H. Yamazaki et al., Decreases in phenytoin hydroxylation activities catalyzed by liver microsomal cytochrome P450 enzymes in phenytoin-treated rats, DRUG META D, 29(4), 2001, pp. 427-434
Phenytoin, 5,5-diphenylhydantoin, is a widely used anticonvulsant agent wit
h a variety of toxicities, including drug interactions. The formation of fo
ur oxidative metabolites, 4'-hydroxylated (4'-HPPH), 3'-hydroxylated (3'-HP
PH), a catechol (3', 4'-diHPPH), and the 3', 4'-dihydrodiol form of phenyto
in was examined in rat liver microsomes. In 11 cDNA-expressed rat P450 enzy
mes tested, CYP2C6 had the highest activities in 4'- and 3'-HPPH formation
from phenytoin, followed only by CYP2C11. In contrast, CYP2C11 had high act
ivity for 3', 4'-diHPPH formation from 4'-HPPH, followed by CYP2C6. The rat
es of 4'-HPPH and 3', 4'-diHPPH formation from phenytoin in liver microsome
s in the presence of NADPH were significantly decreased by oral administrat
ion of phenytoin (300 mg/kg for 20 days) to rats, despite the increase in P
450 contents. However, the cumene hydroperoxide-supported formation of 3',4
'-dihydrodiol and 4'-HPPH from phenytoin was induced by phenytoin administr
ation. Hydrogen peroxide formation in reaction mixtures with NADPH was indu
ced by the administration of phenytoin; however, the coupling ratio of phen
ytoin oxidation was decreased in phenytoin-induced liver microsomal P450 sy
stems. These results suggested that phenytoin could not stimulate its own a
pparent oxidative metabolism by liver P450s induced with phenytoin administ
ration. The increase of unmetabolized phenytoin and byproducts of oxygen ge
nerated in the phenytoin-induced liver microsomal P450 system may be involv
ed in phenytoin-related drug toxicity.