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Vol. 28, Issue 8, 945-950, August 2000
Department of Physiology and Pharmacology (L.C., A.J.M., N.A.H.,
J.R.S., E.M.J.G.), and Department of Medicine (W.D.H., R.G.D.),
University of Queensland, St. Lucia, Australia
The anticonvulsant phenytoin (5,5-diphenylhydantoin) provokes a
skin rash in 5 to 10% of patients, which heralds the start of an
idiosyncratic reaction that may result from covalent modification of
normal self proteins by reactive drug metabolites. Phenytoin is
metabolized by cytochrome P450 (P450) enzymes primarily to 5-(p-hydroxyphenyl-),5-phenylhydantoin (HPPH),
which may be further metabolized to a catechol that spontaneously
oxidizes to semiquinone and quinone species that covalently modify
proteins. The aim of this study was to determine which P450s catalyze
HPPH metabolism to the catechol, proposed to be the final enzymatic
step in phenytoin bioactivation. Recombinant human P450s were
coexpressed with NADPH-cytochrome P450 reductase in Escherichia
coli. Novel bicistronic expression vectors were constructed for
P450 2C19 and the three major variants of P450 2C9, i.e., 2C9*1,
2C9*2, and 2C9*3. HPPH metabolism and covalent adduct formation were
assessed in parallel. P450 2C19 was the most effective catalyst of HPPH
oxidation to the catechol metabolite and was also associated with the
highest levels of covalent adduct formation. P450 3A4, 3A5, 3A7, 2C9*1,
and 2C9*2 also catalyzed bioactivation of HPPH, but to a lesser extent. Fluorographic analysis showed that the major targets of adduct formation in bacterial membranes were the catalytic P450 forms, as
suggested from experiments with human liver microsomes. These results
suggest that P450 2C19 and other forms from the 2C and 3A subfamilies
may be targets as well as catalysts of drug-protein adduct formation
from phenytoin.
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