title: Cytochrome P450-mediated oxidation of pentafluorophenol to tetrafluorobenzoquinone as the primary reaction product.
abstract: 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)
authors.affiliation: Department of Toxicology, Agricultural University, Wageningen, The Netherlands.
authors.forename: C
authors.initials: C
authors.lastname: den Besten
authors.forename: P J
authors.initials: PJ
authors.lastname: van Bladeren
authors.forename: E
authors.initials: E
authors.lastname: Duizer
authors.forename: J
authors.initials: J
authors.lastname: Vervoort
authors.forename: I M
authors.initials: IM
authors.lastname: Rietjens
mesh_terms: D000818:Animals; D001555:Benzene Derivatives; D016227:Benzoquinones / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005464:Fluorobenzenes / Q000378:metabolism*; D007462:Iodobenzenes / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008862:Microsomes, Liver / Q000201:enzymology; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D010636:Phenols / Q000378:metabolism*; D051381:Rats; D005466:Fluorocarbons
chemical_list: D001555:Benzene Derivatives; D016227:Benzoquinones; D003577:Cytochrome P-450 Enzyme System; D005464:Fluorobenzenes; D007462:Iodobenzenes; D009249:NADP; D010636:Phenols; C007737:fluoranil; C085539:2,3,4,5,6-pentafluorophenol; D005466:Fluorocarbons; C007164:cumene hydroperoxide; C045453:2,3,5,6-tetrafluorophenol; C037276:iodosobenzene