den Besten C, van Bladeren P J, Duizer E, Vervoort J, Rietjens I M
Department of Toxicology, Agricultural University, Wageningen, The Netherlands.
Chem Res Toxicol. 1993 Sep-Oct;6(5):674-80. doi: 10.1021/tx00035a013.
In the present study the oxidative dehalogenation of a para-halogenated phenol was studied using pentafluorophenol and its non-para-halogenated analogue 2,3,5,6-tetrafluorophenol as model compounds. 19F NMR was used to characterize the metabolite patterns. In order to study the primary oxidation products of the microsomal cytochrome P450-catalyzed conversion, the alternative oxygen donors cumene hydroperoxide (CumOOH) and iodosobenzene (IOB) were used in addition to the use of NADPH and molecular oxygen. In a NADPH/oxygen-driven reaction, but also in a CumOOH- or IOB-driven cytochrome P450 reaction, tetrafluorophenol was converted to tetrafluorohydroquinone. However, for pentafluorophenol, the formation of tetrafluorohydroquinone as a product of its cytochrome P450-mediated conversion was only observed in the NADPH-driven system. Addition of reducing equivalents such as NADH to the CumOOH or IOB incubations resulted in the formation of tetrafluorohydroquinone. From these data it was concluded that the primary reaction product of the cytochrome P450-catalyzed conversion of pentafluorophenol is a reactive species that can be reduced to tetrafluorohydroquinone by NAD(P)H and, thus, must be tetrafluorobenzoquinone. Additional experiments with tetrafluorobenzoquinone, incubated in vitro with either microsomal protein or glutathione in the presence or absence of reducing equivalents, demonstrated that the tetrafluorobenzoquinone ends up bound to proteins, losing its fluorine atoms as fluoride anions. Thus, while cytochrome P450-mediated conversion of the 2,3,5,6-tetrafluorophenol results in the formation of tetrafluorohydroquinone as the primary reaction product, monooxygenation at a fluorinated para position, such as in pentafluorophenol, results in the formation of the reactive tetrafluorobenzoquinone derivative as the primary reaction product.(ABSTRACT TRUNCATED AT 250 WORDS)
在本研究中，以五氟苯酚及其非对卤代类似物2,3,5,6 - 四氟苯酚作为模型化合物，研究了对卤代苯酚的氧化脱卤反应。利用19F核磁共振来表征代谢物模式。为了研究微粒体细胞色素P450催化转化的主要氧化产物，除了使用NADPH和分子氧外，还使用了替代氧供体氢过氧化异丙苯（CumOOH）和亚碘酰苯（IOB）。在NADPH /氧驱动的反应中，以及在CumOOH或IOB驱动的细胞色素P450反应中，四氟苯酚都转化为四氟对苯二酚。然而，对于五氟苯酚，仅在NADPH驱动的系统中观察到其细胞色素P450介导转化产物四氟对苯二酚的形成。向CumOOH或IOB孵育体系中添加诸如NADH等还原当量会导致四氟对苯二酚的形成。从这些数据得出结论，细胞色素P450催化五氟苯酚转化的主要反应产物是一种活性物质，其可被NAD(P)H还原为四氟对苯二酚，因此必定是四氟苯醌。用四氟苯醌进行的额外实验表明，在有或没有还原当量存在的情况下，将其与微粒体蛋白或谷胱甘肽在体外孵育，四氟苯醌最终会与蛋白质结合，并以氟离子的形式失去其氟原子。因此，虽然细胞色素P450介导的2,3,5,6 - 四氟苯酚转化产生四氟对苯二酚作为主要反应产物，但在氟化对位（如在五氟苯酚中）的单加氧作用会产生活性四氟苯醌衍生物作为主要反应产物。（摘要截于250字）
