不支持P4502E1在大鼠嗅觉微粒体中二氯苯腈的代谢活化或NP羟基化中起主要作用，并表明嗅觉黏膜中的这些催化活性可能代表P450的一种常见形式。
