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本研究用不同来源的鼠肝微粒体,测定了40余种取代苯胺生成细胞色素P450代谢中问体(MI)络合物的能力,其结构与活性间关系可归纳如下:(1)在氨基的对位或间位必须存在一个可提供孤对电子的取代基,当此取代基位于邻位时,化合物不能生成P450-MI络合物,(2)在对位取代基中除了可提供孤对电子的基团外,引入亲脂性结构有助于生成P450-MI络合物,(3)间氯或对-氯邻甲苯胺似仅选择性地络合苯巴比妥与Aroclor共诱导的P450亚族,(4)苯环上若无可提供孤对电子的基团,任何疏水性,亲水性或供电子取代基均无助于取代苯胺生成P450-MI络合物。(5)一组可形成P450-MI络合物的取代苯胺(取代对氨基二苯醚)延长小鼠戊巴比妥睡眠时间的能力与取代基的电性相关。
In this study, different sources of rat liver microsomes were used to determine the ability of more than 40 kinds of substituted anilines to produce cytochrome P450 metabolism intermediates (MI) complexes. The relationship between structure and activity can be summarized as follows: (1) Must exist in the para or meta position to provide a lone pair of electrons. When the substituent is in the ortho position, the compound can not form a P450-MI complex. (2) In addition to para-substituents, To the electron group, introduction of a lipophilic structure helps to generate the P450-MI complex, (3) meta-chloro or para-chloro o-toluidine seems to selectively complex only the phenobarbital co-induced with Aroclor P450 subfamily, and (4) any hydrophobic, hydrophilic or electron-donating substituent on the phenyl ring that does not provide a lone-pair electron group does not contribute to the substitution of the aniline to form the P450-MI complex. (5) The ability of a group of substituted anilines that can form P450-MI complexes (instead of p-aminophenyl diphenyl ether) to prolong the sleep time of pentobarbital in mice is related to the electrical properties of the substituents.