Decreases in phenytoin hydroxylation activities catalyzed by liver microsomal cytochrome P450 enzymes in phenytoin-treated rats

Citation
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
Citations number
41
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
DRUG METABOLISM AND DISPOSITION
ISSN journal
0090-9556 → ACNP
Volume
29
Issue
4
Year of publication
2001
Pages
427 - 434
Database
ISI
SICI code
0090-9556(200104)29:4<427:DIPHAC>2.0.ZU;2-K
Abstract
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.