Koerts J, Soffers A E, Vervoort J, De Jager A, Rietjens I M
Departments of Biochemistry and Molecular Physics, Agricultural University, Dreijenlaan 3, 6703 HA Wageningen, The Netherlands.
Chem Res Toxicol. 1998 May;11(5):503-12. doi: 10.1021/tx980053i.
The in vivo cytochrome P450-catalyzed aromatic hydroxylation of a series of fluorobenzenes was investigated with special emphasis on the importance of the fluorine NIH shift. The results obtained demonstrate a minor role for the NIH shift in the metabolism of the fluorobenzenes to phenolic metabolites in control male Wistar rats. These in vivo results could indicate that (1) the NIH shift is an inherently minor process for fluorine substituents or (2) it is a potentially significant process but the presumed epoxide that leads to formation of the NIH-shifted metabolite is lost to an alternative metabolic pathway. In contrast to the in vivo data, in vitro experiments showed a significant amount of an NIH-shifted metabolite for 1,4-difluorobenzene. This result eliminates the explanation that the NIH shift is an inherently minor process for fluorine substituents. Results of additional experiments presented in this paper show that the reduced tendency of fluorine-substituted benzenes to undergo an NIH shift in vivo can-at least in part-be ascribed to the possible existence of alternative pathways for metabolism of the epoxide, such as, for example, GSH conjugation, being more efficient for fluorinated than chlorinated arene oxides.
研究了一系列氟苯在体内细胞色素P450催化下的芳香族羟基化反应，特别强调了氟的NIH迁移的重要性。所得结果表明，在对照雄性Wistar大鼠中，NIH迁移在氟苯代谢为酚类代谢物的过程中作用较小。这些体内结果可能表明：（1）对于氟取代基而言，NIH迁移本质上是一个次要过程；或者（2）它是一个潜在的重要过程，但导致形成NIH迁移代谢物的假定环氧化物通过另一条代谢途径消耗掉了。与体内数据相反，体外实验表明1,4 - 二氟苯会产生大量NIH迁移代谢物。这一结果排除了氟取代基的NIH迁移本质上是一个次要过程的解释。本文所呈现的其他实验结果表明，氟代苯在体内发生NIH迁移的倾向降低，至少部分可归因于环氧化物可能存在其他代谢途径，例如谷胱甘肽结合反应，对于氟代芳烃氧化物而言，该反应比氯代芳烃氧化物更有效。
