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Vol. 280, Issue 1, 200-209, 1997
Faculty of Pharmacy (P.M.K., L.M.W., T.P., P.G.W.) and
Department
of Pharmacology (P.G.W.), University of Toronto, Toronto, Ontario,
Canada
UDP-Glucuronosyltransferases (UGTs) are important in the elimination of
most xenobiotics, including
5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH), the major,
reputedly nontoxic, metabolite of the anticonvulsant drug phenytoin.
However, HPPH alternatively may be bioactivated by peroxidases, such as
prostaglandin H synthase, to a reactive intermediate that initiates DNA
oxidation (reflected by 8-hydroxy-2
-deoxyguanosine), genotoxicity
(reflected by micronuclei) and embryopathy. This hypothesis was
evaluated in skin fibroblasts cultured from heterozygous (+/j) and homozygous (j/j) UGT-deficient Gunn
rats and in mouse embryo culture, with confirmation of direct
N3-glucuronidation of phenytoin in Gunn rats
in vivo. HPPH (80 µM) increased micronuclei by 2.0-, 4.8- and 4.6-fold in +/+ UGT-normal cells (P = .03) and +/j
and j/j UGT-deficient cells (P = .0001), respectively.
HPPH-initiated micronucleus formation was increased 3.0- and 3.4-fold
in +/j (P = .02) and j/j (P = .04)
UGT-deficient cells, respectively, vs. +/+ UGT-normal cells.
Micronuclei were not initiated by 10 µM HPPH in +/+ UGT-normal cells
but were increased by 4- and 3.8-fold in +/j and
j/j UGT-deficient cells (P = .0001), respectively, and
were increased 2.7- and 3.0-fold in +/j (P = .007) and
j/j (P = .0002) UGT-deficient cells, respectively,
vs. +/+ UGT-normal cells. 8-Hydroxy-2-deoxyguanosine was
increased in j/j UGT-deficient but not +/+ UGT-normal cells
treated with 80 µM HPPH (P < .05). The embryopathic potency of
80 µM HPPH in embryo culture, reflected by decreases in anterior
neuropore closure, turning, yolk sac diameter and crown-rump length
(P < .05), was equivalent to that reported for phenytoin.
Phenytoin (80 µM) enhanced micronucleus formation 1.7-, 4.4- and
3.8-fold in +/+ cells (P = .03) and +/j and
j/j UGT-deficient cells (P = .0001), respectively. Phenytoin-initiated micronucleus formation was increased about 4-fold
in both +/j (P = .006) and j/j (P = .009) UGT-deficient cells vs. +/+ UGT-normal cells,
providing the first evidence that the bioactivation and oxidative
toxicity of phenytoin itself may be avoided by direct
N-glucuronidation, which was confirmed by tandem mass
spectrometry. These results further indicate that, with UGT
deficiencies, HPPH potentially is a potent mediator of phenytoin-initiated genotoxicity and embryopathy, which may be relevant
to teratogenesis and other adverse effects of phenytoin.
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