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J Biol Chem, Vol. 273, Issue 39, 25079-25088, September 25, 1998

Free Radical Intermediates of Phenytoin and Related Teratogens
PROSTAGLANDIN H SYNTHASE-CATALYZED BIOACTIVATION, ELECTRON PARAMAGNETIC RESONANCE SPECTROMETRY, AND PHOTOCHEMICAL PRODUCT ANALYSIS

Toufan Parman, Guoman Chen^§, and Peter G. Wells^¶

From the  Faculty of Pharmacy and ^¶ Department of Pharmacology, University of Toronto, Toronto, Ontario M5S 2S2, Canada and the ^§ Department of Clinical Studies, University of Guelph, Guelph, Ontario N1G 2W1, Canada

Phenytoin and related xenobiotics can be bioactivated by embryonic prostaglandin H synthase (PHS) to a teratogenic free radical intermediate. The mechanism of free radical formation was evaluated using photolytic oxidation with sodium persulfate and by EPR spectrometry. Characterization of the products by mass spectrometry suggested that phenytoin photolyzes to a nitrogen-centered radical that rapidly undergoes ring opening to form a carbon-centered radical. PHS-1 was incubated with teratogen (phenytoin, mephenytoin, trimethadione, phenobarbital, and major metabolites) or its vehicle and the free radical spin trap -phenyl-N-t-butylnitrone, and incubations were analyzed by EPR spectrometry. There was no -phenyl-N-t-butylnitrone radical adduct in control incubations. For phenytoin, a putative unstable nitrogen-centered radical adduct and a stable carbon-centered radical adduct were detected. Free radical spin adducts also were detected for all other teratogens and metabolites except carbamazepine. The PHS inhibitor eicosatetraynoic acid abolished the free radical EPR signal. Incubation of 2'-deoxyguanosine with phenytoin and PHS-1 resulted in a 5-fold increase in its oxidation to 8-hydroxy-2'-deoxyguanosine. This is the first direct chemical evidence for PHS-catalyzed bioactivation of phenytoin and related teratogens to a free radical intermediate that initiates DNA oxidation, which may constitute a common molecular mechanism of teratologic initiation.

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