Eriksson C, Brittebo E B
Department of Pharmacology and Toxicology, Swedish University of Agricultural Sciences, Uppsala Biomedial Centre.
Chem Biol Interact. 1991;79(2):165-77. doi: 10.1016/0009-2797(91)90080-q.
The metabolic activation of the herbicide dichlobenil (2,6-dichloro[ring-14C]benzonitrile) in the olfactory mucosa of C57BL mice and Sprague-Dawley rats was examined. In homogenates of the olfactory mucosa (mouse 1000 x g supernatants; rat microsomes), dichlobenil was metabolized and covalently bound to protein. The apparent Km, Vmax and V/K values showed that the olfactory mucosa had both a higher affinity for dichlobenil and a higher capacity/mg protein to activate dichlobenil in comparison to the liver. The covalent binding was dependent on NADPH and was inhibited by the addition of dithionite, metyrapone and glutathione indicating an oxidative cytochrome P-450 dependent activation of dichlobenil into an electrophilic intermediate. The covalent binding was also inhibited by the addition of superoxide dismutase whereas catalase, mannitol or dimethylsulfoxide had no effect indicating the involvement of O2- but not of H2O2 or OH. in the activation. In explants of the olfactory mucosa incubated with [14C]dichlobenil a preferential covalent binding was observed in the Bowman's glands suggesting an activation of dichlobenil in these structures. The highly efficient metabolic activation of dichlobenil to reactive intermediates in the olfactory mucosa is suggested to be of importance for the potent dichlobenil-induced toxicity in this tissue.
研究了除草剂二氯苯腈（2,6-二氯[环-14C]苄腈）在C57BL小鼠和Sprague-Dawley大鼠嗅黏膜中的代谢活化情况。在嗅黏膜匀浆（小鼠1000 x g上清液；大鼠微粒体）中，二氯苯腈被代谢并与蛋白质共价结合。表观Km、Vmax和V/K值表明，与肝脏相比，嗅黏膜对二氯苯腈具有更高的亲和力，且每毫克蛋白质激活二氯苯腈的能力更强。共价结合依赖于NADPH，并受到连二亚硫酸盐、甲吡酮和谷胱甘肽的抑制，表明二氯苯腈通过氧化细胞色素P-450依赖性激活形成亲电中间体。超氧化物歧化酶的添加也抑制了共价结合，而过氧化氢酶、甘露醇或二甲基亚砜则没有影响，表明激活过程涉及O2-而非H2O2或OH。在用[14C]二氯苯腈孵育的嗅黏膜外植体中，观察到在鲍曼腺中有优先的共价结合，表明二氯苯腈在这些结构中被激活。二氯苯腈在嗅黏膜中高效代谢活化为反应性中间体，这被认为对二氯苯腈在该组织中引起的强效毒性具有重要意义。
