Rietjens I M, Tyrakowska B, Veeger C, Vervoort J
Department of Biochemistry, Agricultural University, Wageningen, The Netherlands.
Eur J Biochem. 1990 Dec 27;194(3):945-54. doi: 10.1111/j.1432-1033.1990.tb19490.x.
Pathways for biodehalogenation of fluorinated aniline derivatives were investigated. Microsomal NADPH-dependent dehalogenation of fluoroanilines was shown to proceed by three different reaction pathways. The first route appeared to result in monooxygenation at a fluorinated position and release of the fluorine atom as a fluoride anion. The primary additional reaction product formed is the reactive quinoneimine, not the 4-hydroxyaniline. In NADPH-containing microsomal systems with 4-fluoro-substituted anilines, formation of the 4-hydroxyaniline derivative is observed because NADPH chemically reduces this quinoneimine metabolite. A second pathway for dehalogenation proceeds by protein binding of a fluoro-containing (semi)quinoneimine metabolite, the formation of which may result from the mono-oxygenase reaction (pathway 1) and/or from (re)oxidation of a hydroxyaniline metabolite by superoxide anion radicals produced by the microsomal system. This latter reaction pathway becomes more important with increasing number of fluoro-substituents in the fluoroaniline derivative. The higher ratio of fluoride anion formed to 4-hydroxyaniline derivative detected in incubations with liver microsomes from dexamethasone-treated rats, as compared to incubations with liver microsomes from control rats, can in part be explained by the higher production of superoxide anion radicals observed in the dexamethasone systems. The third mechanism was shown to proceed by formation of a hydroxylated metabolite that loses fluoride anion upon exposure to oxygen. The reactive intermediate formed upon oxygen exposure might be the semiquinoneimine which loses its fluorine atom as a fluoride anion upon dimerization or polymerization and/or protein binding. The fluorohydroxyanilines, in which the hydroxyl group is ortho or para with respect to the fluoro substituent, appear especially to be highly unstable and lose fluoride anion in the presence of oxygen. Finally, it is concluded that all three pathways for dehalogenation of fluorinated aniline derivatives are bioactivation pathways. The reactivity of the (semi)quinoneimines formed in these reactions is dependent on their substitution pattern and increases with increasing number of fluoro-substituents. Therefore, bioactivation for a series of fluorinated aniline derivatives, can be expected to vary with the substitution pattern and to increase with increasing number of halogen substituents.
对氟化苯胺衍生物的生物脱卤途径进行了研究。氟代苯胺的微粒体NADPH依赖性脱卤反应显示通过三种不同的反应途径进行。第一条途径似乎导致在氟化位置发生单加氧反应，并以氟离子的形式释放氟原子。形成的主要额外反应产物是活性醌亚胺，而不是4-羟基苯胺。在含有NADPH的微粒体系统中，对于4-氟取代的苯胺，会观察到4-羟基苯胺衍生物的形成，因为NADPH会化学还原这种醌亚胺代谢物。第二条脱卤途径是通过含氟（半）醌亚胺代谢物的蛋白质结合进行的，其形成可能源于单加氧酶反应（途径1）和/或微粒体系统产生的超氧阴离子自由基对羟基苯胺代谢物的（再）氧化。随着氟代苯胺衍生物中氟取代基数量的增加，后一种反应途径变得更加重要。与用对照大鼠的肝微粒体进行的孵育相比，在用经地塞米松处理的大鼠的肝微粒体进行的孵育中检测到的氟离子与4-羟基苯胺衍生物形成的比例更高，这部分可以通过在地塞米松系统中观察到的超氧阴离子自由基的更高产生来解释。第三条机制显示是通过形成一种羟基化代谢物进行的，该代谢物在暴露于氧气时会失去氟离子。暴露于氧气时形成的反应性中间体可能是半醌亚胺，它在二聚化或聚合和/或蛋白质结合时会以氟离子的形式失去其氟原子。其中羟基相对于氟取代基处于邻位或对位的氟代羟基苯胺似乎特别不稳定，在有氧气存在的情况下会失去氟离子。最后得出结论，氟化苯胺衍生物的所有三种脱卤途径都是生物活化途径。在这些反应中形成的（半）醌亚胺的反应性取决于它们的取代模式，并随着氟取代基数量的增加而增加。因此，可以预期一系列氟化苯胺衍生物的生物活化会因取代模式而异，并随着卤素取代基数量的增加而增加。
