C. Denbesten et al., CYTOCHROME-P450-MEDIATED OXIDATION OF PENTAFLUOROPHENOL TO TETRAFLUOROBENZOQUINONE AS THE PRIMARY REACTION-PRODUCT, Chemical research in toxicology, 6(5), 1993, pp. 674-680
In the present study the oxidative dehalogenation of a para-halogenate
d phenol was studied using pentafluorophenol and its non-para-halogena
ted analogue 2,3,5,6-tetrafluorophenol as model compounds. F-19 NMR wa
s 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 (CumOO
H) and iodosobenzene (IOB) were used in addition to the use of NADPH a
nd 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 cytochrom
e P450-mediated conversion was only observed in the NADPH-driven syste
m. 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 reactiv
e species that can be reduced to tetrafluorohydroquinone by NAD(P)H an
d, thus, must be tetrafluorobenzoquinone. Additional experiments with
tetrafluorobenzoquinone, incubated in vitro with either microsomal pro
tein or glutathione in the presence or absence of reducing equivalents
, demonstrated that the tetrafluorobenzoquinone ends up bound to prote
ins, losing its fluorine atoms as fluoride anions. Thus, while cytochr
ome P450-mediated conversion of the 2,3,5,6-tetrafluorophenol results
in the formation of tetrafluorohydroquinone as the primary reaction pr
oduct, monooxygenation at a fluorinated para position, such as in pent
afluorophenol, results in the formation of the reactive tetrafluoroben
zoquinone derivative as the primary reaction product. This direct form
ation of reactive benzoquinones upon cytochrome P450-catalyzed convers
ion of halogenated compounds may very well have toxicological implicat
ions.