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Comparison of cytochrome P450 from an insect and mammal,substrate specificity and the mechanism of selective inhibition

昆虫和哺乳动物细胞色素P450的比较、底物特异性及选择性抑制机制

基本信息

批准号：
03660039
负责人：
MOTOYAMA Naoki
金额：
$ 1.28万
依托单位：
Chiba University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1991
资助国家：
日本
起止时间：
1991 至 1992
项目状态：
已结题

项目摘要

A series of methylenedioxyphenyl (MDP) compounds were evaluated for inhibition of degradation of ^<14>C-diazinon by microsomes from the housefly abdomen and rat liver. Several MDP compounds inhibited the insect MFO activity selectively with little effect on the mammalian enzyme system. When these compounds were applied topically to the housefly in combination with diazinon, carbaryl and resmethrin, 3,4-methylenedioxybenzene-1-(2'- methoxyethoxymethyl ether)(referred to as No.1) exhibited an excellent synergism with any of the insecticides tested. The synergism of No.1 was also confirmed against green peach aphids and diamondback moth larvae. The MDP compound showed especially high synergism against pyrethroid resistant strains of insect, restoring the efficacy of insecticide. On the other hand, no synergism was observed when the compound was administered orally to the rat in combination with d-resmethrin.The in vitro and in vivo results suggest the No.1 being a MDP compound with desiable selectivity.To investigate the mechanism of selectivity, the Type 1 spectra obtained with the rat liver microsomes and several MDP compounds were examined. Since the MDP compounds with selectivity showed significantly smaller Ks values than those without selectivity, a difference in the affinity appears to be involved in the selective inhibition between the insect and mammal. Similarly, the Type 3 spectra obtained with the rat liver microsomes also resulted in smaller peaks at lambda_<427> and lambda_<455> for the selective as compared with non-selective MDP compounds. An attempt to examine the affinity for MDP-cytochrome P450 complex formation using specific cytochrome P450 isozymes responsible for insecticide degradation was not successful due to insufficient amount of the isozymes isolated from the rat liver and housefly abdomen.

评价了一系列亚甲二氧基苯基(MDP)化合物对家蝇腹部和大鼠肝脏微粒体降解^&lt；14；gt；C-二氮磷的抑制作用。几种MDP化合物选择性地抑制昆虫的MFO活性，而对哺乳动物的酶系统影响不大。当这些化合物与二氮磷、西维因和氯氰菊酯联合应用于家蝇时，3，4-亚甲二氧基苯-1-(2‘-甲氧基乙氧基甲醚)(简称1号)与所测试的任何一种杀虫剂都表现出良好的增效作用。1号对桃蚜和小菜蛾幼虫的增效作用也得到证实。MDP化合物对拟除虫菊酯抗性品系表现出特别高的增效作用，恢复了杀虫剂的药效。体外和体内实验结果表明，1号化合物是一种具有良好选择性的MDP化合物。为了探讨其选择性的机制，我们用大鼠肝微球和几种MDP化合物的类型1光谱进行了研究。由于具有选择性的MDP化合物的Ks值明显小于没有选择性的化合物，亲和力的差异似乎与昆虫和哺乳动物之间的选择性抑制有关。同样，与非选择性MDP化合物相比，大鼠肝微粒体获得的3型光谱也导致选择性MDP化合物在波长427&gt；和波长455&gt；的峰较小。由于从大鼠肝脏和家蝇腹部分离的同工酶数量不足，使用负责杀虫剂降解的特定细胞色素P450同工酶来检测MDP-细胞色素P450复合体形成的亲和力的尝试失败了。