Ohe T, Mashino T, Hirobe M
Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
Drug Metab Dispos. 1997 Jan;25(1):116-22.
When various p-substituted phenols (substituent = NO2, CN, CH2OH, COCH3, COPh, COOH, F, Cl, and Br) were incubated with rat liver microsomes, the substituent was eliminated to produce hydroquinone, and the reaction was inhibited by CO and a cytochrome P450-specific inhibitor. In the case of p-cresol (substituent = CH3), p-toluquinol was formed instead of hydroquinone. Experiments using 18O2 proved that the elimination is accompanied with ipso-substitution by the oxygen atom of the active species in cytochrome P450. These results are similar to those in a cytochrome P450. These results are similar to those in a cytochrome P450 chemical model system (Ohe, T., et al., Tetrahedron Lett. 42, 7681-7684, 1995), implying that the model is a good mimic of cytochrome P450. Substrates that lack a hydroxy group, namely p-substituted toluenes, did not undergo the reaction, thus indicating that a hydroxy group at the p-position to the eliminated substituent is necessary for this pathway. This is the same as the result obtained with the cytochrome P450 model. Finally, to elucidate how the substituent is eliminated, we attempted to detect the product derived from the eliminated group with several substrates. Results indicated that the mechanism of the substituent elimination can be divided into two types: the substituent is eliminated as an anion or as a cation.
当各种对取代苯酚（取代基 = NO2、CN、CH2OH、COCH3、COPh、COOH、F、Cl 和 Br）与大鼠肝微粒体一起孵育时，取代基被消除生成对苯二酚，并且该反应受到一氧化碳和细胞色素 P450 特异性抑制剂的抑制。在对甲酚（取代基 = CH3）的情况下，生成的是对甲苯醌而不是对苯二酚。使用 18O2 进行的实验证明，消除反应伴随着细胞色素 P450 中活性物种的氧原子进行原位取代。这些结果与细胞色素 P450 中的结果相似。这些结果与细胞色素 P450 化学模型系统中的结果相似（大根彻，T.等人，《四面体快报》42，7681 - 7684，1995），这意味着该模型很好地模拟了细胞色素 P450。缺乏羟基的底物，即对取代甲苯，不发生该反应，因此表明在所消除取代基的对位上有一个羟基对于该途径是必要的。这与细胞色素 P450 模型得到的结果相同。最后，为了阐明取代基是如何被消除的，我们尝试用几种底物检测源自被消除基团的产物。结果表明，取代基消除的机制可分为两种类型：取代基作为阴离子或阳离子被消除。
