Degawa M, Nakayama M, Konno Y, Masubuchi K, Yamazoe Y
Faculty of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Biochim Biophys Acta. 1998 Mar 2;1379(3):391-8. doi: 10.1016/s0304-4165(97)00118-9.
We reported previously that 2-methoxy-4-nitroaniline (2-MeO-4-NA) is a selective inducer of cytochrome P4501A2 (CYP1A2) in the rat liver, and its molecular size is the smallest among known CYP1A2-selective inducers. In the present study, a structure-activity relationship on the CYP1A2-selective induction has been investigated using isomeric nitroanisidines and their related chemicals. Western blot analyses revealed that the chemicals removed a substituent (amino, methoxyl or nitro group) from a 2-MeO-4-NA molecule had no capacity for inducing CYP1A enzymes in rat livers. On the other hand, isomeric nitroanisidines such as 2-MeO-4-NA, 2-MeO-5-NA and 4-MeO-2-NA induced both CYP1A2 and CYP1A1 enzymes with different selectivities. As judged from the induced levels of CYP1A proteins, 2-MeO-4-NA (CYP1A2/CYP1A1 ratio; 9.5) and 4-MeO-2-NA (0.3) were the most selective inducers of CYP1A2 and CYP1A1, respectively, among the isomeric nitroanisidines (0.44 mmol/kg) used. The induced level of CYP1A2 protein was in the order 2-MeO-4-NA > 2-MeO-5-NA > 4-MeO-2-NA, although no significant difference was observed on their CYP1A2 mRNA level. On the contrary, increases in the levels of CYP1A1 mRNA and protein were in the order 4-MeO-2-NA > 2-MeO-5-NA > 2-MeO-4-NA. The present findings indicate that all three substituents (amino, methoxyl and nitro groups) are necessary components of nitroanisidines for induction of CYP1A enzymes, and also show that regio-isomeric positions of these substituents determine the selectivity in the induction of CYP1A enzymes.
我们之前报道过，2-甲氧基-4-硝基苯胺（2-MeO-4-NA）是大鼠肝脏中细胞色素P4501A2（CYP1A2）的选择性诱导剂，并且其分子大小在已知的CYP1A2选择性诱导剂中是最小的。在本研究中，使用异构硝基茴香醚及其相关化学物质研究了CYP1A2选择性诱导的构效关系。蛋白质免疫印迹分析显示，从2-MeO-4-NA分子上去除取代基（氨基、甲氧基或硝基）的化学物质没有诱导大鼠肝脏中CYP1A酶的能力。另一方面，异构硝基茴香醚如2-MeO-4-NA、2-MeO-5-NA和4-MeO-2-NA以不同的选择性诱导CYP1A2和CYP1A1酶。从CYP1A蛋白的诱导水平判断，在使用的异构硝基茴香醚（0.44 mmol/kg）中，2-MeO-4-NA（CYP1A2/CYP1A1比率；9.5）和4-MeO-2-NA（0.3）分别是CYP1A2和CYP1A1的最具选择性的诱导剂。尽管在它们的CYP1A2 mRNA水平上未观察到显著差异，但CYP1A2蛋白的诱导水平顺序为2-MeO-4-NA > 2-MeO-5-NA > 4-MeO-2-NA。相反，CYP1A1 mRNA和蛋白水平的增加顺序为4-MeO-2-NA > 2-MeO-5-NA > 2-MeO-4-NA。目前的研究结果表明，所有三个取代基（氨基、甲氧基和硝基）都是硝基茴香醚诱导CYP1A酶的必需成分，并且还表明这些取代基的区域异构位置决定了CYP1A酶诱导的选择性。
