Cytochrome P450-mediated oxidation of pentafluorophenol to tetrafluorobenzoquinone as the primary reaction product

Journal Article · · Chemical Research in Toxicology; (United States)

DOI:https://doi.org/10.1021/tx00035a013· OSTI ID:6755258

Besten, C den; Bladeren, P.J. van; Duizer, E; Vervoort, J; Rietjens, I M.C.M. ^[1]

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1. Agricultural Univ., Wageningen (Netherlands)

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. [sup 19]F 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 tetraflurobenzoquinone, incubated in vitro with either microsomal protein or glutathione in the presence or absence of reducing equivalents, demonstrated that the tetrafluorobenzo-quinone 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 tetrafluorobenzoquinine derivative as the primary reaction product. This direct formation may very well have toxicological implications. 26 refs., 5 figs., 1 tab.

• OSTI ID: 6755258
• Journal Information: Chemical Research in Toxicology; (United States), Journal Name: Chemical Research in Toxicology; (United States) Vol. 6:5; ISSN CRTOEC; ISSN 0893-228X
• Country of Publication: United States
• Language: English

Related Subjects

550200 -- Biochemistry
560300* -- Chemicals Metabolism & Toxicology
59 BASIC BIOLOGICAL SCIENCES
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
AROMATICS
BENZOQUINONES
BIOCHEMICAL REACTION KINETICS
CHEMICAL REACTIONS
CYTOCHROMES
DEHALOGENATION
ENZYME ACTIVITY
HYDROXY COMPOUNDS
KINETICS
ORGANIC COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
OXIDATION
PHENOLS
PIGMENTS
PROTEINS
QUINONES
REACTION KINETICS
TOXICITY